Research News
| November 10th, 2009 An in vitro Model of the Inhibition of Axon Growth in the Lesion Scar Formed after Central Nervous System Injury After central nervous system (CNS) injury, meningeal fibroblasts migrate in the lesion center to form a fibrotic scar which is surrounded by end feet of reactive astrocytes. The fibrotic scar expresses various axonal growth-inhibitory molecules and creates a major impediment for axonal regeneration. We developed an in vitro model of the scar using coculture of cerebral astrocytes and meningeal fibroblasts by adding transforming growth factor-?1 (TGF-?1), a potent fibrogenic factor. Addition of TGF-?1 to this coculture resulted in enhanced proliferation of fibroblasts and the formation of cell clusters which consisted of fibroblasts inside and surrounded by astrocytes. The cell cluster in culture densely accumulated the extracellular matrix molecules and axonal growth-inhibitory molecules similar to the fibrotic scar, and remarkably inhibited the neurite outgrowth of cerebellar neurons. Therefore, this culture system can be available to analyze the inhibitory property in the lesion site of CNS. |
| November 8th, 2009 Effective repair of traumatically injured spinal cord by nanoscale block copolymer micelles Spinal cord injury results in immediate disruption of neuronal membranes, followed by extensive secondary neurodegenerative processes. A key approach for repairing injured spinal cord is to seal the damaged membranes at an early stage. Here, we show that axonal membranes injured by compression can be effectively repaired using self-assembled monomethoxy poly(ethylene glycol)-poly(d,l-lactic acid) di-block copolymer micelles. Injured spinal tissue incubated with micelles (60 nm diameter) showed rapid restoration of compound action potential and reduced calcium influx into axons for micelle concentrations much lower than the concentrations of polyethylene glycol, a known sealing agent for early-stage spinal cord injury. Intravenously injected micelles effectively recovered locomotor function and reduced the volume and inflammatory response of the lesion in injured rats, without any adverse effects. Our results show that copolymer micelles can interrupt the spread of primary spinal cord injury damage with minima |
| November 2nd, 2009 Sustained delivery of thermostabilized chABC enhances axonal sprouting and functional recovery after spinal cord injury Chondroitin sulfate proteoglycans (CSPGs) are a major class of axon growth inhibitors that are up-regulated after spinal cord injury (SCI) and contribute to regenerative failure. Chondroitinase ABC (chABC) digests glycosaminoglycan chains on CSPGs and can thereby overcome CSPG-mediated inhibition. But chABC loses its enzymatic activity rapidly at 37 °C, necessitating the use of repeated injections or local infusions for a period of days to weeks. These infusion systems are invasive, infection-prone, and clinically problematic. To overcome this limitation, we have thermostabilized chABC and developed a system for its sustained local delivery in vivo, obviating the need for chronically implanted catheters and pumps. Thermostabilized chABC remained active at 37 °C in vitro for up to 4 weeks. CSPG levels remained low in vivo up to 6 weeks post-SCI when thermostabilized chABC was delivered by a hydrogel-microtube scaffold system. Axonal growth and functional recovery following the sustained local release of thermo |
| October 29th, 2009 Combined Intrinsic and Extrinsic Neuronal Mechanisms Facilitate Bridging Axonal Regeneration One Year after Spinal Cord Injury Despite advances in promoting axonal regeneration after acute spinal cord injury (SCI), elicitation of bridging axon regeneration after chronic SCI remains a formidable challenge. We report that combinatorial therapies administered 6 weeks, and as long as 15 months, after SCI promote axonal regeneration into and beyond a midcervical lesion site. Provision of peripheral nerve conditioning lesions, grafts of marrow stromal cells, and establishment of NT-3 gradients supports bridging regeneration. Controls receiving partial components of the full combination fail to exhibit bridging. Notably, intraneuronal molecular mechanisms recruited by delayed therapies mirror those of acute injury, including activation of transcriptional activators and regeneration-associated genes. Collectively, these findings provide evidence that regeneration is achievable at unprecedented postinjury time points. |
| October 28th, 2009 Human embryonic Stem Cell-Derived Oligodendrocyte Progenitor Cell Transplants Improve Recovery after Cervical Spinal Cord Injury. Evidence that cell transplants can improve recovery outcomes in spinal cord injury (SCI) models substantiates treatment strategies involving cell replacement for humans with SCI. Most pre-clinical studies of cell replacement in SCI examine thoracic injury models. However, as most human injuries occur at the cervical level, it is critical to assess potential treatments in cervical injury models and examine their effectiveness using at-level histological and functional measures. To directly address cervical SCI, we used a C5 midline contusion injury model and assessed the efficacy of a candidate therapeutic for thoracic SCI in this cervical model. The contusion generates reproducible, bilateral movement and histological deficits, although a number of injury parameters such as acute severity of injury, affected gray to white matter ratio, extent of endogenous remyelination, and at-level locomotion deficits do not correspond with these parameters in thoracic SCI. Based on reported benefits in thoracic SCI, we tra |
| October 9th, 2009 KLF family members regulate intrinsic axon regeneration ability Neurons in the central nervous system (CNS) lose their ability to regenerate early in development, but the underlying mechanisms are unknown. By screening genes developmentally regulated in retinal ganglion cells (RGCs), we identified Krüppel-like factor-4 (KLF4) as a transcriptional repressor of axon growth in RGCs and other CNS neurons. RGCs lacking KLF4 showed increased axon growth both in vitro and after optic nerve injury in vivo. Related KLF family members suppressed or enhanced axon growth to differing extents, and several growth-suppressive KLFs were up-regulated postnatally, whereas growth-enhancing KLFs were down-regulated. Thus, coordinated activities of different KLFs regulate the regenerative capacity of CNS neurons. |
| October 6th, 2009 Promoting oligodendrogenesis and myelin repair using the multiple sclerosis medication glatiramer acetate. The formation of oligodendrocytes (oligodendrogenesis) and myelin is regulated by several neurotrophic factors. Strategies to increase the level of these trophic molecules may facilitate repair in demyelinating conditions, such as multiple sclerosis (MS). Because leukocytes are a source of neurotrophic factors, and as glatiramer acetate (GA) generates T helper 2 (Th2) lymphocytes that are not known to be harmful, we tested the hypothesis that GA regulates oligodendrogenesis and myelin formation. First, we generated GA-reactive Th2 cells and determined that they produced transcripts for neurotrophic factors, including insulin-like growth factor-1 (IGF-1). The conditioned medium from GA-reactive T cells elevated IGF-1 protein and promoted the formation of oligodendrocyte precursor cells (OPCs) from embryonic brain-derived forebrain cells in culture. We next subjected mice to lysolecithin-induced demyelination of the spinal cord. At 7 days after the insult, the number of OPCs in the demyelinated dorsal column wa |
| October 6th, 2009 Identification of functional marker proteins in the mammalian growth cone Identification of proteins in the mammalian growth cone has the potential to advance our understanding of this critical regulator of neuronal growth and formation of neural circuit; however, to date, only one growth cone marker protein, GAP-43, has been reported. Here, we successfully used a proteomic approach to identify 945 proteins present in developing rat forebrain growth cones, including highly abundant, membrane-associated and actin-associated proteins. Almost 100 of the proteins appear to be highly enriched in the growth cone, as determined by quantitative immunostaining, and for 17 proteins, the results of RNAi suggest a role in axon growth. Most of the proteins we identified have not previously been implicated in axon growth and thus their identification presents a significant step forward, providing marker proteins and candidate neuronal growth-associated proteins |
| September 21st, 2009 B cells produce pathogenic antibodies and impair recovery after spinal cord injury in mice Traumatic spinal cord injury causes permanent disability or loss of movement (paralysis) and sensation below the site of the injury. Currently, there are no treatments that can reverse the damage to the spinal cord, there are only approaches to prevent further damage and to help people return to an active lifestyle. However, Philip Popovich and colleagues, at the Ohio State University College of Medicine, Columbus, have studied the problem in mice and identified potential new therapeutic targets for minimizing injury and/or promoting repair after traumatic spinal cord injury. |
| September 16th, 2009 Therapeutic DNA Vaccination as a Repair Strategy Following Spinal Cord Injury Myelin-derived proteins, such as tenascin-R (TN-R), myelin associate glycoprotein (MAG), oligodendrocyte-myelin glycoprotein (OMgp), and Nogo-A, inhibit the central nervous system regeneration. In this study, the DNA vaccine encoding for oligodendrocyte and myelin-related antigens was employed to attenuate the axonal growth inhibitory properties of myelin in the setting of spinal cord injury. Using a rat spinal cord dorsal hemisection model, the vaccine directed against the inhibitory epitopes of Nogo-A, MAG, OMgp, and TN-R was administered intramuscularly once a week following spinal cord injury, supplemented with local application of specific anti-sera against the four antigens. Anterograde labeling of dorsal column fibers showed active axonal regeneration through the lesion site at the eighth week following the treatment in experimental group but not in control groups. Light microscopic and ultrastructural analysis revealed that vaccination with these myelin-related antigens did not lead to demyelinating d |
| September 4th, 2009 Sensory axon targeting is increased by NGF gene therapy within the lesioned adult femoral nerve. Even though peripheral nerves regenerate well, axons are often misrouted and reinnervate inappropriate distal pathways post-injury. Misrouting most likely occurs at branch points where regenerating axons make choices. Here, we show that the accuracy of sensory axon reinnervation is enhanced by overexpression of the guidance molecule nerve growth factor (NGF) distal to the bifurcation. We used the femoral nerve as model, which contains both sensory and motor axons that intermingle in the parent trunk and distally segregate into the saphenous (SB) and motor branch (MB). Transection of the parent trunk resulted in misrouting of axon reinnervation to SB and MB. To enhance sensory axon targeting, recombinant adenovirus encoding NGF was injected along the SB close to the bifurcation one week post-injury. The accuracy of axon reinnervation was assessed by retrograde tracing at 3 or 8 weeks after nerve injury. NGF overexpression significantly increased the accuracy of SB axon reinnervation to the appropriate nerve br |
| August 17th, 2009 The Drosophila immunoglobulin gene turtle encodes guidance molecules involved in axon pathfinding Neuronal growth cones follow specific pathways over long distances in order to reach their appropriate targets. Research over the past 15 years has yielded a large body of information concerning the molecules that regulate this process. Some of these molecules, such as the evolutionarily conserved netrin and slit proteins, are expressed in the embryonic midline, an area of extreme importance for early axon pathfinding decisions. A general model has emerged in which netrin attracts commissural axons towards the midline while slit forces them out. However, a large number of commissural axons successfully cross the midline even in the complete absence of netrin signaling, indicating the presence of a yet unidentified midline attractant. |
| August 2nd, 2009 Chemotropic guidance facilitates axonal regeneration and synapse formation after spinal cord injury A principal objective of spinal cord injury (SCI) research is the restoration of axonal connectivity to denervated targets. We tested the hypothesis that chemotropic mechanisms would guide regenerating spinal cord axons to appropriate brainstem targets. We subjected rats to cervical level 1 (C1) lesions and combinatorial treatments to elicit axonal bridging into and beyond lesion sites. Lentiviral vectors expressing neurotrophin-3 (NT-3) were then injected into an appropriate brainstem target, the nucleus gracilis, and an inappropriate target, the reticular formation. NT-3 expression in the correct target led to reinnervation of the nucleus gracilis in a dose-related fashion, whereas NT-3 expression in the reticular formation led to mistargeting of regenerating axons. Axons regenerating into the nucleus gracilis formed axodendritic synapses containing rounded vesicles, reflective of pre-injury synaptic architecture. Thus, we report for the first time, to the best of our knowledge, the reinnervation of brainst |
| June 22nd, 2009 Human embryonic stem cell-derived neural precursor transplants in collagen scaffolds promote recovery in injured rat spinal cord We report on the generation of NPC as neural-like tubes in adherent and feeder-free hESC using a defined media supplemented with growth factors, and their transplantation in collagen scaffolds in adult rats subjected to midline lateral hemisection SCI. hESC-NPC were highly expressed molecular features of NPC such as Nestin, Sox1 and Pax6. Furthermore, these cells exhibited the multipotential characteristic of differentiating into neurons and glials in vitro. Implantation of xenografted hESC-NPC into the spinal cord with collagen scaffold improved the recovery of hindlimb locomotor function and sensory responses in an adult rat model of SCI. Analysis of transplanted cells showed migration toward the spinal cord and both neural and glial differentiation in vivo. |
| June 22nd, 2009 P90 Ribosomal s6 kinase 2 negatively regulates axon growth in motoneurons Mutations in Ribosomal S6 Kinase 2 (Rsk2) are associated with severe neuronal dysfunction in Coffin-Lowry Syndrome (CLS) patients, flies and mice. So far, the mechanisms how Rsk2 regulates development, maintenance and activity of neurons are not understood. We have investigated the consequences of Rsk2 deficiency in mouse spinal motoneurons. Survival of isolated Rsk2 deficient motoneurons is not reduced, but these cells grow significantly longer neurites. Conversely, overexpression of a constitutively active form of Rsk2 leads to reduced axon growth. Increased axon growth in Rsk2 deficient neurons was accompanied by higher Erk 1/2 phosphorylation, and the knockout phenotype could be rescued by pharmacological inhibition of MAPK/Erk kinase (Mek). These data indicate that Rsk2 negatively regulates axon elongation via the MAPK pathway. Thus, the functional defects observed in the nervous system of CLS patients and animal models with Rsk2 deficiency might be caused by dysregulated neurite growth rather than prima |
| June 9th, 2009 Axonal mRNAs: Characterisation and role in the growth and regeneration of dorsal root ganglion axons and growth cones We have developed a compartmentalised culture model for the purification of axonal mRNA from embryonic, neonatal and adult rat dorsal root ganglia. This mRNA was used un-amplified for RT-qPCR. We assayed for the presence of axonal mRNAs encoding molecules known to be involved in axon growth and guidance. mRNAs for ?-actin, ?-tubulin, and several molecules involved in the control of actin dynamics and signalling during axon growth were found, but mRNAs for microtubule-associated proteins, integrins and cell surface adhesion molecules were absent. Quantification of ?-actin mRNA by means of qPCR showed that the transcript is present at the same level in embryonic, newborn and adult axons. Using the photoconvertible reporter Kaede we showed that there is local translation of ?-actin in axons, the rate being increased by axotomy. Knock down of ?-actin mRNA by RNAi inhibited the regeneration of new axon growth cones after in vitro axotomy, indicating that local translation of actin-related molecules is important fo |
| May 28th, 2009 Accelerated release of a sparingly soluble drug from an injectable hyaluronan-methylcellulose hydrogel. An injectable hydrogel, comprised of hyaluronan and methylcellulose (HAMC), shows promise for localized, sustained delivery of growth factors for treatment of spinal cord injury (SCI). To better understand its potential for the delivery of small molecules, the release of sparingly soluble neuroprotectant, nimodipine, was investigated experimentally and via continuum modeling. This revealed that the MC in HAMC increased the solubility of sparingly soluble drug by over an order of magnitude, and enabled highly tunable release rates to be achieved by varying the method by which the drug was introduced into the scaffold. When nimodipine was introduced into HAMC in solubilized form, it was rapidly released from the scaffold within 8 h. Conversely, when nimodipine was blended into HAMC in particulate form, the release rates were greatly reduced, giving rise to complete release over 2 - 3 days for small, sub-micron particles, and longer times for large, 100 mum particles. The nimodipine particle-loaded gels yielded |
| May 28th, 2009 Effects of extracellular matrix molecules on the growth properties of oligodendrocyte progenitor cells in vitro The extracellular matrix (ECM) is a component of neural cell niches and regulates multiple functions of diverse cell types. To date, limited information is available concerning its biological effects on the growth properties of oligodendrocyte progenitor cells (OPCs). In the present study, we examined effects of several ECM components, i.e., fibronectin, laminin, and Matrigel, on the survival, proliferation, migration, process extension, and purity of OPCs isolated from embryonic day 15 rat spinal cords. All three ECM components enhanced these biological properties of the OPCs compared with a non-ECM substrate, poly-D-lysine. However, the extents of their effects were somewhat different. Among these ECMs, fibronectin showed the strongest effect on almost all aspects of the growth properties of OPCs, implying that this molecule is a better substrate for the growth of OPCs in vitro. Because of its survival- and growth-promoting effects on OPCs, fibronectin may be considered as a candidate substrate for enhancin |
| May 27th, 2009 Dantrolene can reduce secondary damage after spinal cord injury. The aim of this experimental study was to investigate the possible protective effects of dantrolene on traumatic spinal cord injury (SCI). Twenty-four New Zealand rabbits were divided into three groups: Sham (no drug or operation, n = 8), Control (SCI + 1 mL saline intraperitoneally (i.p.), n = 8), and DNT (SCI + 10 mg/kg dantrolene in 1 mL, i.p., n = 8). Laminectomy was performed at T10 and balloon catheter was applied extradurally. Four and 24 h after surgery, rabbits were evaluated according to the Tarlov scoring system. Blood, cerebrospinal fluid and tissue sample from spinal cord were taken for measurements of antioxidant status or detection of apoptosis. After 4 h SCI, all animals in control or DNT-treated groups became paraparesic. Significant improvement was observed in DNT-treated group, 24 h after SCI, with respect to control. Traumatic SCI led to an increase in the lipid peroxidation and a decrease in enzymic or non-enzymic endogenous antioxidative defense systems, and increase in apoptotic cell nu |
| May 27th, 2009 Neuronal differentiation of neural precursor cells is promoted by the methyl-CpG-binding protein MeCP2 Methyl-CpG-binding protein 2 (MeCP2), a methyl-CpG-binding domain protein family member which is expressed predominantly in neurons in the nervous system, acts as a transcriptional repressor by binding to methylated genes, and mutations in mecp2 cause the neurological disorder known as Rett syndrome (RTT). Although MeCP2 has been reported to regulate neuronal maturation rather than fate specification of neural precursor cells (NPCs), we have previously shown that it inhibits astrocyte differentiation of NPCs when ectopically expressed. Here, we show that expression of MeCP2 in NPCs not only suppresses astrocytic differentiation but actually promotes neuronal differentiation, even in the presence of well-known astrocyte-inducing cytokines. This dual function of MeCP2 was abolished by the MEK inhibitor U0126. Moreover, we observed that a truncated form of MeCP2 found in RTT patients fails to promote neuronal differentiation. We further demonstrate that transplanted MeCP2-expressing NPCs differentiate in vivo in |
| May 26th, 2009 An in vitro model of adult mammalian nerve repair. The role of pathway-derived growth factors in the support of peripheral axon regeneration remains elusive. Few appropriate knock-out mice are available, and gene silencing techniques are rarely 100% effective. To overcome these difficulties, we have developed an in vitro organotypic co-culture system that accurately models peripheral nerve repair in the adult mammal. Spinal cord sections from P4 mice that express YFP in their neurons are used to innervate segments of P4 peripheral nerve. This reconstructed ventral root is then transected and joined to a nerve graft. Growth of axons across the nerve repair and into the graft can be imaged repeatedly with fluorescence microscopy to define regeneration speed, and parent neurons can be labeled in retrograde fashion to identify contributing neurons. Nerve graft harvested from adult mice remains viable in culture by both morphologic and functional criteria. Motoneurons are supported with GDNF for the first week in culture, after which they survive axotomy, and are |
| April 7th, 2009 Researchers Regenerate Axons Necessary for Voluntary Movement For the first time, researchers have clearly shown regeneration of a critical type of nerve fiber that travels between the brain and the spinal cord and which is required for voluntary movement. The regeneration was accomplished in a brain injury site in rats by scientists at the University of California, San Diego School of Medicine and is described in a study to be published in the April 6th early on-line edition of the Proceedings of the National Academy of Sciences (PNAS). |
| April 2nd, 2009 Chronic spinal hemisection in rats induces a progressive decline in transmission in uninjured fibers to motoneurons Although most spinal cord injuries are anatomically incomplete, only limited functional recovery has been observed in people and rats with partial lesions. To address why surviving fibers cannot mediate more complete recovery, we evaluated the physiological and anatomical status of spared fibers after unilateral hemisection (HX) of thoracic spinal cord in adult rats. We made intracellular and extracellular recordings at L5 (below HX) in response to electrical stimulation of contralateral white matter above (T6) and below (L1) HX. Responses from T6 displayed reduced amplitude, increased latency and elevated stimulus threshold in the fibers across from HX, beginning 1-2 weeks after HX. Ultrastructural analysis revealed demyelination of intact axons contralateral to the HX, with a time course similar to the conduction changes. Behavioral studies indicated partial recovery which arrested when conduction deficits began. In conclusion, this study is the first demonstration of the delayed decline of transmission thr |
| April 2nd, 2009 Acute rolipram/thalidomide treatment improves tissue sparing and locomotion after experimental spinal cord injury Traumatic spinal cord injury (SCI) causes severe and permanent functional deficits due to the primary mechanical insult followed by secondary tissue degeneration. The cascade of secondary degenerative events constitutes a range of therapeutic targets which, if successfully treated, could significantly ameliorate functional loss after traumatic SCI. During the early hours after injury, potent pro-inflammatory cytokines, including tumor necrosis factor alpha (TNF-?) and interleukin-1 beta (IL-1?) are synthesized and released, playing key roles in secondary tissue degeneration. In the present investigation, the ability of rolipram and thalidomide (FDA approved drugs) to reduce secondary tissue degeneration and improve motor function was assessed in an experimental model of spinal cord contusion injury. The combined acute single intraperitoneal administration of both drugs attenuated TNF-? and IL-1? production and improved white matter sparing at the lesion epicenter. This was accompanied by a significant (2.6 po |
| March 31st, 2009 The role of thrombospondin-1 and transforming growth factor-beta after spinal cord injury in the rat Spinal cord injury (SCI) continues to result in high morbidity and mortality throughout the world. An effective neuroprotective agent is still not available to counteract secondary damage caused by traumatic injury. Thrombospondin-1 (TSP-1) and transforming growth factor-beta (TGF-beta) have a role in angiogenesis, scar deposition, inflammation and may affect astrocyte phenotype and mobility. We investigated the role of TSP-1 and TGF-beta in a model of spinal cord injury in rats. Forty female Sprague-Dawley rats were randomly divided into two equal groups: the experimental group was subject to SCI using an impactor and the sham-operated group was not subject to SCI. These animals were sacrificed at 12h and 24h after SCI for immunochemistry and Western blot analysis of the injured spinal segment for the expression of the TSP-1 and TGF-beta proteins. We found that TSP-1 and TGF-beta expression increased immediately after SCI in the injured segment. After 12h, TSP-1 concentrations increased more rapidly and dram |
| March 31st, 2009 Neurotrophic Factor-Expressing Mesenchymal Stem Cells Survive Transplantation into the Contused Spinal Cord without Differentiating into Neural Cells The aim of this study was to assess the feasibility of transplanting mesenchymal stem cells (MSCs), genetically modified to express glial-derived neurotrophic factor (GDNF), to the contused rat spinal cord and to subsequently assess their neural differentiation potential. MSCs expressing green fluorescent protein (GFP) were transduced with a retroviral vector to express the neurotrophin GDNF. The transduction protocol was optimized by using GFP-expressing retroviral constructs; approximately 90% of MSCs were transduced successfully after G418 selection. GDNF-transduced MSCs expressed the transgene and secreted growth factor into the media (~12 ng/500,000 cells secreted into the supernatant 2 weeks after transduction). Injuries were established using an impactor device, which applied a given, reproducible force to the exposed spinal cord. GDNF-expressing MSCs were transplanted rostral and caudal to the site of injury. Spinal cord sections were analyzed 2 and 6 weeks after transplantation. We demonstrate that G |
| March 31st, 2009 Stem cells in the treatment of chronic spinal cord injury: evaluation of somatosensitive evoked potentials in 39 patients Study design:A prospective, non-randomized clinical series trial.Objective:To evaluate the effect of autogenous undifferentiated stem cell infusion for the treatment of patients with chronic spinal cord injury (SCI) on somatosensory evoked potentials (SSEPs).Setting:A public tertiary hospital in São Paulo, Brazil.Methods:Thirty-nine consecutive patients with diagnosed complete cervical and thoracic SCI for at least 2 years and with no cortical response in the SSEP study of the lower limbs were included in the trial. The trial patients underwent peripheral blood stem cell mobilization and collection. The stem cell concentrate was cryopreserved and reinfused through arteriography into the donor patient. The patients were followed up for 2.5 years and submitted to SSEP studies to evaluate the improvement in SSEPs after undifferentiated cell infusion.Results:Twenty-six (66.7%) patients showed recovery of somatosensory evoked response to peripheral stimuli after 2.5 years of follow-up.Conclusion:The 2.5-year trial |
| March 25th, 2009 Macrophages promote axon regeneration with concurrent neurotoxicity. Activated macrophages can promote regeneration of CNS axons. However, macrophages also release factors that kill neurons. These opposing functions are likely induced simultaneously but are rarely considered together in the same experimental preparation. A goal of this study was to unequivocally document the concurrent neurotoxic and neuroregenerative potential of activated macrophages. To do so, we quantified the length and magnitude of axon growth from enhanced green fluorescent protein-expressing dorsal root ganglion (DRG) neurons transplanted into the spinal cord in relationship to discrete foci of activated macrophages. Macrophages were activated via intraspinal injections of zymosan, a potent inflammatory stimulus known to increase axon growth and cause neurotoxicity. Using this approach, a significant increase in axon growth up to macrophage foci was evident. Within and adjacent to macrophages, DRG and spinal cord axons were destroyed. Macrophage toxicity became more evident when zymosan was injected cl |
| March 23rd, 2009 Repulsive guidance molecule b inhibits neurite growth and is increased after spinal cord injury. Neuronal axons are guided by attractive and repulsive cues in their local environment. Since the identification of the repulsive guidance molecule (RGM) a (RGMa) as an axon repellent in the visual system, diverse functions, as part of the developing and adult central nervous system (CNS), have been ascribed to it. The binding of RGMa to its receptor neogenin has been shown to induce RhoA activation, leading to inhibitory/repulsive behavior and the collapse of the neuronal growth cone. In this paper, we provide evidence to suggest the involvement of RGMb, another member of the RGM family, in the rat CNS. RGMb inhibits neurite outgrowth in postnatal cerebellar granule neurons (CGNs) in vitro. RGMb is expressed by oligodendrocytes and neurons in the adult rat CNS, and the expression of this molecule is upregulated around the site of spinal cord injury. RGMb is present in myelin isolated from an adult rat brain. RGMb and neogenin are coexpressed in CGNs and entorhinal cortex neurons. These findings suggest that R |
| February 15th, 2009 GM-CSF inhibits glial scar formation and shows long-term protective effect after spinal cord injury. This study investigated the effects of granulocyte macrophage-colony stimulating factor (GM-CSF) on the scar formation and repair of spinal cord tissues in rat spinal cord injury (SCI) model. METHODS: Sprague-Dawley male rats (8 weeks old) were randomly divided into the sham-operated group, spinal cord injury group, and injury with GM-CSF treated group. A spinal cord injury was induced at T9/10 levels of rat spinal cord using a vascular clip. GM-CSF was administrated via intraperitoneal (IP) injection or on the dural surface using Gelfoam at the time of SCI. The morphological changes, tissue integrity, and scar formation were evaluated until 4 weeks after SCI using histological and immunohistochemical analyses. RESULTS: The administration of GM-CSF either via IP injection or local treatment significantly reduced the cavity size and glial scar formation at 3-4 weeks after SCI. GM-CSF also reduced the expression of core proteins of chondroitin sulfate proteoglycans (CSPGs) such as neurocan and NG2 but not phosp |
| February 13th, 2009 Contactin-1 is a functional receptor for neuroregulatory chondroitin sulfate-E Chondroitin sulfate (CS) plays critical roles in central nervous system development and regeneration, and individual modifications of CS form a "sulfation code" that regulates growth factor signaling or neuronal growth. Although we have shown that CS-E polysaccharide, but not CS-A or -C polysaccharide, has an inherent ability to promote neurite outgrowth toward primary neurons, its molecular mechanism remains elusive. Here, we show the involvement of a plasma membrane-tethered cell adhesion molecule, contactin-1 (CNTN-1), in CS-E-mediated neurite extension in a mouse neuroblastoma cell line and primary hippocampal neurons. CS-E, but not CS-A, -C, or heparan sulfate, engaged CNTN-1 with significant affinity and induced intracellular signaling downstream of CNTN-1, indicating that CS-E is a selective ligand for a potential CS receptor, CNTN-1, leading to neurite outgrowth. Our data provide the first evidence that biological functions of CS are exerted through the CS receptor-mediated signaling pathway(s). |
| February 12th, 2009 The role of fibroblast growth factor-2 in healing the dura mater after inducing cerebrospinal fluid leakage in rats We conducted a study to determine the effectiveness of topically applied recombinant mouse fibroblast growth factor-2 (FGF-2) in healing the dura mater in a rat with dura mater injury and cerebrospinal fluid leakage. Laminectomies were performed in 32 rats at the level of the L2–L4 vertebrae, and a dura mater defect was created. Sixteen rats were treated postoperatively with locally applied recombinant mouse FGF-2, and 16 animals received normal saline. FGF-2 effects on dura mater healing, cerebrospinal fluid leakage, and wound healing were assessed at 3 and 6 weeks postoperatively. The extent of dura mater healing was evaluated by histological analysis. We found that dura mater healing was significantly increased (p < 0.05) in rats treated with FGF-2 compared with rats in the control group. In this experimental model, locally applied FGF-2 effectively increased dura mater healing and induced no side effects. |
| February 6th, 2009 Olfactory ensheathing cells transplantation for central nervous system diseases in 1,255 patients OBJECTIVE: To analyze the therapeutic effect of olfactory ensheathing cells (OECs) transplantation for central nervous system diseases. METHODS: Between November 2001 and January 2008, 1,255 participants with central nervous system diseases were enrolled in this clinical study for fetal OECs transplantation. There were 928 males and 327 females aged 1.2-87 (mean 40) years. The course of disease was (4.52 +/- 4.67) years. Among them, 656 participants suffered from chronic spinal cord injury (SCI), 457 amyotrophic lateral sclerosis (ALS), 68 cerebral palsy (CP), 20 multiple sclerosis (MS), 11 the sequelae of stoke, 10 ataxia, and 33 residual diseases. The participants came from 71 countries or regions. Accidentally abortional fetal olfactory bulbs were donated voluntarily and were cultured for 2 weeks, then were transplanted. RESULTS: One thousand one hundred and twenty-eight cases were followed up for 2-8 weeks (mean 4 weeks) to obtain integrated data. Among them, the neurological functional amelioration was n |
| February 1st, 2009 A new culturing strategy improves functional neuronal development of human neural progenitor cells Cell replacement therapies that rely on in vitro differentiation of human neural progenitor cells (hNPCs) are a promising strategy to compensate the progressive cell loss in neurodegenerative disorders like Parkinson's disease. We and others observed, that the functional differentiation of progenitors in standard differentiation medium (DM) remains limited. The aim of the present study was to optimize neuronal in vitro differentiation by mimicking the physiological shift from depolarizing to hyperpolarizing conditions that occurs during early brain development. Differentiation was initiated using a depolarizing high potassium and low sodium-containing medium (DM-K). Subsequently, DM-K was replaced by a hyperpolarizing medium containing low potassium and high sodium concentrations (DM-Na). This two-phase strategy significantly promoted the expression of neuronal markers, enhanced neurite growth, enlarged sodium inward currents, and increased action potential firing. Thus, de- followed by hyperpolarizing cultur |
| February 1st, 2009 Lithium enhances the neuronal differentiation of neural progenitor cells in vitro and after transplantation into the avulsed ventral horn of adult rats through the secretion of brain-derived neurotrophic factor The present study was undertaken to elucidate the molecular mechanisms by which lithium regulates the development of spinal cord-derived neural progenitor cells (NPCs) in vitro and after transplanted in vivo. Our results show that lithium at the therapeutic concentration significantly increases the proliferation and neuronal differentiation of NPCs in vitro. Specific ELISAs, western blotting and quantitative real-time RT-PCR assays demonstrate that lithium treatment significantly elevates the expression and production of brain-derived neurotrophic factor (BDNF) by NPCs in culture. Application of a BDNF neutralizing antibody in culture leads to a marked reduction in the neurogenesis of lithium-treated NPCs to the control level. However, it shows no effects on the proliferation of lithium-treated NPCs. These findings suggest that the BDNF pathway is possibly involved in the supportive role of lithium in inducing NPC neurogenesis but not proliferation. The present study also provides evidence that lithium is abl |
| January 30th, 2009 Nanoparticle-mediated local delivery of methylprednisolone after spinal cord injury. Systemic administration of a high-dose of Methylprednisolone (MP) can reduce neurological deficits after acute spinal cord injury (SCI). However, the use of high-dose MP in treating acute SCI is controversial due to significant dose related side effects and relatively modest improvements in neurological function. Here, using a rat model of SCI, we compare the efficacy of controlled, nanoparticle-enabled local delivery of MP to the injured spinal cord with systemic delivery of MP, and a single local injection of MP without nanoparticles. Based on histological and behavioral data, we report that local, sustained delivery of MP via nanoparticles is significantly more effective than systemic delivery. Relative to systemic delivery, MP-nanoparticle therapy significantly reduced lesion volume and improved behavioral outcomes. Nanoparticle-enabled delivery of MP presents an effective method for introducing MP locally after SCI and significantly enhances therapeutic effectiveness compared to bare MP administered eith |
| January 30th, 2009 Polypyrrole-coated electrodes for the delivery of charge and neurotrophins to cochlear neurons Sensorineural hearing loss is associated with gradual degeneration of spiral ganglion neurons (SGNs), compromising hearing outcomes with cochlear implant use. Combination of neurotrophin delivery to the cochlea and electrical stimulation from a cochlear implant protects SGNs, prompting research into neurotrophin-eluting polymer electrode coatings. The electrically conducting polypyrrole/para-toluene sulfonate containing neurotrophin-3 (Ppy/pTS/NT3) was applied to 1.7 mm2 cochlear implant electrodes. Ppy/pTS/NT3-coated electrode arrays stored 2 ng NT3 and released 0.1 ng/day with electrical stimulation. Guinea pigs were implanted with Ppy/pTS or Ppy/pTS/NT3 electrode arrays two weeks after deafening via aminoglycosides. The electrodes of a subgroup of these guinea pigs were electrically stimulated for 8 h/day for 2 weeks. There was a loss of SGNs in the implanted cochleae of guinea pigs with Ppy/pTS-coated electrodes indicative of electrode insertion damage. However, guinea pigs implanted with electrically sti |
| January 30th, 2009 PAL31 may play an important role as inflammatory modulator in the repair process of the spinal cord injury rat Functional regeneration in a complete T8 transection model Cheng et al. (1996) and most recently, acidic fibroblast growth factor (aFGF; also known as FGF-1) involved in the repair process of the spinal cord injury (SCI) rat Tsai et al. (2008) have been reported. To further reveal the mechanism of the repair process of SCI, in additionally, we have identified a 30 kDa specific protein kinase A substrate induced at 6 days after SCI. However, the induction of the transducing signal was reduced in samples treated with aFGF. The 30 kDa protein was purified and identified by mass spectrometry as a novel protein, PAL31. The results of immunohistochemical study showed that PAL31 is abundantly expressed in the epicenter of the injured spinal cord and colocalizes with ED1-positive cells (macrophages) and CD8 T lymphocytes. Over-expression of PAL31 in RAW 264.7 cells resulted in the down-regulation of macrophage chemoattractant protein 1, inducible nitric oxide synthase, and signal transducer and activator of transcrip |
| January 23rd, 2009 Axon Regeneration Requires a Conserved MAP Kinase Pathway Regeneration of injured neurons can restore function, but most neurons regenerate poorly or not at all. The failure to regenerate, in some cases, is due to a lack of activation of cell-intrinsic regeneration pathways. Thus, these pathways might be targeted for the development of therapies that can restore neuron function after injury or disease. Here, we show that the DLK-1 mitogen-activated protein (MAP) kinase pathway is essential for regeneration in Caenorhabditis elegans motor neurons. Loss of this pathway eliminates regeneration, whereas activating it improves regeneration. Further, these proteins also regulate the later step of growth cone migration. We conclude that after axon injury, activation of this MAP kinase cascade is required to switch the mature neuron from an aplastic state to a state capable of growth. |
| January 22nd, 2009 Geron receives FDA clearance to begin world's first human clinical trial of embryonic stem cell based therapy for spinal cord injury. Geron Corporation (Nasdaq: GERN) announced today that the U.S. Food and Drug Administration (FDA) has granted clearance of the company's Investigational New Drug (IND) application for the clinical trial of GRNOPC1 in patients with acute spinal cord injury. |
| January 16th, 2009 810 nm Wavelength light: An effective therapy for transected or contused rat spinal cord Light therapy has biomodulatory effects on central and peripheral nervous tissue. Spinal cord injury (SCI) is a severe central nervous system trauma with no effective restorative therapies. The effectiveness of light therapy on SCI caused by different types of trauma was determined |
| January 15th, 2009 Effects of human neural stem cell transplantation in canine spinal cord hemisection. Previous works have reported that the transplantation of neural stem cells (NSCs) may improve functional recovery after spinal cord injury (SCI), but these results have been mainly obtained in rat models. In the present work, the authors sought to determine whether the transplantation of human NSCs improves functional outcome in a canine SCI model and whether transplanted NSCs survive and differentiate. Methods: Human NSCs (HB1.F3 clone) were used in this work. Lateral hemisection at the L2 level was performed in dogs and either (1) Matrigel (200 µl) alone as a growth-promoting matrix or (2) Matrigel seeded with human NSCs (107 cells/200 µl) were transplanted into hemisected gaps. Using a canine hind limb locomotor scale, functional outcomes were assessed over 12 weeks. Immunofluorescence staining was performed to examine cell survival, differentiation and axonal regeneration. Results: Compared with dogs treated with Matrigel alone, dogs treated with Matrigel + human NSCs showed significantly better function |
| January 12th, 2009 Engineering angiogenesis following spinal cord injury: a coculture of neural progenitor and endothelial cells in a degradable polymer implant leads to an increase in vessel density and formation of the blood-spinal cord barrier Angiogenesis precedes recovery following spinal cord injury and its extent correlates with neural regeneration, suggesting that angiogenesis may play a role in repair. An important precondition for studying the role of angiogenesis is the ability to induce it in a controlled manner. Previously, we showed that a coculture of endothelial cells (ECs) and neural progenitor cells (NPCs) promoted the formation of stable tubes in vitro and stable, functional vascular networks in vivo in a subcutaneous model. We sought to test whether a similar coculture would lead to the formation of stable functional vessels in the spinal cord following injury. We created microvascular networks in a biodegradable two-component implant system and tested the ability of the coculture or controls (lesion control, implant alone, implant?+?ECs or implant?+?NPCs) to promote angiogenesis in a rat hemisection model of spinal cord injury. The coculture implant led to a fourfold increase in functional vessels compared with the lesion control, |
| January 11th, 2009 Bromocriptine, a dopamine D(2) receptor agonist with the structure of the amino acid ergot alkaloids, induces neurite outgrowth in PC12 cells. To investigate whether dopamine agonists induce neurite outgrowth, we examined the effects of dopamine D(2) receptor agonists such as bromocriptine, talipexole, and pramipexole in PC12 cells, a well-studied model of neurite outgrowth. Bromocriptine significantly induced neurite outgrowth in a concentration-dependent manner. Neither talipexole nor pramipexole induced neurite outgrowth. Domperidone and sulpiride, dopamine D(2) receptor antagonists, did not have any effect on the bromocriptine-induced neurite outgrowth. These results suggest that the stimulation of dopamine D(2) receptors would not affect neurite outgrowth in nerve regeneration. Next, we investigated how bromocriptine-induced neurite outgrowth. Bromocriptine is not only a dopamine D(2) receptor agonist but also an ergot alkaloid. We examined the involvement of the structure of ergot alkaloids in the effect of bromocriptine. Ergot alkaloids have been divided into two groups: amino acid ergot alkaloids, including bromocriptine, and amine ergot alk |
| January 11th, 2009 c-Jun N-terminal kinases mediate Fas-induced neurite regeneration in PC12 cells In response to injury, peripheral neuronal cells initiate complex signalling cascades to promote survival and regeneration. In the present study, we used a model of experimental injury in the rat pheochromocytoma cell line PC12 to investigate receptor signals that lead to neurite outgrowth. Nerve growth factor (NGF) dose-dependently induced sprouting and the expression of the NGF receptors Trk tyrosine kinase receptor (TrkA) and p75 neurotrophin receptor (p75(NTR)) as well as Fas and Fas ligand. Neurite regeneration was decreased by chemical inhibition of TrkA, but not p75(NTR), and by the Fas inhibitor protein Fas-Fc. The mitogen-activated protein kinases (MAPKs) extracellular signal-regulated kinase 1/2 (ERK1/2) and c-Jun N-terminal kinases (JNKs) were activated in response to NGF and both significantly contributed to neurite re-growth. Interestingly, otherwise apoptotic Fas ligation supported neuronal recovery exclusively via JNKs and promoted sprouting parallel to NGF. These findings suggest a novel signa |
| January 11th, 2009 Sox11 transcription factor modulates peripheral nerve regeneration in adult mice The ability of adult peripheral sensory neurons to undergo functional and anatomical recovery following nerve injury is due in part to successful activation of transcriptional regulatory pathways. Previous in vitro evidence had suggested that the transcription factor Sox11, a HMG-domain containing protein that is highly expressed in developing sensory neurons, is an important component of this regenerative transcriptional control program. To further test the role of Sox11 in an in vivo system, we developed a new approach to specifically target small interfering RNAs (siRNAs) conjugated to the membrane permeable molecule Penetratin to injured sensory afferents. Injection of Sox11 siRNAs into the mouse saphenous nerve caused a transient knockdown of Sox11 mRNA that inhibited in vivo regeneration. Electron microscopic level analysis of Sox11 RNAi-injected nerves showed that regeneration of myelinated and unmyelinated axons was inhibited. Nearly all neurons in ganglia of crushed nerves that were Sox11 immunoposit |
| January 11th, 2009 Ibuprofen Enhances Recovery from Spinal Cord Injury by Limiting Tissue Loss and Stimulating Axonal Growth The GTP-binding protein RhoA regulates microfilament dynamics in many cell types and mediates the inhibition of axonal regeneration by myelin and chondroitin sulfate proteoglycans. Unlike most other nonsteroidal anti-inflammatory drugs, ibuprofen suppresses basal RhoA activity (Zhou et al., 2003). A recent report suggested that ibuprofen promotes corticospinal axon regeneration after spinal cord injury (Fu et al., 2007). Here, we confirm that ibuprofen reduces ligand-induced Rho signaling and myelin-induced inhibition of neurite outgrowth in vitro. Following 4 weeks of subcutaneous administration of ibuprofen, beginning 3 days after spinal cord contusion, animals recovered walking function to a greater degree, with twice as many rats achieving a hind limb weight-bearing status. We examined the relative role of tissue sparing, axonal sprouting, and axonal regeneration in the action of ibuprofen. Histologically, ibuprofen-treated animals display an increase in spared tissue without an alteration in astrocytic o |
| January 8th, 2009 Extensive spinal decussation and bilateral termination of cervical corticospinal projections in rhesus monkeys To examine neuroanatomical mechanisms underlying fine motor control of the primate hand, adult rhesus monkeys underwent injections of biotinylated dextran amine (BDA) into the right motor cortex. Spinal axonal anatomy was examined using detailed serial-section reconstruction and modified stereological quantification. Eighty-seven percent of corticospinal tract (CST) axons decussated in the medullary pyramids and descended through the contralateral dorsolateral tract of the spinal cord. Eleven percent of CST axons projected through the dorsolateral CST ipsilateral to the hemisphere of origin, and 2% of axons projected through the ipsilateral ventromedial CST. Notably, corticospinal axons decussated extensively across the spinal cord midline. Remarkably, nearly 2-fold more CST axons decussated across the cervical spinal cord midline (12,000 axons) than were labeled in all descending components of the CST (6,700 axons). These findings suggest that CST axons extend multiple segmental collaterals. Furthermore, ser |
| January 8th, 2009 Deletion of macrophage migration inhibitory factor attenuates neuronal death and promotes functional recovery after compression-induced spinal cord injury in mice Macrophage migration inhibitory factor (MIF) is a multipotential protein that acts as a proinflammatory cytokine, a pituitary hormone, and a cell proliferation and migration factor. The objective of this study was to elucidate the role of MIF in spinal cord injury (SCI) using female MIF knockout (KO) mice. Mouse spinal cord compression injury was produced by application of a static load (T8 level, 20 g, 5 min). We analyzed the motor function of the hind limbs and performed histological examinations. Hind-limb function recovered significantly in the KO mice starting from three weeks after injury. Cresyl-violet staining revealed that the number of surviving neurons in the KO mice was significantly larger than that of WT mice six weeks after injury. Immunohistochemical analysis revealed that the number of NeuN/caspase-3-active, double-positive, apoptotic neurons in the KO mice was significantly smaller than that of the WT mice 24 and 72 h after SCI. These results were related to in-vitro studies showing increase |
| December 12th, 2008 Semaphorin-6A controls guidance of corticospinal tract axons at multiple choice points The trajectory of corticospinal tract (CST) axons from cortex to spinal cord involves a succession of choice points, each of which is controlled by multiple guidance molecules. To assess the involvement of transmembrane semaphorins and their plexin receptors in the guidance of CST axons, we have examined this tract in mutants of Semaphorin-6A (Sema6A), Plexin-A2 (PlxnA2) and Plexin-A4 (PlxnA4). RESULTS: We describe defects in CST guidance in Sema6A mutants at choice points at the mid-hindbrain boundary (MHB) and in navigation through the pons that dramatically affect how many axons arrive to the hindbrain and spinal cord and result in hypoplasia of the CST. We also observe defects in guidance within the hindbrain where a proportion of axons aberrantly adopt a ventrolateral position and fail to decussate. This function in the hindbrain seems to be mediated by the known Sema6A receptor PlxnA4, which is expressed by CST axons. Guidance at the MHB, however, appears independent of this and of the other known recep |
| December 12th, 2008 Novel Multi-Modal Strategies to Promote Brain and Spinal Cord Injury Recovery Stroke is the leading cause of disability in the United States, and yet no definitive interventions can drive the nervous system beyond its measurable but often limited spontaneous recovery. Treatment to limit injury progression and enhance repair after stroke or other types of central nervous system injury is complicated by the heterogeneous nature of cell death and wound healing mechanisms and the multiple barriers to functional recovery. The heterogeneity of injury and repair mechanisms requires interventions that are broad and multi-modal, but also intrinsically safe. We describe a process to identify such interventions by screening multiple individual targets in the historically separate realms of neuroprotection, repair, and regeneration against a library of FDA-approved compounds with known safety. We have identified nearly 10 compounds that are able to activate simultaneously protective and reparative genes. These compounds have a theoretical therapeutic window that spans from evolving injury (minutes |
| December 11th, 2008 Mature Adipocyte-Derived Cells, Dedifferentiated Fat Cells (DFAT), Promoted Functional Recovery From Spinal Cord Injury-Induced Motor Dysfunction in Rats Transplantation of mature adipocyte-derived cells (dedifferentiated fat cells) led to marked functional recovery from spinal cord injury (SCI)-induced motor dysfunction in rats. When mature adipocytes were isolated from rat adipose tissue and grown in ceiling culture, transformation into fibroblast-like cells without lipid droplets occurred. These fibroblast-like cells, termed dedifferentiated fat cells (DFAT), could proliferate and could also differentiate back into adipocytes. DFAT expressed neural markers such as nestin, βIII tubulin, and GFAP. Allografting of DFAT into SCI-induced rats led to significant recovery from hindlimb dysfunction. Grafted cells were detected at the injection site, and some of these cells expressed βIII tubulin. DFAT expressed neurotrophic factors such as BDNF and GDNF prior to transplantation, and grafted cells were also positive for these factors. Therefore, these neurotrophic factors derived from grafted DFAT might have contributed to the promotion of functional recov |
| December 11th, 2008 Potency and Fate Specification in CNS Stem Cell Populations In Vitro To realize the promise of stem cell biology, it is important to identify the precise time in the history of the cell when developmental potential is restricted. To achieve this goal, we developed a real-time imaging system that captures the transitions in fate, generating neurons, astrocytes, and oligodendrocytes from single CNS stem cells in vitro. In the presence of bFGF, tripotent cells normally produce specified progenitors through a bipotent intermediate cell type. Surprisingly, the tripotent state is reset at each passage. The cytokine CNTF is thought to instruct multipotent cells to an astrocytic fate. We demonstrate that CNTF both directs astrogliogenesis from tripotent cells, bypassing two of the three normal bipotent intermediates, and later promotes the expansion of specified astrocytic progenitors. These results show how discrete cell types emerge from a multipotent cell and provide a strong basis for future studies to determine the molecular basis of fate specification. |
| December 2nd, 2008 Repair of thoracic spinal cord injury by chitosan tube implantation in adult rats Spinal cord injury (SCI) is a common outcome of traffic accidents and trauma with severe consequences. There has been no cure for such a condition. We performed experiments to evaluate the feasibility of implanting a chitosan tube filled with semifluid type I collagen into the site of surgically induced SCI to facilitate functional recovery. After a segment of the spinal cord, 4 mm in length and 2/3 of the spinal cord across its width, at the ninth thoracic level of an adult rat was dissected and removed, the biodegradable chitosan tube was implanted into the lesioned site. One year later, we found that axons from the proximal spinal cord regenerated, traversed the dissected area inside the tube and reentered the distal spinal cord, leading to functional restoration of the essentially paralyzed hind limbs. The nerve regeneration and functional recovery were confirmed by immunohistochemistry, electron microscopy, nerve tracing and Basso–Beattie–Bresnahan behavioral evaluation. Such beneficial outcomes were not |
| November 30th, 2008 α4β1 integrin blockade after spinal cord injury decreases damage and improves neurological function The extent of disability caused by spinal cord injury (SCI) relates to secondary tissue destruction arising partly from an intraspinal influx of neutrophils and monocyte/macrophages after the initial injury. The integrin α4β1, expressed by these leukocytes, is a key to their activation and migration into/within tissue. Therefore, blocking this integrin's functions may afford significant neuroprotection. Rats were treated intravenously with a blocking monoclonal antibody (mAb) to the α4 subunit of α4β1 at 2 and 24 h after thoracic clip-compression SCI. Anti-α4β1 treatment significantly decreased neutrophil and monocyte/macrophage influx at 3 d by 47% and 53%, respectively, and decreased neutrophil influx by 61% at 7 d after SCI. Anti-α4β1 treatment also significantly reduced oxidative activity in injured cord homogenates at 3 d. For example, myeloperoxidase activity decreased by 38%, inducible nitric oxide by 44%, dichlorofluorescein (marking free radicals) by |
| November 30th, 2008 An integrin inhibiting molecule decreases oxidative damage and improves neurological function after spinal cord injury Our previous studies have shown that treatment with an α4β1 integrin blocking antibody after spinal cord injury (SCI) in rats decreases intraspinal inflammation and oxidative damage, improving neurological function. Here, we studied effects of a high affinity small molecule α4β1 inhibitor, BIO5192. First, rats were treated intravenously with BIO5192 (10 mg/kg) or with vehicle (controls) to assess effects of integrin blockade for 24 h or 72 h after thoracic clip-compression SCI. BIO5192 treatment significantly decreased the MPO enzymatic activity (neutrophil infiltration) and ED-1 expression (macrophage density) by 40% and 38% at 24 h and by 52% and 25% at 72 h post injury, respectively. In cord homogenates, BIO5192 treatment decreased expression of the oxidative enzymes gp91phox, inducible nitric oxide and cyclooxygenase-2 by 40% at both times of analysis. Free radical concentration decreased by 30% and lipid peroxidation decreased by 34% and 46%, respectively, at 24 h and 72 h after SC |
| November 20th, 2008 Macro-Architectures in Spinal Cord Scaffold Implants Influence Regeneration Biomaterial scaffold architecture has not been investigated as a tunable source of influence on spinal cord regeneration. This study compared regeneration in a transected spinal cord within various designed-macro-architecture scaffolds to determine if these architectures alone could enhance regeneration. Three-dimensional (3-D) designs were created and molds were built on a 3-D printer. Salt-leached porous poly(?-caprolactone) was cast in five different macro-architectures: cylinder, tube, channel, open-path with core, and open-path without core. The two open-path designs were created in this experiment to compare different supportive aspects of architecture provided by scaffolds and their influence on regeneration. Rats received T8 transections and implanted scaffolds for 1 and 3 months. Overall morphology and orientation of sections were characterized by H&E, luxol fast blue, and cresyl violet staining. Borders between intact gray matter and non-regenerated defect were observed from GFAP immunolabeling. Ner |
| November 18th, 2008 Functional restoration of rabbit spinal cord using collagen-filament scaffold We report the first success of functional restoration of transected rabbit spinal cord using collagen-filament nerve scaffold. We grafted 5 mm-long 6000 collagen filaments parallel to the axis of the spinal cord to bridge 3 mm defects of 21 adult rabbit spinal cords; 18 rabbits were used as controls. Of the 39 rabbits, 22 survived the experimental period. At 12 weeks postoperatively, regenerated axons crossed the proximal spinal cord-implant interfaces in four out of six rabbits. At 24 weeks postoperatively, regenerated axons crossed the proximal and distal spinal cord-implant interfaces in four out of six rabbits. At 24 weeks postoperatively, the Basso-Beattie-Bresnahan (BBB) locomotor rating scale scores of the rabbits in the collagen-filament grafted group were 4.7 +/- 2.3, while the score in the control group was 2.8 +/- 0.5. The BBB scale scores of the grafted group were significantly better than the control group. The results suggest that the collagen-filament nerve scaffold supports the axonal regenera |
| November 17th, 2008 Neurite outgrowth on cultured spiral ganglion neurons induced by erythropoietin. The morphological correlate of deafness is the loss of hair cells with subsequent degeneration of spiral ganglion neurons (SGN). Neurotrophic factors have a neuroprotective effect, and especially brain-derived neurotrophic factor (BDNF) has been demonstrated to protect SGN in vitro and after ototoxic trauma in vivo. Erythropoietin (EPO) attenuates hair cell loss in rat cochlea explants that were treated with gentamycin. Recently, it has also been shown that EPO reduces the apoptose rate in hippocampal neurons. Therefore, the aim of the study was to examine the effects of EPO on SGN in vitro. Spiral ganglion cells were isolated from neonatal rats and cultured for 48 h in serum-free medium supplemented with EPO and/or BDNF. Results showed that survival rates of SGN were not significantly improved when cultivated with EPO alone. Also, EPO did not further increase BDNF-induced survival of SGN. However, significant elongation of neurites was determined when SGN were cultivated with EPO alone. Even though a less th |
| November 6th, 2008 Coaxing Injured Nerves to Regrow The adult central nervous system has limited ability to repair itself. That's why spinal cord injuries leave people permanently paralyzed. Now a study with mice finds that removing a particular signaling molecule in adult neurons restores their ability to regenerate damaged axons, the long extensions that convey signals from one neuron to another. The find potentially paves the way for repairing spinal cords and other nervous system injuries. "It's one of the most dramatic results in the history of this field," says Ben Barres, a neurobiologist at Stanford University in Palo Alto, California. |
| November 6th, 2008 PirB is a Functional Receptor for Myelin Inhibitors of Axonal Regeneration A major barrier to regenerating axons after injury in the mammalian central nervous system is an unfavorable milieu. Three proteins found in myelin—Nogo, MAG, and OMgp—inhibit axon regeneration in vitro and bind to the glycosylphosphatidylinositol-anchored Nogo receptor (NgR). However, genetic deletion of NgR has only a modest disinhibitory effect, suggesting that other binding receptors for these molecules probably exist. With the use of expression cloning, we have found that paired immunoglobulin-like receptor B (PirB), which has been implicated in nervous system plasticity, is a high-affinity receptor for Nogo, MAG, and OMgp. Interfering with PirB activity, either with antibodies or genetically, partially rescues neurite inhibition by Nogo66, MAG, OMgp, and myelin in cultured neurons. Blocking both PirB and NgR activities leads to near-complete release from myelin inhibition. Our results implicate PirB in mediating regeneration block, identify PirB as a potential target for axon regeneration therapies, and |
| November 2nd, 2008 Undesired effects of a combinatorial treatment for spinal cord injury - transplantation of olfactory ensheathing cells and BDNF infusion to the red nucleus. Transplantations of olfactory ensheathing cells (OECs) have been reported to promote axonal regeneration and functional recovery after spinal cord injury, but have demonstrated limited growth promotion of rat rubrospinal axons after a cervical dorsolateral funiculus crush. Rubrospinal neurons undergo massive atrophy after cervical axotomy and show only transient expression of regeneration-associated genes. Cell body treatment with brain-derived neurotrophic factor (BDNF) prevents this atrophy, stimulates regeneration-associated gene expression and promotes regeneration of rubrospinal axons into peripheral nerve transplants. Here, we hypothesized that the failure of rubrospinal axons to regenerate through a bridge of OEC transplants was due to this weak intrinsic cell body response. Hence, we combined BDNF treatment of rubrospinal neurons with transplantation of highly enriched OECs derived from the nasal mucosa and assessed axonal regeneration as well as behavioral changes after a cervical dorsolateral funicu |
| October 28th, 2008 Differential effects of lentiviral vector-mediated overexpression of nerve growth factor and glial cell line-derived neurotrophic factor on regenerating sensory and motor axons in the transected peripheral nerve. Even after reconstructive surgery, major functional impairments remain in the majority of patients with peripheral nerve injuries. The application of novel emerging therapeutic strategies, such as lentiviral (LV) vectors, may help to stimulate peripheral nerve regeneration at a molecular level. In the experiments described here, we examined the effect of LV vector-mediated overexpression of nerve growth factor (NGF) and glial cell line-derived neurotrophic factor (GDNF) on regeneration of the rat peripheral nerve in a transection/repair model in vivo. We showed that LV vectors can be used to locally elevate levels of NGF and GDNF in the injured rat peripheral nerve and this has profound and differential effects on regenerating sensory and motor neurons. For sensory neurons, increased levels of NGF and GDNF do not affect the number of regenerated neurons 1 cm distal to a lesion at 4 weeks post-lesion but do cause changes in the expression of markers for different populations of nociceptive neurons. These chang |
| October 18th, 2008 Inactivation of glycogen synthase kinase 3 promotes axonal growth and recovery in the CNS. Axonal regeneration is minimal after CNS injuries in adult mammals and medical treatments to recover neurological deficits caused by axon disconnection are extremely limited. The failure of axonal elongation is principally attributed to the nonpermissive environment and reduced intrinsic growth capacity. In this report, we studied the role of glycogen synthase kinase-3 (GSK-3) inactivation on neurite and axon growth from adult neurons via combined in vitro and in vivo approaches. We found that the major CNS inhibiting substrates including chondroitin sulfate proteoglycans could inactivate protein kinase B (Akt) and activate GSK-3beta signals in neurons. GSK-3 inactivation with pharmacologic inhibitors enhances neurite outgrowth of dorsal root ganglion neurons derived from adult mice or cerebellar granule neurons from postnatal rodents cultured on CNS inhibitors. Application of GSK-3 inhibitors stimulates axon formation and elongation of mature neurons whether in presence or absence of inhibitory substrates. S |
| October 17th, 2008 Nicotine attenuates iNOS expression and contributes to neuroprotection in a compressive model of spinal cord injury. Primary impact to the spinal cord results in stimulation of secondary processes that potentiate the initial trauma. In the present study, we hypothesized that the altered expression of nitric oxide synthase (NOS) may contribute to these effects. Recent evidence indicates that nicotine can exert potent antioxidant and neuroprotective effects in spinal cord injury (SCI). Therefore, the aim of the present study was to evaluate whether the administration of nicotine can influence expression of inducible NOS (iNOS) and/or neuronal NOS (nNOS) in injured spinal cords. Adult male Long-Evans rats were subjected to a moderate contusion model of SCI and received a single intraperitoneal injection of either saline or nicotine (0.35, 3.5, or 7 mg/kg) 2 hr after trauma. SCI dramatically increased iNOS (but not nNOS) mRNA and protein levels in microglial cells in the thoracic and lumbar regions of spinal cords. iNOS overexpression resulted in increased nitrotyrosine formation, decreased number of NeuN (neuronal nuclei)-immu |
| October 17th, 2008 Generation of spinal motor neurons from human fetal brain-derived neural stem cells: Role of basic fibroblast growth factor. Neural stem cells (NSCs) have some specified properties but are generally uncommitted and so can change their fate after exposure to environmental cues. It is unclear to what extent this NSC plasticity can be modulated by extrinsic cues and what are the molecular mechanisms underlying neuronal fate determination. Basic fibroblast growth factor (bFGF) is a well-known mitogen for proliferating NSCs. However, its role in guiding stem cells for neuronal subtype specification is undefined. Here we report that in-vitro-expanded human fetal forebrain-derived NSCs can generate cholinergic neurons with spinal motor neuron properties when treated with bFGF within a specific time window. bFGF induces NSCs to express the motor neuron marker Hb9, which is blocked by specific FGF receptor inhibitors and bFGF neutralizing antibodies. This development of spinal motor neuron properties is independent of selective proliferation or survival and does not require high levels of MAPK activation. Thus our study indicates that bFGF |
| October 17th, 2008 FK1706, a novel non-immunosuppressant neurophilin ligand, ameliorates motor dysfunction following spinal cord injury through its neuroregenerative action. Injured spinal cord axons fail to regenerate in part due to a lack of trophic support. While various methods for replacing neurotrophins have been pursued, clinical uses of these methods face significant barriers. FK1706, a non-immunosuppressant neurophilin ligand, potentiates nerve growth factor signaling, suggesting therapeutic potential for functional deficits following spinal cord injury. Here, we demonstrate that FK1706 significantly improves behavioral outcomes in animal models of spinal cord hemisection and contusion injuries in rats. Furthermore, we show that FK1706 is effective even if administration is delayed until 1 week after injury, suggesting that FK1706 has a reasonable therapeutic time-window. Morphological analysis of injured axons in the dorsal corticospinal tract showed an increase in the radius and perimeter of stained axons, which were reduced by FK1706 treatment, suggesting that axonal swelling and retraction balls observed in injured spinal cord were improved by the neurotrophic effect |
| October 15th, 2008 Monkeys move paralysed muscles with their minds A monkey's paralysed wrist can be moved and controlled by electrical signals artificially routed from its brain, according to scientists who say that their experiment is a step towards helping paralysed people to regain the use of their limbs. |
| October 10th, 2008 The influence of substrate curvature on neurite outgrowth is cell type dependent. Damage to axonal tracts of the central nervous system results in costly and permanent disability. The observations of aborted neurite outgrowth and disorganized scarring in injured central nervous system tissue have motivated the hypothesis that engineered bridging devices might facilitate regeneration. It is thought that both the shape and surface chemistry are important design parameters, however, their relative importance is poorly understood. Previously, we utilized smooth cylindrical surfaces to demonstrate that surfaces designed with directionally varying curvature bias in a stereotyped way postnatal dorsal root ganglion axonal regeneration in the direction of minimum curvature independent of surface chemistry. In the present study, we extend this analysis to include adult dorsal root ganglion neurons and cerebellar granule cells, cell types more representative of the challenge faced clinically. We found that axonal outgrowth of both the adult neuron and the central neuron was less sensitive to substrat |
| October 10th, 2008 Myelin pathogenesis and functional deficits following SCI are age-associated. Most spinal cord injuries (SCI) occur in young adults. In the past few decades however, the average age at time of SCI and the percentage of injuries in persons over the age of 60 have increased. Studies have shown that there is an age-associated delay in the rate of remyelination following toxin-induced demyelination of the spinal cord, suggesting that there may be an age-associated difference in regenerative efficiency. Here we examine for the first time locomotor recovery, bladder recovery, and myelin pathology in young (3 months), aged (12 months), and geriatric (24 months) female rats following contusion SCI. Our assessments indicate that aged and geriatric rats have a delayed rate of locomotor recovery following contusion SCI as compared to young rats. Additionally, aged and geriatric rats have significantly slower bladder recovery as compared to young rats. Examination of myelin pathology reveals that aged and geriatric rats have significantly greater area of pathology and amount of demyelination, as w |
| October 9th, 2008 V3 Spinal Neurons Establish a Robust and Balanced Locomotor Rhythm during Walking. A robust and well-organized rhythm is a key feature of many neuronal networks, including those that regulate essential behaviors such as circadian rhythmogenesis, breathing, and locomotion. Here we show that excitatory V3-derived neurons are necessary for a robust and organized locomotor rhythm during walking. When V3-mediated neurotransmission is selectively blocked by the expression of the tetanus toxin light chain subunit (TeNT), the regularity and robustness of the locomotor rhythm is severely perturbed. A similar degeneration in the locomotor rhythm occurs when the excitability of V3-derived neurons is reduced acutely by ligand-induced activation of the allatostatin receptor. The V3-derived neurons additionally function to balance the locomotor output between both halves of the spinal cord, thereby ensuring a symmetrical pattern of locomotor activity during walking. We propose that the V3 neurons establish a regular and balanced motor rhythm by distributing excitatory drive between both halves of the spi |
| October 8th, 2008 Modification of Schwann cell gene expression by electroporation in vivo. Clinical outcomes of nerve grafting are often inferior to those of end-to-end nerve repair. This may be due, in part, to the routine use of cutaneous nerve to support motor axon regeneration. In previous work, we have demonstrated that Schwann cells express distinct sensory and motor phenotypes, and that these promote regeneration in a modality-specific fashion. Intra-operative modification of graft Schwann cell phenotype might therefore improve clinical outcomes. This paper demonstrates the feasibility of electroporating genes into intact nerve to modify Schwann cell gene expression. Initial trials established 70V, 5ms as optimum electroporation parameters. Intact, denervated, and reinnervated rat tibial nerves were electroporated with the YFP gene and evaluated serially by counting S-100 positive cells that expressed YFP. In intact nerve, a mean of 28% of Schwann cells expressed the gene at 3 days, falling to 20% at 7 days with little expression at later times. There were no significant differences among th |
| October 8th, 2008 Role of GluR1 in Activity-Dependent Motor System Development. Activity-dependent specification of neuronal architecture during early postnatal life is essential for refining the precision of communication between neurons. In the spinal cord under normal circumstances, the AMPA receptor subunit GluR1 is expressed at high levels by motor neurons and surrounding interneurons during this critical developmental period, although the role it plays in circuit formation and locomotor behavior is unknown. Here, we show that GluR1 promotes dendrite growth in a non-cell-autonomous manner in vitro and in vivo. The mal-development of motor neuron dendrites is associated with changes in the pattern of interneuronal connectivity within the segmental spinal cord and defects in strength and endurance. Transgenic expression of GluR1 in adult motor neurons leads to dendrite remodeling and supernormal locomotor function. GluR1 expression by neurons within the segmental spinal cord plays an essential role in formation of the neural network that underlies normal motor behavior. |
| October 7th, 2008 PRMT1 and Btg2 regulates neurite outgrowth of Neuro2a cells. Neurite outgrowth is one of the crucial events in the formation of neural circuits. The majority of studies on neurite outgrowth have focused on signal transduction processes based on phosphorylation and acetylation; a few studies have suggested the involvement of other molecular mechanisms. Recent progress in understanding the nature of protein arginine N-methyltransferases (PRMTs) raises the possibility of the involvement of protein methylation accompanied by cell shape changes during neuronal differentiation. Here, we show that PRMT1 play a pivotal role in the neurite outgrowth of Neuro2a cells. Our results revealed that PRMT1 depletion specifically affected neurite outgrowth but not the physiological processes involved in cell growth and differentiation. Furthermore, we demonstrated that Btg2, one of the PRMT1 binding partner, depletion down-regulated arginine methylation in the nucleus and inhibited neurite outgrowth. These results indicate that protein arginine methylation by PRMT1 in the nucleus is an |
| October 7th, 2008 Plasticity of polarization: changing dendrites into axons in neurons integrated in neuronal circuits. Developing neurons can change axonal and dendritic fate upon axonal lesion, but it is unclear whether neurons retain such plasticity when they are synaptically interconnected. To address whether polarity is reversible in mature neurons, we cut the axon of GFP-labeled hippocampal neurons in dissociated and organotypic cultures and found that a new axon arose from a mature dendrite. The regenerative response correlated with the length of the remaining stump: proximal axotomies (<35 microm) led to the transformation of a dendrite into an axon (identity change), whereas distal cuts (>35 microm) induced axon regrowth, similar to what is seen in young neurons. Searching for a putative landmark in the distal axon that could determine axon identity, we focused on the stability of microtubules, which regulate initial neuronal polarization during early development. We found that functionally polarized neurons contain a distinctively high proportion of stable microtubules in the distal axon. Moreover, pharmacological st |
| October 1st, 2008 Researchers use nanoparticles to deliver treatment for brain, spinal cord injuries. A team led by Richard Borgens of the School of Veterinary Medicine's Center for Paralysis Research and Welden School of Biomedical Engineering coated silica nanoparticles with a polymer to target and repair injured guinea pig spinal cords. That research is being published in the October edition of the journal Small. |
| September 19th, 2008 Transplanted astrocytes derived from BMP- or CNTF-treated glial-restricted precursors have opposite effects on recovery and allodynia after spinal cord injury. Our results show that not all astrocytes derived from embryonic precursors are equally beneficial for spinal cord repair and they provide the first identification of a differentiated neural cell type that can cause pain syndromes on transplantation into the damaged spinal cord, emphasizing the importance of evaluating the capacity of candidate cells to cause allodynia before initiating clinical trials. They also confirm the particular promise of GDAs treated with bone morphogenetic protein for spinal cord injury repair. |
| September 8th, 2008 Upregulation of the GABA-transporter GAT-1 in the spinal cord contributes to pain behaviour in experimental neuropathy Sciatic nerve ligation in rats (chronic constriction injury (CCI)) induces signs and symptoms that mimic human conditions of neuropathy. The central mechanisms that have been implicated in the pathogenesis of neuropathic pain include increased neuronal excitability, possibly a consequence of decreased availability of spinal GABA. GABA availability is regulated by the presence of the GABA-transporters (GATs). This study investigates the dorsal horn expression of the transporter GAT-1 and its functional involvement towards pain behaviour in the CCI model. Male Lewis rats (total n = 37) were subjected to CCI or to a sham procedure. A sub-group of animals was treated with the GAT-1 antagonist NO-711. Behavioural testing was performed pre-surgery and at 7 days post-surgery. Testing included evaluation of mechanical allodynia using Von Frey filaments, thermal allodynia with a hot-plate test and observational testing of spontaneous pain behaviour. Subsequently, spinal protein expression of GAT-1 was assessed by West |
| September 8th, 2008 Chondroitin-4-sulfation negatively regulates axonal guidance and growth. Glycosaminoglycan (GAG) side chains endow extracellular matrix proteoglycans with diversity and complexity based upon the length, composition and charge distribution of the polysaccharide chain. Using cultured primary neurons, we show that specific sulfation in the GAG chains of chondroitin sulfate mediates neuronal guidance cues and axonal growth inhibition. Chondroitin-4-sulfate (CS-A), but not chondroitin-6-sulfate (CS-C), exhibits a strong negative guidance cue to mouse cerebellar granule neurons. Enzymatic and gene-based manipulations of 4-sulfation in the GAG side chains alter their ability to direct growing axons. Furthermore, 4-sulfated chondroitin sulfate GAG chains are rapidly and significantly increased in regions that do not support axonal regeneration proximal to spinal cord lesions in mice. Thus, our findings show that specific sulfation along the carbohydrate backbone carries instructions to regulate neuronal function. |
| September 8th, 2008 Inactivation of glycogen synthase kinase 3 promotes axonal growth and recovery in the CNS. Axonal regeneration is minimal after CNS injuries in adult mammals and medical treatments to recover neurological deficits caused by axon disconnection are extremely limited. The failure of axonal elongation is principally attributed to the nonpermissive environment and reduced intrinsic growth capacity. In this report, we studied the role of glycogen synthase kinase-3 (GSK-3) inactivation on neurite and axon growth from adult neurons via combined in vitro and in vivo approaches. We found that the major CNS inhibiting substrates including chondroitin sulfate proteoglycans could inactivate protein kinase B (Akt) and activate GSK-3beta signals in neurons. GSK-3 inactivation with pharmacologic inhibitors enhances neurite outgrowth of dorsal root ganglion neurons derived from adult mice or cerebellar granule neurons from postnatal rodents cultured on CNS inhibitors. Application of GSK-3 inhibitors stimulates axon formation and elongation of mature neurons whether in presence or absence of inhibitory substrates. S |
| September 8th, 2008 Neuroprotective potential of phase II enzyme inducer diallyl trisulfide. Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease, selectively involving the upper and lower motor neurons. Glutamate excitotoxicity and oxidative stress are important mechanisms for the pathogenesis of ALS. Nuclear-factor erythroid 2-related factor 2 (Nrf2) is a master transcriptional regulator of many cytoprotective genes. Nrf2 signal pathway could induce a series of antioxidant enzyme, anti-inflammatory and antitoxic protein. The expression of these antioxidant enzymes and antioxidant proteins in nervous system exhibited broad neuroprotection against injury by glutamate. Diallyl trisulfide (DATS) was previously shown to induce many Nrf2 target genes in non-nervous cells. Our studies have shown that DATS at 50 microM caused activation of Nrf2 and Nrf2 target gene in rat spinal cord explants. DATS also protected motor neurons against glutamate-induced excitotoxicity. These have identified DATS as a promising neuroprotective agent and suggest that the activation of Nrf2 signal pat |
| September 2nd, 2008 BAG1 promotes axonal outgrowth and regeneration in vivo via Raf-1 and reduction of ROCK activity. Improved survival of injured neurons and the inhibition of repulsive environmental signalling are prerequisites for functional regeneration. BAG1 (Bcl-2-associated athanogene-1) is an Hsp70/Hsc70-binding protein, which has been shown to suppress apoptosis and enhance neuronal differentiation. We investigated BAG1 as a therapeutic molecule in the lesioned visual system in vivo. Using an adeno-associated viral vector, BAG1 (AAV.BAG1) was expressed in retinal ganglion cells (RGC) and then tested in models of optic nerve axotomy and optic nerve crush. BAG1 significantly increased RGC survival as compared to adeno-associated viral vector enhanced green fluorescent protein (AAV.EGFP) treated controls and this was independently confirmed in transgenic mice over-expressing BAG1 in neurons. The numbers and lengths of regenerating axons after optic nerve crush were also significantly increased in the AAV.BAG1 group. In pRGC cultures, BAG1-over-expression resulted in a approximately 3-fold increase in neurite length and |
| August 28th, 2008 Tail Regeneration in Xenopus laevis as a Model for Understanding Tissue Repair Augmentation of regenerative ability is a powerful strategy being pursued for the biomedical management of traumatic injury, cancer, and degeneration. While considerable attention has been focused on embryonic stem cells, it is clear that much remains to be learned about how somatic cells may be controlled in the adult organism. The tadpole of the frog Xenopus laevis is a powerful model system within which fundamental mechanisms of regeneration are being addressed. The tadpole tail contains spinal cord, muscle, vasculature, and other terminally differentiated cell types and can fully regenerate itself through tissue renewal—a process that is most relevant to mammalian healing. Recent insight into this process has uncovered fascinating molecular details of how a complex appendage senses injury and rapidly repairs the necessary morphology. Here, we review what is known about the chemical and bioelectric signals underlying this process and draw analogies to evolutionarily conserved pathways in other patterning s |
| August 28th, 2008 Reggies/flotillins regulate cytoskeletal remodeling during neuronal differentiation via CAP/ponsin and Rho GTPases The reggies/flotillins were discovered as proteins upregulated during axon regeneration. Here, we show that expression of a trans-negative reggie-1/flotillin-2 deletion mutant, R1EA, which interferes with oligomerization of the reggies/flotillins, inhibited insulin-like growth factor (IGF)-induced neurite outgrowth in N2a neuroblastoma cells and impaired in vitro differentiation of primary rat hippocampal neurons. Cells expressing R1EA formed only short and broad membrane protrusions often with abnormally large growth cones. R1EA expression strongly perturbed the balanced activation of the Rho-family GTPases Rac1 and cdc42. Furthermore, focal adhesion kinase (FAK) activity was also enhanced by R1EA expression, while other signaling pathways like ERK1/2, PKC or PKB signaling were unaffected. These severe signaling defects were caused by an impaired recruitment of the reggie/flotillin-associated adaptor molecule CAP/ponsin to focal contacts at the plasma membrane. Thus, the reggies/flotillins are crucial for co |
| August 28th, 2008 A quantitative ELISA for bioactive anti-Nogo-A, a promising regenerative molecule for spinal cord injury repair. The detection and quantification of bioactive anti-Nogo-A mAb, which is of interest for the treatment of spinal cord injury, has previously been accomplished using cellular or indirect immunoassays. In one such assay the presence of Nogo-A inhibits neurite outgrowth from the PC12 neuronal cell line: pre-treatment with anti-Nogo-A overcomes this inhibition and the concentration of anti-Nogo-A is correlated with the reduction in growth inhibition. In the current work we demonstrate the first anti-Nogo-A sandwich ELISA utilizing a Nogo-A fragment in the role of capture agent and the anti-Nogo-A mAb 11c7 as the soluble analyte. Because the Nogo-A fragment contains the amino acid sequence against which 11c7 was raised, we postulate this combination reproduces the native binding mechanism and results in the detection of bioactive anti-Nogo-A. In support of this hypothesis, we have found good agreement between the inhibitory action of the Nogo-A fragment and myelin proteins used in existing PC12 cell assays. Importa |
| August 28th, 2008 LIM-Only-Protein 4 (LMO4) interacts directly with the RGM A Receptor Neogenin. RGM A (Repulsive Guidance Molecule A) was recently described as a potent inhibitor of neuroregeneration in a rat spinal cord injury model. The receptor mediating RGM A's repulsive activity was shown to be Neogenin, a member of the Deleted in Colorectal Cancer (DCC) family of netrin receptors. Binding of RGM A to Neogenin induces activation of the small GTPase RhoA and of its effector Rho-kinase by an unknown mechanism. Here we show, that the cytoplasmic tail of Neogenin interacts directly with the transcriptional coactivator LIM domain only 4 (LMO4) in human SH-SY5Y cells, human Ntera neurons, and in embryonic rat cortical neurons. RGM A binding to Neogenin but not binding of Netrin-1, induces release of LMO4 from Neogenin. Downregulation of LMO4 neutralizes the repulsive activity of RGM A in neuronal cell lines and embryonic rat cortical neurons and prevents RhoA activation. These results show for the first time that an interaction of Neogenin with LMO4 is involved in the RGM A - Neogenin signal transduction |
| August 20th, 2008 Critical Role of Acrolein in Secondary Injury Following Ex Vivo Spinal Cord Trauma The pathophysiology of spinal cord injury (SCI) is characterized by the initial, primary injury followed by secondary injury processes in which oxidative stress is a critical component. Secondary injury processes not only exacerbate pathology at the site of primary injury, but also result in spreading of injuries to the adjacent, otherwise healthy tissue. The lipid peroxidation byproduct acrolein has been implicated as one potential mediator of secondary injury. In order to further and rigorously elucidate the role of acrolein in secondary injury, a unique ex vivo model is utilized to isolate the detrimental effects of mechanical injury from toxins such as acrolein that are produced endogenously following SCI. We demonstrate that: 1) acrolein-lys adducts are capable of diffusing from compressed tissue to adjacent, otherwise uninjured tissue; 2) secondary injury by itself produces significant membrane damage and increased superoxide production; and 3) these injuries are significantly attenuated by the acrolein |
| August 20th, 2008 Neuroprotective effects of erythropoietin posttreatment against kainate-induced excitotoxicity in mixed spinal cultures. Although the neuroprotective effects of erythropoietin (EPO) preconditioning are well known, the potential of postapplied EPO to protect neurons against excitotoxic injury has not been clearly established. Here we show that kainate (KA)-induced excitotoxicity, which plays a key role in secondary spinal cord injury, decreased neuron survival, inhibited neurite extension, and significantly reduced the expression of erythropoietin receptors (EpoR) in cultured spinal neurons. Posttreatment with EPO for 48 hr protected neurons against KA-induced injury, opposing KA-induced apoptosis and promoting regrowth of motoneuron neurites. These neuroprotective effects were paralleled by a restoration of EpoR expression. The importance of the EpoR signaling pathway was demonstrated using an EpoR blocking antibody, which neutralized the neuroprotective action of EPO posttreatment and prevented EPO-induced increases in EpoR expression. We also found that up-regulated EpoR stimulated the Janus kinase 2 (JAK2) pathway, which is |
| August 16th, 2008 Repulsive Wnt signaling inhibits axon regeneration after CNS injury. Failure of axon regeneration in the mammalian CNS is attributable in part to the presence of various inhibitory molecules, including myelin-associated proteins and proteoglycans enriched in glial scars. Here, we evaluate whether axon guidance molecules also regulate regenerative growth after injury in adulthood. Wnts are a large family of axon guidance molecules that can attract ascending axons and repel descending axons along the length of the developing spinal cord. Their expression (all 19 Wnts) is not detectable in normal adult spinal cord by in situ hybridization. However, three of them are clearly reinduced after spinal cord injury. Wnt1 and Wnt5a, encoding potent repellents of the descending corticospinal tract (CST) axons, were robustly and acutely induced broadly in the spinal cord gray matter after unilateral hemisection. Ryk, the conserved repulsive Wnt receptor, was also induced in the lesion area, and Ryk immunoreactivity was found on the lesioned CST axons. Wnt4, which attracts ascending sensory |
| August 15th, 2008 Treatment of chronic thoracic spinal cord injury patients with autologous Schwann cell transplantation: An interim report on safety considerations and possible outcomes Several experimental studies have introduced Schwann cell transplantation as a means of recovery in animal models of spinal cord injury (SCI). The reported promising results together with the availability of autologous sources for Schwann cells indicate Schwann cell transplantation as a possible treatment for SCI. To address the safety and feasibility concerns we report 1-year follow-up of four patients aged between 22 and 43 years who had stable chronic (28–80 months) spinal cord injury at mid-thoracic level and treated with autologous Schwann cell transplantation. Purified Schwann cells used for transplantation were acquired from autologous sural nerve and cultured without the use of any specific mitogenic or growth factors. The patients were evaluated by means of American Spinal Injury Association (ASIA) criteria, sphincter, sexual function and Magnetic Resonance Imaging assessments for 1 year after transplantation. None of the patients were found to have any adverse effects indicating transfer of infectio |
| August 15th, 2008 A novel purification method for CNS projection neurons leads to the identification of brain vascular cells as a source of trophic support for corticospinal motor neurons One of the difficulties in studying cellular interactions in the CNS is the lack of effective methods to purify specific neuronal populations of interest. We report the development of a novel purification scheme, cholera toxin beta (CTB) immunopanning, in which a particular CNS neuron population is selectively labeled via retrograde axonal transport of the cell-surface epitope CTB, and then purified via immobilization with anti-CTB antibody. We have demonstrated the usefulness and versatility of this method by purifying both retinal ganglion cells and corticospinal motor neurons (CSMNs). Genomic expression analyses of purified CSMNs revealed that they express significant levels of many receptors for growth factors produced by brain endothelial cells; three of these factors, CXCL12, pleiotrophin, and IGF2 significantly enhanced purified CSMN survival, similar to previously characterized CSMN trophic factors BDNF and IGF1. In addition, endothelial cell conditioned medium significantly promoted CSMN neurite outg |
| August 8th, 2008 Autologous olfactory ensheathing cell transplantation in human paraplegia: a 3-year clinical trial Olfactory ensheathing cells show promise in preclinical animal models as a cell transplantation therapy for repair of the injured spinal cord. This is a report of a clinical trial of autologous transplantation of olfactory ensheathing cells into the spinal cord in six patients with complete, thoracic paraplegia. We previously reported on the methods of surgery and transplantation and the safety aspects of the trial 1 year after transplantation. Here we address the overall design of the trial and the safety of the procedure, assessed during a period of 3 years following the transplantation surgery. All patients were assessed at entry into the trial and regularly during the period of the trial. Clinical assessments included medical, psychosocial, radiological and neurological, as well as specialized tests of neurological and functional deficits (standard American Spinal Injury Association and Functional Independence Measure assessments). Quantitative test included neurophysiological tests of sensory and motor f |
| August 6th, 2008 Intraspinal microinjection of chondroitinase ABC following injury promotes axonal regeneration out of a peripheral nerve graft bridge. Chondroitin sulfate proteoglycans (CSPG) within the glial scar formed after central nervous system (CNS) injury are thought to play a crucial role in regenerative failure. We previously showed that delivery of the CSPG-digesting enzyme chondroitinase ABC (ChABC) via an osmotic minipump allowed axonal regeneration and functional recovery in a peripheral nerve graft (PNG)-bridging model. In this study, we sought to overcome the technical limitations associated with minipumps by microinjecting ChABC directly into the distal lesion site in the PN bridging model. Microinjection of ChABC immediately rostral and caudal to an injury site resulted in extensive CSPG digestion. We also demonstrate that this delivery technique is relatively atraumatic and does not result in a noticeable inflammatory response. Importantly, microinjections of ChABC into the lesion site permitted more regenerating axons to exit a PNG and reenter spinal cord tissue than saline injections. These results are similar to our previous findings wh |
| August 6th, 2008 Pursuing a 'turning point' in growth cone research. Growth cones are highly motile structures found at the leading edge of developing and regenerating nerve processes. Their role in axonal pathfinding has been well established and many guidance cues that influence growth cone behavior have now been identified. Many studies are now providing insights into the transduction and integration of signals in the growth cone, though a full understanding of growth cone behavior still eludes us. This review focuses on recent studies adding to the growing body of literature on growth cone behavior, focusing particularly on the level of autonomy the growth cone possesses and the role of local protein synthesis. |
| August 6th, 2008 Ceramide is responsible for the failure of compensatory nerve sprouting in apolipoprotein E knock-out mice Apolipoprotein E (apoE) is a key transporter of the cholesterol and phospholipids required for membrane synthesis and nerve growth. We now report a virtual absence in apoE knock-out (KO) mice of normal nerve growth factor (NGF)-driven compensatory sprouting of undamaged cutaneous nociceptive nerves. In contrast, NGF-independent regeneration of crushed axons was unaffected. Essentially similar results came from aged wild-type mice. In apoE KO mice, the endogenous sprouting stimulus was suspect, because NGF administration induced normal sprouting; nevertheless, NGF increased normally in denervated skin, transported normally in the axons, and led to phosphorylation of trkA, erk1, and erk2. However, sprouting was restored in apoE KO mice (although not in aged mice) by fumonisin B1, an inhibitor of ceramide synthesis. A shotgun analysis revealed a wide array of changes in individual ceramide species in DRG neurons of apoE KO mice, and the changes for ceramide species OH_N15:0 made it a candidate inhibitor of sprou |
| July 31st, 2008 Treatment of chronic thoracic spinal cord injury patients with autologous Schwann cell transplantation: An interim report on safety considerations and possible outcomes. Several experimental studies have introduced Schwann cell transplantation as a means of recovery in animal models of spinal cord injury (SCI). The reported promising results together with the availability of autologous sources for Schwann cells indicate Schwann cell transplantation as a possible treatment for SCI. To address the safety and feasibility concerns we report 1-year follow-up of four patients aged between 22 and 43 years who had stable chronic (28-80 months) spinal cord injury at mid-thoracic level and treated with autologous Schwann cell transplantation. Purified Schwann cells used for transplantation were acquired from autologous sural nerve and cultured without the use of any specific mitogenic or growth factors. The patients were evaluated by means of American Spinal Injury Association (ASIA) criteria, sphincter, sexual function and Magnetic Resonance Imaging assessments for 1 year after transplantation. None of the patients were found to have any adverse effects indicating transfer of infectio |
| July 29th, 2008 Spinal activation of the cAMP-PKA pathway induces respiratory motor recovery following high cervical spinal cord injury. The present study investigated the involvement of the adenosine 3'5'-cyclic monophosphate-dependent protein kinase A (cAMP-PKA) pathway in the activation of the crossed-phrenic pathways after left C2 spinal cord hemisection. Experiments were conducted on left C2 spinal cord hemisected, anesthetized, vagotomized, pancuronium paralyzed, and artificially ventilated male Sprague-Dawley rats. One week post-injury, the ipsilateral phrenic nerve exhibited no respiratory-related activity indicating a functionally complete hemisection. Intrathecal spinal cord administration of the cAMP analog, 8-Br-cAMP at the level of the phrenic nucleus resulted in an enhancement of contralateral phrenic nerve output and a restoration of respiratory-related activity in the phrenic nerve ipsilateral to the hemisection. Furthermore, pre-treatment with Rp-8-Br-cAMP, a PKA inhibitor, abolished the effects of 8-Br-cAMP. These results suggest that PKA activation is necessary for the cAMP-mediated respiratory recovery following high cervic |
| July 29th, 2008 Directed differentiation of hippocampal stem/progenitor cells in the adult brain Adult neurogenesis is a lifelong feature of brain plasticity; however, the potency of adult neural stem/progenitor cells in vivo remains unclear. We found that retrovirus-mediated overexpression of a single gene, the bHLH transcription factor Ascl1, redirected the fate of the proliferating adult hippocampal stem/progenitor (AHP) progeny and lead to the exclusive generation of cells of the oligodendrocytic lineage at the expense of newborn neurons, demonstrating that AHPs in the adult mouse brain are not irrevocably specified in vivo. These data indicate that AHPs have substantial plasticity, which might have important implications for the potential use of endogenous AHPs in neurological disease. |
| July 29th, 2008 Decorin promotes robust axon growth on inhibitory CSPGs and myelin via a direct effect on neurons Inhibitory chondroitin sulfate proteoglycans (CSPGs) and myelin-associated molecules are major impediments to axon regeneration within the adult central nervous system (CNS). Decorin infusion can however suppress the levels of multiple inhibitory CSPGs and promote axon growth across spinal cord injuries [Davies, J.E., Tang, X., Denning, J.W., Archibald, S.J., and Davies, S.J., 2004. Decorin suppresses neurocan, brevican, phosphacan and NG2 expression and promotes axon growth across adult rat spinal cord injuries. Eur. J. Neurosci. 19, 1226-1242]. A question remained as to whether decorin can also increase axon growth on inhibitory CSPGs and myelin via a direct effect on neurons. We have therefore conducted an in vitro analysis of neurite extension by decorin-treated adult dorsal root ganglion (DRG) neurons cultured on substrates of inhibitory CSPGs or myelin membranes mixed with laminin. Decorin treatment promoted 14.5 and 5-fold increases in average neurite length/neuron over untreated controls on CSPGs or m |
| July 24th, 2008 Treatment of chronic spinal cord injured patients with autologous bone marrow-derived hematopoietic stem cell transplantation: 1-year follow-up. Background Transplanted bone marrow (BM) cells have been found to improve neurologic disease in central nervous system (CNS) injury models by generating neural cells or myelin-producing cells. The results in treated patients and animal models suggest that BM cells could potentially be used as a therapy for spinal cord injury (SCI) patients. Methods Nine patients with chronic complete SCI with American Spinal Injury Association (ASIA) Impairment Scale (ASIA) grade A were included in this study. They were treated with autologous BM-derived hematopoietic progenitor stem cell transplantation without any serious complications. All patients completed the protocols successfully. Results Three weeks after the operation all patients' movements and sensations were improved. All patients had ASIA grade B or C after the operation. Discussion We used autologous hematopoietic progenitor stem cells in order to avoid the problems associated with immunologic rejection and graft-versus-host (GvH) reactions, which are frequentl |
| July 23rd, 2008 Allen Institute for Brain Science Unveils World's First Genome-Wide Spinal Cord Atlas. The Allen Institute for Brain Science today unveiled the groundbreaking Allen Spinal Cord Atlas, the world’s first genome-wide map of the mouse spinal cord. Researchers can immediately access the free online data to advance their research surrounding spinal cord diseases and disorders. |
| July 22nd, 2008 Directed Evolution of Motor Neurons from Genetically Engineered Neural Precursors. Stem cell-based therapies hold therapeutic promise for degenerative motor neuron diseases such as amyotrophic lateral sclerosis and for spinal cord injury. Fetal neural progenitors present less risk of tumor formation than embryonic stem (ES) cells but inefficiently differentiate into motor neurons, in line with their low expression of motor neuron-specific transcription factors and poor response to soluble external factors. To overcome this limitation, we genetically engineered fetal rat spinal cord neurospheres to express the transcription factors HB9, Nkx6.1 and Ngn2. Enforced expression of the three factors rendered neural precursors responsive to sonic hedgehog and retinoic acid and directed their differentiation into cholinergic motor neurons that projected axons and formed contacts with co-cultured myotubes. When transplanted in the injured adult rat spinal cord, a model of acute motor neuron degeneration, the engineered precursors transiently proliferated, colonized the ventral horn, expressed motor n |
| July 15th, 2008 Blocking connexin43 expression reduces inflammation and improves functional recovery after spinal cord injury After traumatic CNS injury, a cascade of secondary events expands the initial lesion. The gap-junction protein connexin43 (Cx43), which is transiently up-regulated, has been implicated in the spread of 'bystander' damage. We have used an antisense oligodeoxynucleotide (asODN) to suppress Cx43 up-regulation in two rat models of spinal cord injury. Within 24h of compression injury, rats treated with Cx43-asODN scored higher than sense-ODN and vehicle-treated controls on behavioural tests of locomotion. Their spinal cords showed less swelling and tissue disruption, less up-regulation of astrocytic GFAP, and less extravasation of fluorescently-labelled bovine serum albumin and neutrophils. The locomotor improvement was sustained over at least 4weeks. Following partial spinal cord transection, Cx43-asODN treatment reduced GFAP immunoreactivity, neutrophil recruitment, and the activity of OX42(+) microglia in and around the lesion site. Cx43 has many potential roles in the pathophysiology of CNS injury and may be a |
| July 15th, 2008 Carbamylated erythropoietin to treat neuronal injury: new development strategies Carbamylated erythropoietin (CEPO) is a modified erythropoietin molecule not affecting hematocrit. It is a potentially important pharmacological agent that may be applied to the treatment of several diseases affecting central and peripheral system neurons. Objective: Carbamylated erythropoietin is a prime candidate for development because of its potent cell survival and function enhancing effects. This article reviews the preclinical development profile of CEPO in animal models to determine whether further clinical development is justified. Methods: The review spans a detailed analysis of patents and scientific publications related to CEPO in animal models. Results/conclusions: Use of CEPO in treating diseases such as stroke and traumatic brain and spinal cord injuries is important because these conditions affect millions of patients every year. Extensive preclinical studies support further clinical studies of CEPO for acute ischemic stroke. However, further studies are required for testing CEPO in patients w |
| July 15th, 2008 Single, High-Dose Intraspinal Injection of Chondroitinase Reduces Glycosaminoglycans in Injured Spinal Cord and Promotes Corticospinal Axonal Regrowth after Hemisection but Not Contusion Chondroitin sulfate proteoglycans (CSPGs) inhibit axonal growth, and treatment with chondroitinase ABC promotes axonal regeneration in some models of central nervous system (CNS) injury. The aims of this study were (1) to compare the spatiotemporal appearance of CSPG expression between spinal cord contusion and hemisection models, and (2) to evaluate chondroitinase treatment effects on axonal regrowth in the two injury models. After hemisection, CSPG-immunoreactivity (IR) in the injury site rose to peak levels at 18 days but then decreased dramatically by 49 days; in contrast, CSPG-IR remained high for at least 49 days after contusion. After hemisection, many anterogradely labeled corticospinal tract (CST) axons remained close to CSPG-rich lesion sites, but after contusion, most CST axons retracted by approximately 1 mm rostral from the rostral-most CSPG-rich cyst. Intraspinal injection of chondroitinase at 0, 1, 2, and 4 weeks following injury dramatically reduced CSPG-IR in both injury models within 4 days, |
| July 15th, 2008 Regeneration of nigrostriatal dopaminergic axons after transplantation of olfactory ensheathing cells and fibroblasts prevents fibrotic scar formation at the lesion site. The fibrotic scar formed after central nervous system injury has been considered an obstacle to axonal regeneration. The present study was designed to examine whether cell transplantation into a damaged central nervous system can reduce fibrotic scar formation and promote axonal regeneration. Nigrostriatal dopaminergic axons were unilaterally transected in rats and cultures of olfactory-ensheathing cells (OECs), and olfactory nerve fibroblasts were transplanted into the lesion site. In the absence of transplants, few tyrosine hydroxylase-immunoreactive axons extended across the lesion 2 weeks after the transection. Reactive astrocytes increased around the lesion, and a fibrotic scar containing type IV collagen deposits developed in the lesion center. The immunoreactivity of chondroitin sulfate side chains and core protein of NG2 proteoglycan increased in and around the lesion. One and 2 weeks after transection and simultaneous transplantation, dopaminergic axons regenerated across the transplanted tissues, wh |
| July 15th, 2008 Comparative gene expression profiling of olfactory ensheathing glia and Schwann cells indicates distinct tissue repair characteristics of olfactory ensheathing glia. Olfactory ensheathing glia (OEG) are a specialized type of glia that support the growth of primary olfactory axons from the neuroepithelium in the nasal cavity to the brain. Transplantation of OEG in the injured spinal cord promotes sprouting of injured axons and results in reduced cavity formation, enhanced axonal and tissue sparing, remyelination, and angiogenesis. Gene expression analysis may help to identify the molecular mechanisms underlying the ability of OEG to recreate an environment that supports regeneration in the central nervous system. Here, we compared the transcriptome of cultured OEG (cOEG) with the transcriptomes of cultured Schwann cells (cSCs) and of OEG directly obtained from their natural environment (nOEG), the olfactory nerve layer of adult rats. Functional data mining by Gene Ontology (GO)-analysis revealed a number of overrepresented GO-classes associated with tissue repair. These classes include "response to wounding," "blood vessel development," "cell adhesion," and GO-classes rela |
| July 15th, 2008 Semaphorin signaling: progress made and promises ahead. Semaphorins were initially characterized according to their role in repulsive axon guidance but are now recognized as crucial regulators of morphogenesis and homeostasis over a wide range of organ systems. The pleiotropic nature of semaphorin signaling and its implication in human disease has triggered an enormous interest in the receptor and intracellular signaling mechanisms that direct the cell-type-specific and diverse biological effects of semaphorins. Recent breakthroughs in our understanding of semaphorin signaling link integrin and semaphorin signaling pathways, identify novel ligand-receptor interactions and provide insight into the cellular and molecular bases of bifunctional and reverse signaling events. These discoveries could lead to therapeutic advances in axonal regeneration, cancer and other diseases |
| July 7th, 2008 BrainStorm study positive for spinal cord injuries. BrainStorm Cell Therapeutics Inc., a leading developer of adult stem cell technologies and therapeutics, has completed a preclinical study in collaboration with the W.M. Keck Center for Collaborative Neuroscience at Rutgers, The State University of New Jersey. The study conducted at the Keck Center was an effort to repair spinal cord injuries in animals through the transplantation of Brainstorm’s neurotrophic factor (NTF) adult stem cells. The results showed a positive trend of the NTF cells in the male animals. |
| June 26th, 2008 BioArctic Neuroscience and Swenora Biotech Enter into Exclusive Licensing Agreement for a Novel Treatment of Spinal Cord Injury. To promote nerve grafting procedures, a biodegradable device has been constructed where peripheral nerves are inserted together with a growth factor. The device is used during the neurosurgical procedure, when injured tissue is replaced, to connect viable nerves on each side of the injured segment. The procedure aims at rerouting regenerative pathways with multiple neuronal autografts and promoting the outgrowth of neurites. |
| June 24th, 2008 Stable in vivo imaging of densely populated glia, axons and blood vessels in the mouse spinal cord using two-photon microscopy. In vivo imaging has revolutionized our understanding of biological processes in brain physiology and pathology. However, breathing-induced movement artifacts have impeded the application of this powerful tool in studies of the living spinal cord. Here we describe in detail a method to image stably and repetitively, using two-photon microscopy, the living spinal tissue in mice with dense fluorescent cells or axons, without the need for animal intubation or image post-processing. This simplified technique can greatly expand the application of in vivo imaging to study spinal cord injury, regeneration, physiology and disease. |
| June 19th, 2008 Synapse Biomedical Receives FDA Approval of NeuRx Diaphragm Pacing System For Spinal Cord Injury Breathing Applications PRNewswire-Synapse Biomedical Inc. announced today it has received approval from the U.S. Food and Drug Administration (FDA) for its NeuRx DPS(TM) for ventilator-dependent Spinal Cord Injury (SCI) patients who lack voluntary control of their diaphragms. With the FDA's approval, SCI patients and their caregivers throughout the U.S. can now access this technology that was previously only available to clinical trial participants. |
| June 18th, 2008 Development of Polymeric Nerve Guidance Conduits That Contain Anisotropic Cues Including Aligned Microfibers and Gradients of Adsorbed Laminin-1 Structures that direct neurite extension are important for regeneration following spinal cord injury and peripheral nerve injury. Within the spinal cord, neurons encounter a glial scar environment that impedes regeneration. In the peripheral nervous system, endogenous regeneration cannot occur across nerve gaps greater than 2 mm. Current repair strategies use guidance conduits to channel axonal growth towards distal targets. While showing promise, conduit walls do not provide a suitable environment for neuronal attachment or extension, and axonal growth within conduits remains tortuous. Hence, there is a need for development of three-dimensional (3D) structures that use contact guidance—rather than confinement—as a means of guided regeneration. Our laboratory has developed aligned, electrospun fiber matrices that have been shown to direct neurite extension in vitro. In addition, a gradient of the glycoprotein laminin-1 has been adsorbed onto aligned microfiber matrices to stimulate directional growth. These |
| June 18th, 2008 Biocompatible hydrogels in spinal cord injury repair Spinal cord injury results in a permanent neurological deficit due to tissue damage. Such a lesion is a barrier for "communication" between the brain and peripheral tissues, effectors as well as receptors. One of the primary goals of tissue engineering is to bridge the spinal cord injury and re-establish the damaged connections. Hydrogels are biocompatible implants used in spinal cord injury repair. They can create a permissive environment and bridge the lesion cavities by providing a scaffold for the regeneration of neurons and their axons, glia and other tissue elements. The advantage of using artificial materials is the possibility to modify their physical and chemical properties in order to develop the best implant suitable for spinal cord injury repair. As a result, several types of hydrogels have been tested in experimental studies so far. We review our work that has been done during the last 5 years with various types of hydrogels and their applications in experimental spinal cord injury repair. |
| June 18th, 2008 Acute and delayed implantation of positively charged 2-hydroxyethyl methacrylate scaffolds in spinal cord injury in the rat. OBJECT: Hydrogels are nontoxic, chemically inert synthetic polymers with a high water content and large surface area that provide mechanical support for cells and axons when implanted into spinal cord tissue. METHODS: Macroporous hydrogels based on 2-hydroxyethyl methacrylate (HEMA) were prepared by radical copolymerization of monomers in the presence of fractionated NaCl particles. Male Wistar rats underwent complete spinal cord transection at the T-9 level. To bridge the lesion, positively charged HEMA hydrogels were implanted either immediately or 1 week after spinal cord transection; control animals were left untreated. Histological evaluation was performed 3 months after spinal cord transection to measure the volume of the pseudocyst cavities and the ingrowth of tissue elements into the hydrogels. |
| June 12th, 2008 Geron working with FDA to remove hold on IND application for HESC clinical trial. While speaking at the recent Needham & Company Biotechnology and Medical Technology Conference, Geron President and CEO Thomas Okarma stated that Geron is working with the FDA to resolve the issues concerning the hold on Geron's IND application of GRNOPC1 for the treatment of spinal cord injury. Okarma stated that the company still hopes to begin clinical trials later this year. |
| June 5th, 2008 Bioengineering neural stem/progenitor cell-coated tubes for spinal cord injury repair. The aim of this study was to understand the survival and differentiation of neural stem/progenitor cells (NSPCs) cultured on chitosan matrices in vivo in a complete transection model of spinal cord injury. |
| May 31st, 2008 Cell fate: The path to neurogenesis In mice, oxidative conditions increase the interaction between the histone deacetylase Sirt1 and the transcription factor Hes1, which represses expression of the pro-neuronal-fate transcription factor Mash1 and promotes differentiation of neural progenitor cells. |
| May 29th, 2008 Spontaneous regeneration of intrinsic spinal cord axons in a novel spinal cord slice culture model Until now no spinal cord slice culture model for the study of axonal growth has been available. Here we present a spinal cord slice culture model that is well suited for the study of axonal growth. |
| April 29th, 2008 Effect of weight-bearing activities on bone mineral density in spinal cord injured patients during the period of the first two years Objectives: To evaluate the loss of bone mineral density (BMD) in various body regions of patients with spinal cord injury (SCI) and its dependence on weight bearing activities during 2 years post injury |
| March 19th, 2008 Biotechnology company Mapreg announces its lead compound, MAP4343, has been granted orphan drug status for the treatment of spinal cord injury. MAP4343 is patent-protected and has an identified and validated molecular target, namely Microtubule Associated Protein type 2 (MAP2). The product’s main advantage resides in its efficiency when administered by peripheral injection up to 24 hours after the trauma. The results of studies on animal models yielded so far are unmatched elsewhere. Regulatory preclinical studies will be completed shortly (having shown no significant signs of toxicity so far) and a Phase I clinical trial could be initiated towards the end of 2008. Company website www.mapreg.com |
| March 3rd, 2008 Nerve repair using acidic fibroblast growth factor in human cervical spinal cord injury: a preliminary Phase I clinical study. Object The aim of this study was to assess functional outcomes of nerve repair using acidic fibroblast growth factor (FGF) in patients with cervical spinal cord injury (SCI). Methods Nine patients who had cervical SCI for longer than 5 months were included in pre- and postoperative assessments of their neurological function. The assessments included evaluating activities of daily living, associated functional ability, and degree of spasticity, motor power, sensation, and pain perception. After the first set of assessments, the authors repaired the injured segment of the spinal cord using a total laminectomy followed by the application of fibrin glue containing acidic FGF. |
| March 3rd, 2008 Cyberkinetics Andara OFS Therapy Featured in Presentations at the AANS/CNS Meeting Researchers report that people with spinal cord injuries treated with Cyberkinetics Andara OFS System showed significantly greater neurological improvement than those in a separate study who received no therapy for their spinal cord injuries. |
| February 28th, 2008 Distinct cellular and molecular mechanisms mediate initial axon development and adult-stage axon regeneration in C. elegans. The molecular and cellular mechanisms that allow adult-stage neurons to regenerate following damage are poorly understood. Recently, axons of motoneurons and mechanosensory neurons in adult C. elegans were found to regrow after being snipped by femtosecond laser ablation. Here, we explore the molecular determinants of adult-stage axon regeneration using the AVM mechanosensory neurons. The first step in AVM axon development is a pioneer axonal projection from the cell body to the ventral nerve cord. We show that regeneration of the AVM axon to the ventral nerve cord lacks the deterministic precision of initial axon development, requiring competition and pruning of unwanted axon branches. Nevertheless, axons of injured AVM neurons regrow to the ventral nerve cord with over 60% reliability in adult animals. In addition, in contrast to initial development, axon guidance during regeneration becomes heavily dependent on cytoplasmic protein MIG-10/Lamellipodin but independent of UNC-129/TGF-beta repellent and UNC-40 |
| February 28th, 2008 FGF-2-treatment improves locomotor function via axonal regeneration in the transected rat spinal cord We examined the effects on locomotor function of the FGF-2 injected into the completely transected rat spinal cord. The locomotor function of the FGF-2-treated animals was substantially recovered up to extent where the joint of the hind limb moves 6 weeks after transection, but the recovery was not seen at all on the locomotor activity of the vehicle-treated animals. |
| February 26th, 2008 StemCyte Expands Support of World Renowned Spinal Cord Injury Researcher Through Agreement with Rutgers University NEW YORK, Feb. 26 /PRNewswire/ -- StemCyte Inc. and Rutgers, The State University of New Jersey, today announced at the Stem Cell Summit that they have entered into a research and licensing agreement for a spinal cord injury therapy being developed by Wise Young, M.D., Ph.D., that uses StemCyte's proprietary human umbilical cord blood (UCB) stem cells in conjunction with lithium. |
| February 20th, 2008 Researchers Map Signaling Networks that Control Neuron Function In the first large-scale proteomics study of its kind, researchers at the University of California, San Diego (UCSD) School of Medicine have mapped thousands of neuronal proteins to discover how they connect into complex signaling networks that guide neuron function. Their research – using quantitative mass spectrometry, computational software and bioinformatics to match the proteins to their cellular functions – may lead to a better understanding of brain development, neurodegenerative diseases, and spinal cord regeneration. |
| February 13th, 2008 Greatly improved neurological outcome after spinal cord compression injury in AQP4-deficient mice. Aquaporin-4 (AQP4) is a water channel protein expressed in astrocytes throughout the CNS. In brain, AQP4 facilitates water balance and glial scar formation, which are important determinants of outcome after injury. Here, we provide evidence for AQP4-dependent spinal cord swelling following compression injury, resulting in remarkably improved outcome in AQP4-null mice. Two days after transient T6 spinal cord compression injury, wild-type mice developed more severe hindlimb weakness than AQP4-null mice, as assayed by the Basso open-field motor score, inclined plane method and footprint analysis. Basso motor scores were 1.3 +/- 0.5 (wild-type) versus 4.9 +/- 0.6 (AQP4-null) (SE, P < 0.001). Improved motor outcome in AQP4-null mice was independent of mouse strain and persisted at least 4 weeks. AQP4-null mice also had improved sensory outcome at 2 days, as assessed by spinal somatosensory evoked responses, with signal amplitudes approximately 10 muV (uninjured), 1.7 +/- 0.7 muV (wild-type) and 6.4 +/- 1.3 muV (AQ |
| February 11th, 2008 Acute and delayed implantation of positively charged 2-hydroxyethyl methacrylate scaffolds in spinal cord injury in the rat Hydrogels are nontoxic, chemically inert synthetic polymers with a high water content and large surface area that provide mechanical support for cells and axons when implanted into spinal cord tissue. |
| February 6th, 2008 Functional MRI of the brain detects neuropathic pain in experimental spinal cord injury. Functional magnetic resonance imaging (fMRI) has been used to map cerebral activations related to nociceptive stimuli in rodents. Here, we used fMRI to investigate abnormally increased responses to noxious or innocuous stimuli, in a well-established rat model of chronic neuropathic pain induced by photochemical lumbar spinal cord injury. In this model, a subpopulation of rats exhibits allodynia-like hypersensitivity to mechanical and cold stimulation of the trunk area. In those rats that do not develop overt hypersensitivity after identical spinal cord injury (i.e. non-hypersensitive rats), touch evoked pain can be triggered by the opioid receptor antagonist, naloxone. We show that cerebral activations in contralateral primary somatosensory cortex (SI) are markedly correlated with different behavioural characteristics of these animals. Identical electrical stimulation, applied on trunks of spinally injured hypersensitive and non-hypersensitive rats, evoked significantly higher responses in SI of the former th |
| February 1st, 2008 Actin-binding proteins take the reins in growth cones Higher-order actin-based networks (actin superstructures) are important for growth-cone motility and guidance. Principles for generating, organizing and remodelling actin superstructures have emerged from recent findings in cell-free systems, non-neuronal cells and growth cones. This Review examines how actin superstructures are initiated de novo at the leading-edge membrane and how the spontaneous organization of actin superstructures is driven by ensembles of actin-binding proteins. How the regulation of actin-binding proteins can affect growth-cone turning and axonal regeneration is also discussed. |
| February 1st, 2008 Microfluidic-based Strip Assay for Testing the Effects of Various Surface-bound Inhibitors in Spinal Cord Injury Here we introduce a microfluidic-based strip assay that utilizes cultures of dissociated neurons to model the organized structure of the spinal cord, such as spatial separation of the axonal extensions from the cell bodies. Utilizing this technology, we have demonstrated preferential attachment of the cell bodies to a homogeneous healthy substrate (PLL/Laminin) while the axons are exposed to the inhibitor molecules presented to them in alternating strips. The reproducible in-vitro assay, herein described, is simple and straightforward such that it can be readily adapted by the SCI research community and can provide a platform for comparing results across laboratories. |
| February 1st, 2008 Clinical studies in spinal cord injury: moving towards successful trials Spinal cord injury is a devastating condition for which there is still no cure. Many new therapies have emerged in the past few decades that have attempted to improve the outcome after injury, with varying levels of supporting experimental and clinical data. Most studies have been preliminary and have lacked control groups, but positive results can often be embraced by clinicians and patients who are faced without an alternative, despite the poor design and bias of many studies. This article is a review of clinical studies in spinal cord injury and discusses guidelines for future clinical trial design. |
| January 30th, 2008 Christopher and Dana Reeve Foundation awards nearly $2 million in individual research grants The Christopher and Dana Reeve Foundation (CDRF), which is dedicated to curing spinal cord injury by funding innovative research and improving the quality of life for people living with paralysis through grants, information and advocacy, today announced it has awarded $1,996,745 million to 16 laboratories through its Individual Research Grants Program. At the forefront of molecular and cellular studies, CDRF's Individual Research Grant Program is the Foundation's largest, most comprehensive research initiative. The grants awarded today represent an overall $77 million commitment to research by the Foundation since 1982. |
| January 24th, 2008 BMP inhibition enhances axonal growth and functional recovery after spinal cord injury Bone morphogenetic proteins (BMPs) are multifunctional growth factors that belong to the transforming growth factor-β superfamily. BMPs regulate several crucial aspects of embryonic development and organogenesis. The reemergence of BMPs in the injured adult central nervous system suggests their involvement in the pathogenesis of the lesion. Here, we demonstrate that BMPs are potent inhibitors of axonal regeneration in the adult spinal cord. The expression of BMP-2/4 is elevated in oligodendrocytes and astrocytes around the injury site following spinal cord contusion. Intrathecal administration of noggin - a soluble BMP antagonist - leads to enhanced locomotor activity and reveals significant regrowth of the corticospinal tract after spinal cord contusion. Thus, BMPs play a role in inhibiting axonal regeneration and limiting functional recovery following injury to the central nervous system. |
| January 23rd, 2008 The European Human Embryonic Stem Cell Registry The European Human Embryonic Stem Cell Registry gives researchers, regulators and the general public access to broad information about all available human embryonic stem-cell lines developed in Europe and their use. The site went live on January 18th, 2008. |
| January 17th, 2008 Reduction in lung function in chronic spinal cord injury linked to modifiable factors in addition to age |
| November 6th, 2007 Adult spinal cord progenitor cells are repelled by netrin-1 in the embryonic and injured adult spinal cord Adult neural progenitor cells (aNPCs) exhibit limited migration in vivo with the exception of the rostral migratory stream and injury-induced movement. Surprisingly little is known regarding those signals regulating attraction or inhibition of the aNPC. These studies demonstrate that aNPCs respond principally to a repulsive cue expressed at the embryonic floor plate (FP) and also the injured adult CNS. Adult spinal cord progenitor cells (aSCPs) were seeded onto organotypic slice preparations of the intact embryonic or injured adult spinal cord. Cell migration assays combined with genetic and molecular perturbation of FP-derived migration cues or aSCP receptors establish netrin-1 (Ntn-1) but not Slit-2, Shh, or Ephrin-B3 as the primary FP-derived repellant. When slices were prepared from injured spinal cord, aSCP migration away from the injury core was Ntn-1-dependent. These studies establish Ntn-1 as a critical regulator of aSCP migration in the intact and injured CNS. |
| January 8th, 2007 Post-trauma Lipitor treatment prevents endothelial dysfunction, facilitates neuroprotection, and promotes locomotor recovery following spinal cord injury. We have previously reported neuroprotection in spinal cord injury (SCI) by Lipitor [atorvastatin (AT)]-pre-treatment. Though informative, pre-treatment studies find only limited clinical application as trauma occurrence is unpredictable. Therefore, this study investigates the efficacy of AT treatment post-SCI. In a rat model of contusion-SCI resulting in complete hindlimb paralysis, AT treatment (5 mg/kg; gavage) was begun 2, 4, or 6 h post-SCI followed by a once daily dose thereafter for 6 weeks. While the placebo vehicle (VHC)-SCI rats showed substantial functional deficit, AT-SCI animals exhibited significant functional recovery. |
| October 26th, 2006 Reknitting the injured spinal cord by self-assembling peptide nanofiber scaffold In traumatic spinal cord injury, loss of neurological function is due to the inability of damaged axons to regenerate across large, cystic cavities. It has recently been demonstrated that a self-assembled nanofiber scaffold (SAPNS) could repair the injured optical pathway and restore visual function. To demonstrate the possibility of using it to repair spinal cord injury, transplanted neural progenitor cells and Schwann cells were isolated from green fluorescent protein-transgenic rats, cultured within SAPNS, and then transplanted into the transected dorsal column of spinal cord of rats. Here we report the use of SAPNS to bridge the injured spinal cord of rats, demonstrating robust migration of host cells, growth of blood vessels, and axons into the scaffolds, indicating that SAPNS provides a true three-dimensional environment for the migration of living cells. |
| April 26th, 2006 Omega-3 Fatty Acids Improve Recovery, whereas Omega-6 Fatty Acids Worsen Outcome, after Spinal Cord Injury in the Adult Rat This report shows a striking difference in efficacy between the effects of treatment with -3 and -6 PUFAs on the outcome of SCI, with -3 PUFAs being neuroprotective and -6 PUFAs having a damaging effect. Given the proven clinical safety of -3 PUFAs, our observations show that these PUFAs have significant therapeutic potential in SCI. In contrast, the use of preparations enriched in -6 PUFAs after injury could worsen outcome after SCI |
Identifying spinal interneurons critical for locomotor recovery after spinal cord injury
Start Date:2008-01-30
University of Montreal
Primary Investigator:Alain Frigon, Ph.D.
Analysis of LKB1 as a Regulator of Axon Outgrowth
Start Date:2008-01-30
University of North Carolina at Chapel Hill
Primary Investigator:Barnes, Anthony Paul., Ph.D.
Restore continence and micturition after SCI by perigenital electrical stimulation
Start Date:2008-01-30
University of Pittsburgh. Pittsburgh, PA
Primary Investigator:Changfeng Tai Ph.D.
Cortical Control of Intraspinal Stimulation
Start Date:2008-01-30
University of Washington. Seattle, WA
Primary Investigator:Eberhard Erich Fetz, Ph.D
Eph receptors mediate apoptosis following spinal cord injury
Start Date:2008-01-30
University of Miami. Miami, FL.
Primary Investigator:Erik Runko, Ph.D.
Manipulation of endogenous fate-mapped stem cells in the injured spinal cord.
Start Date:2008-01-30
Karolinska Institutet. Stockholm
Primary Investigator:Fanie Barnabé-Heider, Ph.D.
Non-hormonal gender differences in SCI and sulfonylurea therapy
Start Date:2008-01-30
University of Maryland. Baltimore, MD.
Primary Investigator:J. Marc Simard, M.D., Ph.D.
Delivery of proprioceptive feedback from a brain-controlled prosthesis through cortical microstimulation
Start Date:2008-01-30
University of California-Berkeley. Berkeley, CA.
Primary Investigator:Jose M. Carmena, Ph.D.
Interlimb Coordination during Walking Post-SCI
Start Date:2008-01-30
University of Florida. Gainesville, FL.
Primary Investigator:Nicole J. Tester, Ph.D.
Targeting phosphodiesterase isoforms to promote axon regeneration
Start Date:2008-01-30
University of California. Irvine, CA.
Primary Investigator:Oswald Steward, Ph.D.
Microtubule-based method for enhancing axonal regeneration after injury.
Start Date:2008-01-30
Drexel University College of Medicine. Philadelphia, PA.
Primary Investigator:Peter W. Baas, Ph.D.
Assessing Spinal Lesions with Magnetic Resonance Diffusion Tensor Imaging (DTI) in Animal Models
Start Date:2008-01-30
University of Montreal. Montreal, Quebec
Primary Investigator:Serge Rossignol, M.D., Ph.D.
Influence of proprioceptive input on adaptive modifications to flexor muscle activity during walking in people with incomplete SCI
Start Date:2008-01-30
The University of British Columbia. Vancouver, BC Canada
Primary Investigator:Tania Lam, Ph.D.
Functional regeneration and sprouting of respiratory pathways after spinal cord injury.
Start Date:2008-01-30
Case Western Reserve University. Cleveland, OH.
Primary Investigator:Warren Joseph Alilain, Ph.D.
Effectiveness of local cooling on enhancing tissue tolerance to loading pressure.
Start Date:2008-01-30
University of Pittsburgh. Pittsburgh, PA.
Primary Investigator:Yih-Kuen Jan, P.T, Ph.D.
Neurotrophins and Function of the Injured Spinal Cord
Start Date:2007-04-01
State University of New York - Stony Brook
Primary Investigator:Victor L. Arvanian, Ph.D.
Manipulation of Glycans in Repair of Spinal Cord Injury
Start Date:2007-04-01
Memorial Sloan-Kettering Center
Primary Investigator:Urs S. Rutishauser, Ph.D.
Decoding Motor Intention from Human Microelectrode Grid Data
Start Date:2007-04-01
Columbia University
Primary Investigator:Ronald G. Emerson, M.D.
Chondroitinase in Treatment of Spinal Cord Injury
Start Date:2007-04-01
Rensselaer Polytechnic Institute
Primary Investigator:Robert J. Linhardt, Ph.D.
Harnessing Corticospinal Activity to Promote Motor Recovery
Start Date:2007-04-01
Columbia University
Primary Investigator:John H. Martin, Ph.D.
Investigation of GDNF in Neural Survival and Maintenance
Start Date:2007-04-01
State University of New York - Buffalo
Primary Investigator:Brian A. Pierchala, Ph.D.
Spontaneous Spreading Depression Enhances Ischemic Spinal Cord Injury
Start Date:2007-04-01
New York Medical College
Primary Investigator:Renato Rozental, M.D., Ph.D.
Aquaporin-4 Water Channels in Spinal Cord Injury
Start Date:2007-04-01
Helen Hayes Hospital
Primary Investigator:Helen E. Scharfman, Ph.D.
Intrinsic neuronal response of propriospinal neurons to SCI
Start Date:2007-04-01
State University of New York - Upstate Medical University
Primary Investigator:Dennis J. Stelzner, Ph.D.
Guided Neuronal and Glial Migration in Electrically Conductive Collagen-Carbon Nanotube Scaffolds
Start Date:2007-04-01
Rensselaer Polytechnic Institute
Primary Investigator:Deanna M. Thompson, Ph.D.
Interactions between Glial Cells in Spinal Cord Injury
Start Date:2007-04-01
University of Rochester
Primary Investigator:Guo-Feng Tian, M.D., Ph.D.
An Integrated Approach to Neural Differentiation of Human Embryonic Stem Cells
Start Date:2006-11-21
Yale University
Primary Investigator:Michael P. Snyder
Directing Production and Functional Integration of Embryonic Stem Cell-Derived Neural Stem Cells
Start Date:2006-11-21
Wesleyan University
Primary Investigator:Laura B. Grabel
Optimizing Axonal Regeneration Using a Polymer Implant Containing hESC-derived Glia
Start Date:2006-11-21
University of Connecticut
Primary Investigator:Akiko Nishiyama
Magnetic Resonance Imaging of Directed Endogenous Neural Progenitor Cell Migration
Start Date:2006-11-21
Yale University School of Medicine
Primary Investigator:Erik Shapiro
Engineering Embryonic Spinal Cord Stem Cells for Spinal Cord Injury
Start Date:2006-01-01
Albany Medical College
Primary Investigator:Sally Temple Ph.D.
Bypassing Spinal Cord Injury to Promote Motor Function
Start Date:2006-01-01
Columbia University
Primary Investigator:John Martin Ph.D.