Dr young....

[Cherry]

Are you familiar with

Cummings, B.J., et al. Human neural stem cells differentiate and promote locomotor recovery in spinal cord-injured mice. 2005. Proc Natl Acad Sci USA.102:14069-14074.

and

Iwanami, A., et al. Transplantation of human neural stem cells for spinal cord injury in primates. 2005. J Neurosci Res. 80:182-190.

As they are new publications I wonder if you could shed some light. I hear Cummings was very successful

TIA, jen

[Wise Young]

cherrylips,

There have been many many neural stem cell therapies of animal spinal cord injury models. Most of the studies are showing some improvements in function in various models but few have shown significant improvements in the contusion model (which is more like the human condition). There is a growing consensus amongst researchers in the field that cell transplants alone are not sufficient to produce substantial recovery and that treatments must include two additional components: continued growth factor secretion and blockade of growth inhibitors such as nogo and chondroitin-6-sulfate proteoglycans (by chondroitinase).

I attach the abstracts of the papers that you mentioned.

Wise.

• Cummings BJ, Uchida N, Tamaki SJ, Salazar DL, Hooshmand M, Summers R, Gage FH and Anderson AJ (2005). Human neural stem cells differentiate and promote locomotor recovery in spinal cord-injured mice. Proc Natl Acad Sci U S A 102: 14069-74. We report that prospectively isolated, human CNS stem cells grown as neurospheres (hCNS-SCns) survive, migrate, and express differentiation markers for neurons and oligodendrocytes after long-term engraftment in spinal cord-injured NOD-scid mice. hCNS-SCns engraftment was associated with locomotor recovery, an observation that was abolished by selective ablation of engrafted cells by diphtheria toxin. Remyelination by hCNS-SCns was found in both the spinal cord injury NOD-scid model and myelin-deficient shiverer mice. Moreover, electron microscopic evidence consistent with synapse formation between hCNS-SCns and mouse host neurons was observed. Glial fibrillary acidic protein-positive astrocytic differentiation was rare, and hCNS-SCns did not appear to contribute to the scar. These data suggest that hCNS-SCns may possess therapeutic potential for CNS injury and disease. Department of Physical Medicine and Rehabilitation, Reeve-Irvine Research Center, University of California, Irvine, CA 92697, USA. cummings@uci.edu http://www.ncbi.nlm.nih.gov/entrez/q..._uids=16172374
  
• Ikegami T, Nakamura M, Yamane J, Katoh H, Okada S, Iwanami A, Watanabe K, Ishii K, Kato F, Fujita H, Takahashi T, Okano HJ, Toyama Y and Okano H (2005). Chondroitinase ABC combined with neural stem/progenitor cell transplantation enhances graft cell migration and outgrowth of growth-associated protein-43-positive fibers after rat spinal cord injury. Eur J Neurosci 22: 3036-46. We previously reported that the transplantation of neural stem/progenitor cells (NSPCs) can contribute to the repair of injured spinal cord in adult rats and monkeys. In some cases, however, most of the transplanted cells adhered to the cavity wall and failed to migrate and integrate into the host spinal cord. In this study we focused on chondroitin sulfate proteoglycan (CSPG), a known constituent of glial scars that is strongly expressed after spinal cord injury (SCI), as a putative inhibitor of NSPC migration in vivo. We hypothesized that the digestion of CSPG by chondroitinase ABC (C-ABC) might promote the migration of transplanted cells and neurite outgrowth after SCI. An in vitro study revealed that the migration of NSPC-derived cells was inhibited by CSPG and that this inhibitory effect was attenuated by C-ABC pre-treatment. Consistently, an in vivo study of C-ABC treatment combined with NSPC transplantation into injured spinal cord revealed that C-ABC pre-treatment promoted the migration of the transplanted cells, whereas CSPG-immunopositive scar tissue around the lesion cavity prevented their migration into the host spinal cord in the absence of C-ABC pre-treatment. Furthermore, this combined treatment significantly induced the outgrowth of a greater number of growth-associated protein-43-positive fibers at the lesion epicentre, compared with NSPC transplantation alone. These findings suggested that the application of C-ABC enhanced the benefits of NSPC transplantation for SCI by reducing the inhibitory effects of the glial scar, indicating that this combined treatment may be a promising strategy for the regeneration of injured spinal cord. Department of Orthopaedic Surgery, Keio University School of Medicine, Tokyo, Japan. http://www.ncbi.nlm.nih.gov/entrez/q..._uids=16367770
  

By the way, here is a partial list of other papers on cell transplantation therapies of spinal cord injury in the last 12 months:

• Cai PQ, Tang X, Lin YQ, Martin O, Sun GY, Xu L, Yang YK and Zhou TH (2006). The experimental study of genetic engineering human neural stem cells mediated by lentivirus to express multigene. Chin J Traumatol 9: 43-9. OBJECTIVE: To explore the feasibility to construct genetic engineering human neural stem cells (hNSCs) mediated by lentivirus to express multigene in order to provide a graft source for further studies of spinal cord injury (SCI). METHODS: Human neural stem cells from the brain cortex of human abortus were isolated and cultured, then gene was modified by lentivirus to express both green fluorescence protein (GFP) and rat neurotrophin-3 (NT-3); the transgenic expression was detected by the methods of fluorescence microscope, dorsal root ganglion of fetal rats and slot blot. RESULTS: Genetic engineering hNSCs were successfully constructed. All of the genetic engineering hNSCs which expressed bright green fluorescence were observed under the fluorescence microscope. The conditioned medium of transgenic hNSCs could induce neurite flourishing outgrowth from dorsal root ganglion (DRG). The genetic engineering hNSCs expressed high level NT-3 which could be detected by using slot blot. CONCLUSIONS: Genetic engineering hNSCs mediated by lentivirus can be constructed to express multigene successfully. Department of Orthopaedics, First People's Hospital of Yibin, Yibin 644000, China. cpq20032002@yahoo.com.cn http://www.ncbi.nlm.nih.gov/entrez/q..._uids=16393516
• Ke Y, Chi L, Xu R, Luo C, Gozal D and Liu R (2005). Early Response of Endogenous Adult Neural Progenitor Cells to Acute Spinal Cord Injury in Mice. Stem Cells Adult neural progenitor cells (NPCs) are an attractive source for functional replacement in neurodegenerative diseases and traumatic injury to the central nervous systems (CNS). It has been shown that transplantation of neural stem cells or NPCs into the lesioned region partially restores CNS function. However, the capacity of endogenous NPCs in replacement of neuronal cell loss and functional recovery of spinal cord injury (SCI) is apparently poor. Furthermore, the temporal and spatial response of endogenous adult NPCs to SCI remains largely undefined. To this end, we have analyzed the early organization, distribution, and potential function of NPCs in response to SCI, using nestin enhancer (promoter) controlled LacZ reporter transgenic mice. We showed that there was an increase of NPC proliferation, migration, and neurogenesis in adult spinal cord after traumatic compression SCI. The proliferation of NPCs detected by BrdU incorporation and LacZ staining was restricted to the ependymal zone (EZ) of the central canal. During acute SCI, NPCs in the EZ of the central canal migrated vigorously toward the dorsal direction, where the compression lesion is generated. The optimal NPC migration occurred in the adjacent region close to the epicenter. More significantly, there was an increased de novo neurogenesis from NPCs 24 hours after SCI. The enhanced proliferation, migration, and neurogenesis of (from) endogenous NPCs in the adult spinal cord in response to SCI suggest a potential role for NPCs in attempting to restore SCImediated neuronal dysfunction. Grand Forks, North Dakota. http://www.ncbi.nlm.nih.gov/entrez/q..._uids=16339643
• Johnson RD (2006). Descending pathways modulating the spinal circuitry for ejaculation: effects of chronic spinal cord injury. Prog Brain Res 152: 415-26. Sexual dysfunction is a common complication in men with chronic spinal cord injury. In particular, ejaculation is severely compromised or absent and the resulting infertility issues are important to this group of predominantly young men. To investigate the neural circuits and descending spinal pathways involved in ejaculation, animal models have been developed in normal and spinal cord-injured preparations. Primarily through studies in rats, spinal ejaculatory circuits have been described including (i) autonomic circuits at the thoracolumbar and lumbosacral levels mediating the emission phase of ejaculation, (ii) somatic circuits at the lumbosacral level controlling the expulsion phase of ejaculation through sequential and rhythmic contraction of perineal striated muscles (e.g. bulbospongiosus), and (iii) a proposed ejaculatory pattern generator in the lumbar cord. Midthoracic incomplete chronic spinal cord injury has revealed the dependency of spinal ejaculatory circuits on bilateral spinal pathways from the brainstem via modulation of pudendal motor neuron reflexes and pudendal nerve autonomic fibers. Accordingly, sensory input from the dorsal nerve of the penis, required to trigger the ejaculatory response in animals and humans, is no longer inhibited from the lateral paragigantocellularis nucleus in the ventrolateral medulla. This inhibitory effect, likely presynaptic through a serotonergic pathway, is thought to be necessary to provide the rhythmic, bursting, and sequential contractions of the perineal muscles during ejaculation. Chronic lateral hemisection injury, which severs half of the descending lateral funiculus-located pathways, results in new functional connections of the pudendal reflex inhibitory and pudendal sympathetic activation pathways across the midline, above and below the lesion, respectively. Clinical correlations in spinal cord-injured men have demonstrated the validity of the rodent animal for the study of ejaculatory dysfunction after chronic injury. Department of Physiological Sciences, College of Veterinary Medicine and the McKnight Brain Institute, University of Florida, Gainesville, FL 32610-0144, USA. johnson@ufi.ufl.edu http://www.ncbi.nlm.nih.gov/entrez/q..._uids=16198717
• Howard MJ, Liu S, Schottler F, Joy Snider B and Jacquin MF (2005). Transplantation of apoptosis-resistant embryonic stem cells into the injured rat spinal cord. Somatosens Mot Res 22: 37-44. Murine embryonic stem cells were induced to differentiate into neural lineage cells by exposure to retinoic acid. Approximately one million cells were transplanted into the lesion site in the spinal cords of adult rats which had received moderate contusion injuries 9 days previously. One group received transplants of cells genetically modified to over-express bcl-2, which codes for an anti-apoptotic protein. A second group received transplants of the wild-type ES cells from which the bcl-2 line was developed. In the untransplanted control group, only medium was injected. Locomotor abilities were assessed using the Basso, Beattie and Bresnahan (BBB) rating scale for 6 weeks. There was no incremental locomotor improvement in either transplant group when compared to control over the survival period. Morbidity and mortality were significantly more prevalent in the transplant groups than in controls. At the conclusion of the 6-week survival period, the spinal cords were examined. Two of six cords from the bcl-2 group and one of 12 cords from the wild-type group showed gross evidence of abnormal growths at the site of transplantation. No similar growth was seen in the control. Pathological examination of the abnormal cords showed very large numbers of undifferentiated cells proliferating at the injection site and extending up to 1.5 cm rostrally and caudally. These results suggest that transplanting KD3 ES cells, or apoptosis-resistant cells derived from the KD3 line, into the injured spinal cord does not improve locomotor recovery and can lead to tumor-like growth of cells, accompanied by increased debilitation, morbidity and mortality. Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA. howardm@neuro.wustl.edu http://www.ncbi.nlm.nih.gov/entrez/q..._uids=16191756
• Okada S, Ishii K, Yamane J, Iwanami A, Ikegami T, Katoh H, Iwamoto Y, Nakamura M, Miyoshi H, Okano HJ, Contag CH, Toyama Y and Okano H (2005). In vivo imaging of engrafted neural stem cells: its application in evaluating the optimal timing of transplantation for spinal cord injury. Faseb J 19: 1839-41. Neural stem/progenitor cells (NSPCs) hold promise in neural tissue replacement therapy after spinal cord injury. However, understanding the survival time of grafted NSPCs and determining the extent of migration away from transplantation sites are essential for optimizing treatment regimens. Here, we used in vivo bioluminescence imaging to noninvasively assess the survival and residence time of transplanted NSPCs at the injury sites in living animals, and we used histologic analyses to assess cell integration and morphology. Third-generation lentiviral vectors enabled efficient transduction and stable expression of both luciferase and a variant of green fluorescent protein in primary cultured NSPCs. Signals from these cells were detectable for up to 10 months or more after transplantation into the injured spinal cords of C57BL/6J mice. Histological and functional data supported the imaging data and suggest that the timing of NSPC transplantation may be a key determinant of the fates and function of integrated cells since cell survival and migration depended on the time of transplantation relative to injury. Optimization of cell therapies can be greatly accelerated and refined by imaging, and the methods in the present study can be widely applied to various research fields of regeneration medicine, including transplantation study. Department of Physiology, Keio University School of Medicine, Shinjuku, Tokyo, Japan. http://www.ncbi.nlm.nih.gov/entrez/q..._uids=16141363
• Enzmann GU, Benton RL, Woock JP, Howard RM, Tsoulfas P and Whittemore SR (2005). Consequences of noggin expression by neural stem, glial, and neuronal precursor cells engrafted into the injured spinal cord. Exp Neurol 195: 293-304. Bone morphogenetic proteins (BMPs) are a large class of secreted factors, which serve as modulators of development in multiple organ systems, including the CNS. Studies investigating the potential of stem cell transplantation for restoration of function and cellular replacement following traumatic spinal cord injury (SCI) have demonstrated that the injured adult spinal cord is not conducive to neurogenesis or oligodendrogenesis of engrafted CNS precursors. In light of recent findings that BMP expression is modulated by SCI, we hypothesized that they may play a role in lineage restriction of multipotent grafts. To test this hypothesis, neural stem or precursor cells were engineered to express noggin, an endogenous antagonist of BMP action, prior to transplantation or in vitro challenge with recombinant BMPs. Adult rats were subjected to both contusion and focal ischemic SCI. One week following injury, the animals were transplanted with either EGFP- or noggin-expressing neural stem or precursor cells. Results demonstrate that noggin expression does not antagonize terminal astroglial differentiation in the engrafted stem cells. Furthermore, neutralizing endogenous BMP in the injured spinal cord significantly increased both the lesion volume and the number of infiltrating macrophages in injured spinal cords receiving noggin-expressing stem cell grafts compared with EGFP controls. These data strongly suggest that endogenous factors in the injured spinal microenvironment other than the BMPs restrict the differentiation of engrafted pluripotent neural stem cells as well as suggest other roles for BMPs in tissue protection in the injured CNS. Kentucky Spinal Cord Injury Research Center (KSCIRC), 511 South Floyd Street, MDR 617, Louisville, KY 40202, USA. http://www.ncbi.nlm.nih.gov/entrez/q..._uids=16087174
• Cao Q, Xu XM, Devries WH, Enzmann GU, Ping P, Tsoulfas P, Wood PM, Bunge MB and Whittemore SR (2005). Functional recovery in traumatic spinal cord injury after transplantation of multineurotrophin-expressing glial-restricted precursor cells. J Neurosci 25: 6947-57. Demyelination contributes to the physiological and behavioral deficits after contusive spinal cord injury (SCI). Therefore, remyelination may be an important strategy to facilitate repair after SCI. We show here that rat embryonic day 14 spinal cord-derived glial-restricted precursor cells (GRPs), which differentiate into both oligodendrocytes and astrocytes, formed normal-appearing central myelin around axons of cultured DRG neurons and had enhanced proliferation and survival in the presence of neurotrophin 3 (NT3) and brain-derived neurotrophin factor (BDNF). We infected GRPs with retroviruses expressing the multineurotrophin D15A (with both BDNF and NT3 activities) and then transplanted them into the contused adult thoracic spinal cord at 9 d after injury. Expression of D15A in the injured spinal cord is five times higher in animals receiving D15A-GRP grafts than ones receiving enhanced green fluorescent protein (EGFP)-GRP or DMEM grafts. Six weeks after transplantation, the grafted GRPs differentiated into mature oligodendrocytes expressing both myelin basic protein (MBP) and adenomatus polyposis coli (APC). Ultrastructural analysis showed that the grafted GRPs formed morphologically normal-appearing myelin sheaths around the axons in the ventrolateral funiculus (VLF) of spinal cord. Expression of D15A significantly increased the percentage of APC+ oligodendrocytes of grafted GRPs (15-30%). Most importantly, 8 of 12 rats receiving grafts of D15A-GRPs recovered transcranial magnetic motor-evoked potential responses, indicating that conduction through the demyelinated VLF axons was restored. Such electrophysiological recovery was not observed in rats receiving grafts of EGFP-GRPs, D15A-NIH3T3 cells, or an injection of an adenovirus expressing D15A. Recovery of hindlimb locomotor function was also significantly enhanced only in the D15A-GRP-grafted animals at 4 and 5 weeks after transplantation. Therefore, combined treatment with neurotrophins and GRP grafts can facilitate functional recovery after traumatic SCI and may prove to be a useful therapeutic strategy to repair the injured spinal cord. Kentucky Spinal Cord Injury Research Center, University of Louisville, Louisville, Kentucky 40202, USA. http://www.ncbi.nlm.nih.gov/entrez/q..._uids=16049170
• Azari MF, Profyris C, Zang DW, Petratos S and Cheema SS (2005). Induction of endogenous neural precursors in mouse models of spinal cord injury and disease. Eur J Neurol 12: 638-48. Adult neural precursor cells (NPCs) in the mammalian central nervous system (CNS) have been demonstrated to be responsive to conditions of injury and disease. Here we investigated the response of NPCs in mouse models of spinal cord disease [motor neuron disease (MND)] with and without sciatic nerve axotomy, and spinal cord injury (SCI). We found that neither axotomy, nor MND alone brought about a response by Nestin-positive NPCs. However, the combination of the two resulted in mobilization of NPCs in the spinal cord. We also found that there was an increase in the number of NPCs following SCI which was further enhanced by systemic administration of the neuregulatory cytokine, leukaemia inhibitory factor (LIF). NPCs were demonstrated to differentiate into astrocytes in axotomized MND mice. However, significant differentiation into the various neural cell phenotypes was not demonstrated at 1 or 2 weeks following SCI. These data suggest that factors inherent to injury mechanisms are required for induction of an NPC response in the mammalian spinal cord. Department of Anatomy and Cell Biology, Faculty of Medicine, Monash University, Clayton, Australia. http://www.ncbi.nlm.nih.gov/entrez/q..._uids=16053474
• Kuh SU, Cho YE, Yoon DH, Kim KN and Ha Y (2005). Functional recovery after human umbilical cord blood cells transplantation with brain-derived neutrophic factor into the spinal cord injured rat. Acta Neurochir (Wien) 147: 985-92. There have been many efforts to recover neuronal function from spinal cord injuries, but there are some limitations in the treatment of spinal cord injuries.The neural stem cell has been noted for its pluripotency to differentiate into various neural cell types. The human umbilical cord blood cells (HUCBs) are more pluripotent and genetically flexible than bone marrow neural stem cells. The HUCBs could be more frequently used for spinal cord injury treatment in the future.Moderate degree spinal cord injured rats were classified into 3 subgroups, group A: media was injected into the cord injury site, group B: HUCBs were transplanted into the cord injury site, and group C: HUCBs with BDNF (Brain-derived neutrophic factor) were transplanted into the cord injury site. We checked the BBB scores to evaluate the functional recovery in each group at 8 weeks after transplantation. We then, finally checked the neural cell differentiation with double immunofluorescence staining, and we also analyzed the axonal regeneration with retrograde labelling of brain stem neurons by using fluorogold. The HUCBs transplanted group improved, more than the control group at every week after transplantation, and also, the BDNF enabled an improvement of the BBB locomotion scores since the 1 week after its application (P<0.05). 8 weeks after transplantation, the HUCBs with BDNF transplanted group had more greatly improved BBB scores, than the other groups (P<0.001). The transplanted HUCBs were differentiated into various neural cells, which were confirmed by double immunoflorescence staining of BrdU and GFAP & MAP-2 staining. The HUCBs and BDNF each have individual positive effects on axonal regeneration. The HUCBs can differentiate into neural cells and induce motor function improvement in the cord injured rat models. Especially, the BDNF has effectiveness for neurological function improvement due to axonal regeneration in the early cord injury stage. Thus the HUCBs and BDNF have recovery effects of a moderate degree for cord injured rats. Department of Neurosurgery, Yonsei University College of Medicine, Seoul, Korea. http://www.ncbi.nlm.nih.gov/entrez/q..._uids=16010451
• Nakamura M, Okano H, Toyama Y, Dai HN, Finn TP and Bregman BS (2005). Transplantation of embryonic spinal cord-derived neurospheres support growth of supraspinal projections and functional recovery after spinal cord injury in the neonatal rat. J Neurosci Res 81: 457-68. Great interest exists in using cell replacement strategies to repair the damaged central nervous system. Previous studies have shown that grafting rat fetal spinal cord into neonate or adult animals after spinal cord injury leads to improved anatomic growth/plasticity and functional recovery. It is clear that fetal tissue transplants serve as a scaffold for host axon growth. In addition, embryonic Day 14 (E14) spinal cord tissue transplants are also a rich source of neural-restricted and glial-restricted progenitors. To evaluate the potential of E14 spinal cord progenitor cells, we used in vitro-expanded neurospheres derived from embryonic rat spinal cord and showed that these cells grafted into lesioned neonatal rat spinal cord can survive, migrate, and differentiate into neurons and oligodendrocytes, but rarely into astrocytes. Synapses and partially myelinated axons were detected within the transplant lesion area. Transplanted progenitor cells resulted in increased plasticity or regeneration of corticospinal and brainstem-spinal fibers as determined by anterograde and retrograde labeling. Furthermore, transplantation of these cells promoted functional recovery of locomotion and reflex responses. These data demonstrate that progenitor cells when transplanted into neonates can function in a similar capacity as transplants of solid fetal spinal cord tissue. Department of Neuroscience, Georgetown University Medical Center, Washington, DC 20007, USA. http://www.ncbi.nlm.nih.gov/entrez/q..._uids=15968644
• Lepore AC, Bakshi A, Swanger SA, Rao MS and Fischer I (2005). Neural precursor cells can be delivered into the injured cervical spinal cord by intrathecal injection at the lumbar cord. Brain Res 1045: 206-16. Neural precursor cells (NPCs) are promising grafts for treatment of traumatic CNS injury and neurodegenerative disorders because of their potential to differentiate into neurons and glial cells. When designing clinical protocols for NPC transplantation, it is important to develop alternatives to direct parenchymal injection, particularly at the injury site. We reasoned that since it is minimally invasive, intrathecal delivery of NPCs at lumbar spinal cord (lumbar puncture) represents an important and clinically applicable strategy. We tested this proposition by examining whether NPCs can be delivered to the injured cervical spinal cord via lumbar puncture using a mixed population of neuronal-restricted precursors (NRPs) and glial-restricted precursors (GRPs). For reliable tracking, the NPCs were derived from the embryonic spinal cord of transgenic donor rats that express the marker gene, human placental alkaline phosphatase, under the control of the ubiquitous Rosa 26 promoter. We found that mixed NRP/GRP grafts can be efficiently delivered to a cervical hemisection injury site by intrathecal delivery at the lumbar cord. Similar to direct parenchymal injections, transplanted NRP/GRP cells survive at the injury cavity for at least 5 weeks post-engraftment, migrate into intact spinal cord along white matter tracts and differentiate into all three mature CNS cell types, neurons, astrocytes, and oligodendrocytes. Furthermore, very few graft-derived cells localize to areas outside the injury site, including intact spinal cord and brain. These results demonstrate the potential of delivering lineage-restricted NPCs using the minimally invasive lumbar puncture method for the treatment of spinal cord injury. Department of Neurobiology and Anatomy, 2900 Queen Lane, Drexel University College of Medicine, Philadelphia, PA 19129, USA. http://www.ncbi.nlm.nih.gov/entrez/q..._uids=15910779
• Lepore AC and Fischer I (2005). Lineage-restricted neural precursors survive, migrate, and differentiate following transplantation into the injured adult spinal cord. Exp Neurol 194: 230-42. Fetal spinal cord from embryonic day 14 (E14/FSC) has been used for numerous transplantation studies of injured spinal cord. E14/FSC consists primarily of neuronal (NRP)- and glial (GRP)-restricted precursors. Therefore, we reasoned that comparing the fate of E14/FSC with defined populations of lineage-restricted precursors will test the in vivo properties of these precursors in CNS and allow us to define the sequence of events following their grafting into the injured spinal cord. Using tissue derived from transgenic rats expressing the alkaline phosphatase (AP) marker, we found that E14/FSC exhibited early cell loss at 4 days following acute transplantation into a partial hemisection injury, but the surviving cells expanded to fill the entire injury cavity by 3 weeks. E14/FSC grafts integrated into host tissue, differentiated into neurons, astrocytes, and oligodendrocytes, and demonstrated variability in process extension and migration out of the transplant site. Under similar grafting conditions, defined NRP/GRP cells showed excellent survival, consistent migration out of the injury site and robust differentiation into mature CNS phenotypes, including many neurons. Few immature cells remained at 3 weeks in either grafts. These results suggest that by combining neuronal and glial restricted precursors, it is possible to generate a microenvironmental niche where emerging glial cells, derived from GRPs, support survival and neuronal differentiation of NRPs within the non-neurogenic and non-permissive injured adult spinal cord, even when grafted into acute injury. Furthermore, the NRP/GRP grafts have practical advantages over fetal transplants, making them attractive candidates for neural cell replacement. Department of Neurobiology and Anatomy, 2900 Queen Lane, Drexel University College of Medicine, Philadelphia, PA 19129, USA. http://www.ncbi.nlm.nih.gov/entrez/q..._uids=15899260
• Xiao M, Klueber KM, Lu C, Guo Z, Marshall CT, Wang H and Roisen FJ (2005). Human adult olfactory neural progenitors rescue axotomized rodent rubrospinal neurons and promote functional recovery. Exp Neurol 194: 12-30. Previously, our lab reported the isolation of patient-specific neurosphere-forming progenitor lines from human adult olfactory epithelium from cadavers as well as patients undergoing nasal sinus surgery. RT-PCR and ELISA demonstrated that the neurosphere-forming cells (NSFCs) produced BDNF. Since rubrospinal tract (RST) neurons have been shown to respond to exogenous BNDF, it was hypothesized that if the NSFCs remained viable following engraftment into traumatized spinal cord, they would rescue axotomized RS neurons from retrograde cell atrophy and promote functional recovery. One week after a partial cervical hemisection, GFP-labeled NSFCs suspended in Matrigel matrix or Matrigel matrix alone was injected into the lesion site. GFP-labeled cells survived up to 12 weeks in the lesion cavity or migrated within the ipsilateral white matter; the apparent number and mean somal area of fluorogold (FG)-labeled axotomized RST neurons were greater in the NSFC-engrafted rats than in lesion controls. Twelve weeks after engraftment, retrograde tracing with FG revealed that some RST neurons regenerated axons 4-5 segments caudal to the engraftment site; anterograde tracing with biotinylated dextran amine confirmed regeneration of RST axons through the transplants within the white matter for 3-6 segments caudal to the grafts. A few RST axons terminated in gray matter close to motoneurons. Matrix alone did not elicit regeneration. Behavioral analysis revealed that NSFC-engrafted rats displayed better performance during spontaneous vertical exploration and horizontal rope walking than lesion Matrigel only controls 11 weeks post transplantation. These results emphasize the unique potential of human olfactory neuroepithelial-derived progenitors as an autologous source of stem cells for spinal cord repair. Department of Anatomical Sciences and Neurobiology, School of Medicine, University of Louisville, Louisville, KY 40292, USA. http://www.ncbi.nlm.nih.gov/entrez/q..._uids=15899240
• Zeng YS, Ding Y, Wu LZ, Guo JS, Li HB, Wong WM and Wu WT (2005). Co-transplantation of schwann cells promotes the survival and differentiation of neural stem cells transplanted into the injured spinal cord. Dev Neurosci 27: 20-6. The present study investigates whether Schwann cells (SCs) could promote the survival and differentiation of neural stem cells in the injured spinal cord. Neural stem cells were dissociated and cloned from the hippocampal tissue of newborn rats. SCs were also dissociated and purified simultaneously from the sciatic nerves of 4-day-old rats. The results showed that the number of surviving neural stem cells and differentiated neuron-like cells was significantly increased in the co-grafted (SCs and neural stem cells) group compared with the control group (neural stem cells only). Neuron-like cells that developed axon-like processes were observed more commonly in the co-grafted group. These results demonstrate that SCs can promote the survival and differentiation of transplanted neural stem cells in the injured spinal cord. Division of Neuroscience, Department of Histology and Embryology, Zhongshan Medical College, Sun Yat-Sen University at Guangzhou, Guangzhou, China. http://www.ncbi.nlm.nih.gov/entrez/q..._uids=15886481
• Hasegawa K, Chang YW, Li H, Berlin Y, Ikeda O, Kane-Goldsmith N and Grumet M (2005). Embryonic radial glia bridge spinal cord lesions and promote functional recovery following spinal cord injury. Exp Neurol 193: 394-410. Radial glial cells are neural stem cells (NSC) that are transiently found in the developing CNS. To study radial glia, we isolated clones following immortalization of E13.5 GFP rat neurospheres with v-myc. Clone RG3.6 exhibits polarized morphology and expresses the radial glial markers nestin and brain lipid binding protein. Both NSC and RG3.6 cells migrated extensively in the adult spinal cord. However, RG3.6 cells differentiated into astroglia slower than NSC, suggesting that immortalization can delay differentiation of radial glia. Following spinal cord contusion, implanted RG3.6 cells migrated widely in the contusion site and into spared white matter where they exhibited a highly polarized morphology. When injected immediately after injury, RG3.6 cells formed cellular bridges surrounding spinal cord lesion sites and extending into spared white matter regions in contrast to GFP fibroblasts that remained in the lesion site. Behavioral analysis indicated higher BBB scores in rats injected with RG3.6 cells than rats injected with fibroblasts or medium as early as 1 week after injury. Spinal cords transplanted with RG3.6 cells or dermal fibroblasts exhibited little accumulation of chondroitin sulfate proteoglycans (CSPG) including NG2 proteoglycans that are known to inhibit axonal growth. Reduced levels of CSPG were accompanied by little accumulation in the injury site of activated macrophages, which are a major source of CSPG. However, increased staining and organization of neurofilaments were found in injured rats transplanted with RG3.6 cells suggesting neuroprotection or regrowth. The combined results indicate that acutely transplanted radial glia can migrate to form bridges across spinal cord lesions in vivo and promote functional recovery following spinal cord injury by protecting against macrophages and secondary damage. W. M. Keck Center for Collaborative Neuroscience, 604 Allison Road, Rutgers, State University of New Jersey, Piscataway, NJ 08854-8082, USA. http://www.ncbi.nlm.nih.gov/entrez/q..._uids=15869942
• Regala C, Duan M, Zou J, Salminen M and Olivius P (2005). Xenografted fetal dorsal root ganglion, embryonic stem cell and adult neural stem cell survival following implantation into the adult vestibulocochlear nerve. Exp Neurol 193: 326-33. Sensorineural hearing loss is a disabling condition. In the post-embryonic and adult mammalian inner ear, the regeneration of auditory hair cells, spiral ganglion neurons or their axons does not occur naturally. This decrease in excitable neurons limits the success of auditory rehabilitation. Allografts and xenografts have shown promise in the treatment of a variety of neurological diseases. Fetal dorsal root ganglion (DRG) neurons can extend functional connections in the rat spinal cord. Embryonic stem cells (ES cells) and adult neural stem cells (ANSC) have the potential to differentiate into neurons. We have implanted embryonic days (E) 13-16 fetal mouse DRGs from transgenic mouse lines that express Enhanced Green Fluorescent Protein (EGFP) or lacZ reporter genes, EGFP-expressing ES cells or lacZ-expressing ANSC into the injured vestibulocochlear nerve of adult rats and guinea pigs. Survival of the implants was assessed 2 to 4 weeks postoperatively. For further evaluation of the differentiation of the implanted ES-cells, we double labeled with the mouse-specific neuronal antibody Thy 1.2. The rats implanted with EGFP- or lacZ-expressing DRGs showed labeled DRGs after sacrifice. In addition, EGFP-positive nerve fibers were seen growing within the proximal nerve. The results from the EGFP ES cells and lacZ ANSC revealed reporter-expressing cells at the site of injection in the vestibulocochlear nerve of the host rats and guinea pigs but also within the brain stem. Thy 1.2 profiles were seen among the EGFP ES cells within the 8th cranial nerve. The findings of this study indicate that the vestibulocochlear nerve of adult rats and guinea pigs will support xenotransplants of embryonic DRG, ES cells and ANSC. This may have future clinical applicability in recreating a neuronal conduit following neuronal injury between the inner ear and the central nervous system (CNS). Department of Clinical Neuroscience, Section of Otorhinolaryngology, Karolinska Institutet, Karolinska Hospital, PO Box SE-171 76 Stockholm, Sweden. http://www.ncbi.nlm.nih.gov/entrez/q..._uids=15869935
• Sigurjonsson OE, Perreault MC, Egeland T and Glover JC (2005). Adult human hematopoietic stem cells produce neurons efficiently in the regenerating chicken embryo spinal cord. Proc Natl Acad Sci U S A 102: 5227-32. Hematopoietic stem cells (HSCs) have been proposed as a potential source of neural cells for use in repairing brain lesions, but previous studies indicate a low rate of neuronal differentiation and have not provided definite evidence of neuronal phenotype. To test the neurogenic potential of human HSCs, we implanted CD34+ HSCs from adult human bone marrow into lesions of the developing spinal cord in the chicken embryo and followed their differentiation by using immunohistochemistry, retrograde labeling, and electrophysiology. We find that human cells derived from the implanted population express the neuronal markers NeuN and MAP2 at substantially higher rates than previously reported. We also find that these cells exhibit neuronal cytoarchitecture, extend axons into the ventral roots or several segments in length within the spinal white matter, are decorated with synaptotagmin+ and GABA+ synaptic terminals, and exhibit active membrane properties and spontaneous synaptic potentials characteristic of functionally integrated neurons. Neuronal differentiation is accompanied by loss of CD34 expression. Careful examination with confocal microscopy reveals no signs of heterokaryons, and human cells never express a chicken-specific antigen, suggesting that fusion with host chicken cells is unlikely. We conclude that the microenvironment in the regenerating spinal cord of the chicken embryo stimulates substantial proportions of adult human HSCs to differentiate into full-fledged neurons. This may open new possibilities for a high-yield production of neurons from a patient's own bone marrow. Institute of Immunology, Rikshospitalet University Hospital and University of Oslo Rikshospitalet, 0027 Oslo, Norway. http://www.ncbi.nlm.nih.gov/entrez/q..._uids=15790679
• Iwanami A, Kaneko S, Nakamura M, Kanemura Y, Mori H, Kobayashi S, Yamasaki M, Momoshima S, Ishii H, Ando K, Tanioka Y, Tamaoki N, Nomura T, Toyama Y and Okano H (2005). Transplantation of human neural stem cells for spinal cord injury in primates. J Neurosci Res 80: 182-90. Recent studies have shown that delayed transplantation of neural stem/progenitor cells (NSPCs) into the injured spinal cord can promote functional recovery in adult rats. Preclinical studies using nonhuman primates, however, are necessary before NSPCs can be used in clinical trials to treat human patients with spinal cord injury (SCI). Cervical contusion SCIs were induced in 10 adult common marmosets using a stereotaxic device. Nine days after injury, in vitro-expanded human NSPCs were transplanted into the spinal cord of five randomly selected animals, and the other sham-operated control animals received culture medium alone. Motor functions were evaluated through measurements of bar grip power and spontaneous motor activity, and temporal changes in the intramedullary signals were monitored by magnetic resonance imaging. Eight weeks after transplantation, all animals were sacrificed. Histologic analysis revealed that the grafted human NSPCs survived and differentiated into neurons, astrocytes, and oligodendrocytes, and that the cavities were smaller than those in sham-operated control animals. The bar grip power and the spontaneous motor activity of the transplanted animals were significantly higher than those of sham-operated control animals. These findings show that NSPC transplantation was effective for SCI in primates and suggest that human NSPC transplantation could be a feasible treatment for human SCI. Department of Physiology, Keio University School of Medicine, Shinjuku, Tokyo, Japan. http://www.ncbi.nlm.nih.gov/entrez/q..._uids=15772979
• Kulbatski I, Mothe AJ, Nomura H and Tator CH (2005). Endogenous and exogenous CNS derived stem/progenitor cell approaches for neurotrauma. Curr Drug Targets 6: 111-26. Neural stem/progenitor cells capable of generating new neurons and glia, reside in specific areas of the adult mammalian central nervous system (CNS), including the ependymal region of the spinal cord and the subventricular zone (SVZ), hippocampus, and dentate gyrus of the brain. Much is known about the neurogenic regions in the CNS, and their response to various stimuli including injury, neurotrophins (NFs), morphogens, and environmental factors like learning, stress, and aging. This work has shaped our current views about the CNS's potential to recover lost tissue and function post-traumatically and the therapies to support the intrinsic regenerative capacity of the brain or spinal cord. Recently, intensive research has explored the potential of harvesting, culturing, and transplanting neural stem/progenitors as a therapeutic intervention for spinal cord injury (SCI) and traumatic brain injury (TBI). Another strategy has focused on maximizing the potential of this endogenous population of cells by stimulating their recruitment, proliferation, migration, and differentiation in vivo following traumatic lesions to the CNS. The promise of such experimental treatments has prompted tissue and biomaterial engineers to implant synthetic three-dimensional biodegradable scaffolds seeded with neural stem/progenitors into CNS lesions. Although there is no definitive answer about the ideal cell type for transplantation, strong evidence supports the use of region specific neural stem/progenitors. The technical and logistic considerations for transplanting neural stem/progenitors are extensive and crucial to optimizing and maintaining cell survival both before and after transplantation, as well as for tracking the fate of transplanted cells. These issues have been systematically addressed in many animal models, that has improved our understanding and approach to clinical therapeutic paradigms. Toronto Western Hospital, 399 Bathurst Street McLaughlin Pavilion #12-423, Toronto, Ontario, M5T-2S8, Canada. http://www.ncbi.nlm.nih.gov/entrez/q..._uids=15720218
• Schultz SS (2005). Adult stem cell application in spinal cord injury. Curr Drug Targets 6: 63-73. The mechanical force incurred by spinal cord injury results in degenerative neural tissue damage beyond the site of initial injury. By nature, the central nervous system (CNS) does not regenerate itself. Cell therapy, in particular, stem cell implantation has become a possible solution for spinal cord injury. Embryonic stem cells and fetal stem cells are the forefathers of the field of stem cell therapy. Isolation and preparation of specific populations of adult stem cells have evolved to the point of stable, long-term culturing with the capability to differentiate into neural phenotypes from all three of the neural lineages: neurons, astrocytes, and oligodendrocytes. Thus, adult stem cells will transcend ethical concerns, technical difficulties, and probably immunorejection. A variety of adult stem cells have been implanted in a rat model of spinal cord injury, ranging from olfactory ensheathing cells, cultured spinal cord stem cells, bone marrow derived stem cells, dermis derived stem cells, and a few others. Although no definite decisions on which adult stem cells are most effective for this CNS injury, their ability to incorporate into the spinal cord, differentiate, and to improve locomotor recovery hold promise for a cure. Department of Neuroscience, Albert Einstein School of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA. sherrischultz5000@yahoo.com http://www.ncbi.nlm.nih.gov/entrez/q..._uids=15720214
• Reier PJ (2004). Cellular transplantation strategies for spinal cord injury and translational neurobiology. NeuroRx 1: 424-51. Basic science advances in spinal cord injury and regeneration research have led to a variety of novel experimental therapeutics designed to promote functionally effective axonal regrowth and sprouting. Among these interventions are cell-based approaches involving transplantation of neural and non-neural tissue elements that have potential for restoring damaged neural pathways or reconstructing intraspinal synaptic circuitries by either regeneration or neuronal/glial replacement. Notably, some of these strategies (e.g., grafts of peripheral nerve tissue, olfactory ensheathing glia, activated macrophages, marrow stromal cells, myelin-forming oligodendrocyte precursors or stem cells, and fetal spinal cord tissue) have already been translated to the clinical arena, whereas others have imminent likelihood of bench-to-bedside application. Although this progress has generated considerable enthusiasm about treating what once was thought to be a totally incurable condition, there are many issues to be considered relative to treatment safety and efficacy. The following review reflects on different experimental applications of intraspinal transplantation with consideration of the underlying pathological, pathophysiological, functional, and neuroplastic responses to spinal trauma that such treatments may target along with related issues of procedural and biological safety. The discussion then moves to an overview of ongoing and completed clinical trials to date. The pros and cons of these endeavors are considered, as well as what has been learned from them. Attention is primarily directed at preclinical animal modeling and the importance of patterning clinical trials, as much as possible, according to laboratory experiences. College of Medicine and McKnight Brain Institute, University of Florida, Gainesville, Florida 32610, USA. reier@mbi.ufl.edu http://www.ncbi.nlm.nih.gov/entrez/q..._uids=15717046
• Hofstetter CP, Holmstrom NA, Lilja JA, Schweinhardt P, Hao J, Spenger C, Wiesenfeld-Hallin Z, Kurpad SN, Frisen J and Olson L (2005). Allodynia limits the usefulness of intraspinal neural stem cell grafts; directed differentiation improves outcome. Nat Neurosci 8: 346-53. Several studies have reported functional improvement after transplantation of neural stem cells into injured spinal cord. We now provide evidence that grafting of adult neural stem cells into a rat thoracic spinal cord weight-drop injury improves motor recovery but also causes aberrant axonal sprouting associated with allodynia-like hypersensitivity of forepaws. Transduction of neural stem cells with neurogenin-2 before transplantation suppressed astrocytic differentiation of engrafted cells and prevented graft-induced sprouting and allodynia. Transduction with neurogenin-2 also improved the positive effects of engrafted stem cells, including increased amounts of myelin in the injured area, recovery of hindlimb locomotor function and hindlimb sensory responses, as determined by functional magnetic resonance imaging. These findings show that stem cell transplantation into injured spinal cord can cause severe side effects and call for caution in the consideration of clinical trials. Department of Neuroscience, Karolinska Institutet, 17177 Stockholm, Sweden. christoph.hofstetter@neuro.ki.se http://www.ncbi.nlm.nih.gov/entrez/q..._uids=15711542
• Gao J, Coggeshall RE, Tarasenko YI and Wu P (2005). Human neural stem cell-derived cholinergic neurons innervate muscle in motoneuron deficient adult rats. Neuroscience 131: 257-62. Motoneuron damage occurs in spinal cord injury and amyotrophic lateral sclerosis. Current advances offer hope that human embryonic stem cells [Science 282 (1998) 1145] or neural stem cells (NSC) [Exp Neurol 161 (2000) 67; Exp Neurol 158 (1999) 265; J Neurosci Methods 85 (1998) 141; Proc Natl Acad Sci USA 97 (2000) 14720; Exp Neurol 156 (1999) 156 ] may be donors to replace lost motoneurons. Previously, we developed a priming procedure that produced cholinergic cells that resemble motoneurons from human NSCs grafted into adult rat spinal cord [Nat Neurosci 5 (2002a) 1271]. However, effective replacement therapy will ultimately rely on successful connection of new motoneurons with their muscle targets. In this study, we examined the potential of human fetal NSC transplantation to replace lost motoneurons in an animal model of chronic motoneuron deficiency (newborn sciatic axotomy) [J Comp Neurol 224 (1984) 252; J Neurobiol 23 (1992) 1231]. We found, for the first time, that human neural stem cell-derived motoneurons send axons that pass through ventral root and sciatic nerve to form neuromuscular junctions with their peripheral muscle targets. Furthermore, this new cholinergic innervation correlates with partial improvement of motor function. Department of Neuroscience and Cell Biology, University of Texas Medical Branch, 301 University Blvd., Galveston, TX 77555-1043, USA. http://www.ncbi.nlm.nih.gov/entrez/q..._uids=15708470
• Talbott JF, Loy DN, Liu Y, Qiu MS, Bunge MB, Rao MS and Whittemore SR (2005). Endogenous Nkx2.2+/Olig2+ oligodendrocyte precursor cells fail to remyelinate the demyelinated adult rat spinal cord in the absence of astrocytes. Exp Neurol 192: 11-24. Chronic demyelination is a pathophysiologic component of compressive spinal cord injury (SCI) and a characteristic finding in demyelinating diseases including multiple sclerosis (MS). A better characterization of endogenous cells responsible for successful remyelination is essential for designing therapeutic strategies aimed at restoring functional myelin. The present study examined the spatiotemporal response of endogenous oligodendrocyte precursor cells (OPCs) following ethidium bromide (EB)-induced demyelination of the adult rat spinal cord. Beginning at 2 days post-EB injection (dpi), a robust mobilization of highly proliferative NG2(+) cells within the lesion was observed, none of which expressed the oligodendrocyte lineage-associated transcription factor Nkx2.2. At 7 dpi, a significant up-regulation of Nkx2.2 by OPCs within the lesion was observed, 90% of which coexpressed NG2 and virtually all of which coexpressed the bHLH transcription factor Olig2. Despite successful recruitment of Nkx2.2(+)/Olig2(+) OPCs within the lesion, demyelinated axons were not remyelinated by these OPCs in regions lacking astrocytes. Rather, Schwann cell remyelination predominated throughout the central core of the lesion, particularly around blood vessels. Oligodendrocyte remyelination was observed in the astrogliotic perimeter, suggesting a necessary role for astrocytes in oligodendrocyte maturation. In addition, reexpression of the radial glial antigen, RC-1, by reactive astrocytes and ependymal cells was observed following injury. However, these cells did not express the neural stem cell (NSC)-associated transcription factors Sox1 or Sox2, suggesting that the endogenous response is primarily mediated by glial progenitors. In vivo electrophysiology demonstrated a limited and unsustained functional recovery concurrent with endogenous remyelination following EB-induced lesions. The MD/PhD Program, University of Louisville, Louisville, KY 40292, USA. http://www.ncbi.nlm.nih.gov/entrez/q..._uids=15698615
• Kitagawa A, Nakayama T, Takenaga M, Matsumoto K, Tokura Y, Ohta Y, Ichinohe M, Yamaguchi Y, Suzuki N, Okano H and Igarashi R (2005). Lecithinized brain-derived neurotrophic factor promotes the differentiation of embryonic stem cells in vitro and in vivo. Biochem Biophys Res Commun 328: 1051-7. The addition of lecithin molecules to brain-derived neurotrophic factor (BDNF) has been reported to markedly enhance its pharmacological effect in vivo. In the current study, we show that lecithinized BDNF (PC-BDNF) has a higher affinity than BDNF for neural precursor cells. Although BDNF only slightly increased the expression of the genes for Mash-1, p35, 68 kDa neurofilament, and TrkB receptor, PC-BDNF caused a significant increase in their expression. PC-BDNF also increased the level of neurofilament protein and dramatically increased TrkB mRNA gene expression, which was followed by a sustained activation of the p42/p44 extracellular-regulated kinases. Finally, transplantation of PC-BDNF-treated cells was more effective than BDNF-treated cells at improving impaired motor function caused by spinal cord injury. These findings showed that PC-BDNF has a better potential than BDNF for promoting neural differentiation, partly due to a higher cellular affinity. Furthermore, PC-BDNF-treated cells could be useful for transplantation therapy for central nervous system injuries. Department of Frontier Medicine, Institute of Medical Science, St. Marianna University School of Medicine, Kawasaki 216-8512, Japan. akikit@marianna-u.ac.jp http://www.ncbi.nlm.nih.gov/entrez/q..._uids=15707984
• Lu P, Jones LL and Tuszynski MH (2005). BDNF-expressing marrow stromal cells support extensive axonal growth at sites of spinal cord injury. Exp Neurol 191: 344-60. Bone marrow stromal cells (MSCs) constitute a heterogeneous cell layer in the bone marrow, supporting the growth and differentiation of hematopoietic stem cells. Recently, it has been reported that MSCs harbor pluripotent stem cells capable of neural differentiation and that simple treatment of MSCs with chemical inducing agents leads to their rapid transdifferentiation into neural cells. We examined whether native or neurally induced MSCs would reconstitute an axonal growth-promoting milieu after cervical spinal cord injury (SCI), and whether such cells could act as vehicles of growth factor gene delivery to further augment axonal growth. One month after grafting to cystic sites of SCI, native MSCs supported modest growth of host sensory and motor axons. Cells "neurally" induced in vitro did not sustain a neural phenotype in vivo and supported host axonal growth to a degree equal to native MSCs. Transduction of MSCs to overexpress brain-derived neurotrophic factor (BDNF) resulted in a significant increase in the extent and diversity of host axonal growth, enhancing the growth of host serotonergic, coerulospinal, and dorsal column sensory axons. Measurement of neurotrophin production from implanted cells in the lesion site revealed that the grafts naturally contain nerve growth factor (NGF) and neurotrophin-3 (NT-3), and that transduction with BDNF markedly raises levels of BDNF production. Despite the extensive nature of host axonal penetration into the lesion site, functional recovery was not observed on a tape removal or rope-walking task. Thus, MSCs can support host axonal growth after spinal cord injury and are suitable cell types for ex vivo gene delivery. Combination therapy with other experimental approaches will likely be required to achieve axonal growth beyond the lesion site and functional recovery. Department of Neurosciences and Center for Neural Repair, University of California at San Diego, La Jolla, CA 92093-0626, USA. http://www.ncbi.nlm.nih.gov/entrez/q..._uids=15649491
• Fernandez E, Mannino S, Tufo T, Pallini R, Lauretti L, Albanese A and Denaro L (2006). The adult "paraplegic" rat: treatment with cell graftings. Surg Neurol 65: 223-37. Spinal cord injury often results in irreversible and permanent neurologic deficits below the lesion level. Nowadays, treatment is limited to drugs and/or physiotherapy aimed at compensating disability. New experimental studies focus on the transplantation of cells capable of surviving, regenerating tissue, recovering functions and/or improving symptoms. A review of such type of studies on spinal cord reconstruction published between 1991 and 2004 is presented. In the latter years, cell transplantation appeared as the most promising approach in spinal cord regeneration research. To date, this promise has not been maintained, despite the appearance of new attractive cell populations for grafting, such as neural stem cells. The demonstration that stem cells exist in the adult brain and that they can be isolated and expanded in vitro offers the possibility to test such interesting cells in the paraplegic rat. Some neurotrophic factors can facilitate axonal regeneration and neuronal survival. Therefore, the development of strategies, such as implanting neural stem cells engineered to secrete neurotrophic factors directly in the lesion site, could be important to promote regeneration in the injured spinal cord. Despite all the strategies used till now, the problem of the paraplegic rat remains. Only the solution of such problem will authorize studies in higher mammals and, finally, the clinical application in human patients. The paraplegic adult rat with a T8 spinal cord transection should be considered the standard experimental model to be used in spinal cord reconstruction studies. Function and anatomic results are undisputed only after spinal cord transection. Department of Neurosurgery, Center of Research on Regeneration in the Nervous System, Catholic University School of Medicine, 00168 Rome, Italy. http://www.ncbi.nlm.nih.gov/entrez/q..._uids=16488239
• Polentes J and Gauthier P (2005). [Transplantation of olfactory ensheathing cells after spinal injury. I--From experimental data to repair strategy after central injury]. Neurochirurgie 51: 421-34. Ensheathing olfactory glial cells (OEC) can be considered, with stem cells, as the other most important cell type for developing therapeutic cellular transplantation strategies following lesion of the central nervous system (CNS) and particularly in the case of spinal cord injury. OECs are macroglial cells whose precursors are located in the olfactory mucosa. OEC ensheath the axons of the sensory olfactory neurons, from the peripheral mucosa to the central olfactory bulbs. These glial cells constitute one of the rare macroglial cells which, after removal in the adult mammal, can survive in culture and multiply. After post-traumatic transplantation in the CNS, these cells have induced several instances of functional recovery after injury of different neural systems. The "OEC transplantation effect" consists in modifying the central inhibitory environment to make it more propitious for axonal regrowth and cell survival (reduction of the glial scar; releasing of numerous survival and neurotrophic factors, and of surface, extracellular matrix and adhesion molecules). In addition to the fact that OEC can ensheath and/or myelinate central axons, migrate in the CNS and accompany the growing axons over a relatively long distance, they also can be obtained from olfactory mucosa. OEC thus constitute a preferential candidate for autologous transplantation for the purposes of repair. Physiologie Neurovegetative, UMR CNRS 6153 INRA 1147, Universite Paul-Cezanne, Faculte des Sciences et Techniques de Saint-Jerome (Aix-Marseille III), Case courrier 352, Avenue Escadrille-Normandie-Niemen, 13397 Marseille Cedex 20. http://www.ncbi.nlm.nih.gov/entrez/q..._uids=16327676
• Hoang TX, Nieto JH and Havton LA (2005). Regenerating supernumerary axons are cholinergic and emerge from both autonomic and motor neurons in the rat spinal cord. Neuroscience 136: 417-23. Multipolar neurons in the mammalian nervous system normally exhibit one axon and several dendrites. However, in response to an axonal injury, adult motoneurons may regenerate supernumerary axons. Supernumerary axons emerge from the cell body or dendritic trees in addition to the stem motor axon. It is not known whether these regenerating axons contain neurotransmitters for synaptic transmission at their terminals. Here, using immunohistochemistry for choline acetyltransferase, an enzyme that synthesizes acetylcholine, we demonstrate the emergence of cholinergic supernumerary axons at 6 weeks after a unilateral L5-S2 ventral root avulsion and acute implantation of the avulsed L6 ventral root into the adult rat spinal cord. Light microscopic serial reconstruction of choline acetyltransferase immunoreactive arbors shows that these supernumerary axons originate from both autonomic and motor neurons. The supernumerary axons emerge from the cell body or dendrites, exhibit an abnormal projection pattern within the intramedullary gray and white matters, make frequent abrupt turns in direction, and form bouton-like swellings as well as growth cone-like terminals. Double labeling immunohistochemistry studies show that the choline acetyltransferase immunoreactive supernumerary axons co-localized with two proteins associated with axonal growth and elongation, growth-associated protein 43 and p75, the low affinity neurotrophic factor receptor. Our findings suggest that regenerating supernumerary axons selectively transport and store choline acetyltransferase, supporting the notion that supernumerary axons may develop functional and active synaptic transmission. Therefore, regenerating supernumerary axons may contribute to the plasticity in neural circuits following injury in the adult nervous system. Department of Neurology and Brain Research Institute, David Geffen School of Medicine at UCLA, 710 Westwood Plaza, Los Angeles, CA 90095-1769, USA. http://www.ncbi.nlm.nih.gov/entrez/q..._uids=16203105
• Dezawa M, Hoshino M, Nabeshima Y and Ide C (2005). Marrow stromal cells: implications in health and disease in the nervous system. Curr Mol Med 5: 723-32. Chronic degenerative diseases and traumatic injuries are responsible for a decline in neuronal function, which often limit life span. While solid organ transplantation such as liver and kidney has been already applied for thousands of patients, great limitation exists in case of nervous system. Cell transplantation is one of the strategies with potential for treatment of such neural disorders, and many kinds of cells including embryonic stem cells and neural stem cells have been considered as candidates for transplantation therapy. Bone marrow stromal cells (MSCs) have great potential as therapeutic agents, since they are easy to isolate and can be expanded from patients without serious ethical and technical problems. We found a method for the highly efficient and specific induction of functional neurons and Schwann cells from both rat and human MSCs. Induced neurons and Schwann cells were transplanted in animal models of Parkinson's disease, stroke, peripheral nerve injury, and spinal cord injury resulting in the successful integration of transplanted cells and improvement in behavior of transplanted animals. Here we focus on the respective potentials of MSC-derived cells and discuss the possibility of clinical application in neurodegenerative and neurotraumatic diseases. Department of Anatomy and Neurobiology, Kyoto University Graduate School of Medicine, Yoshidakonoe-cho, Sakyo-ku, Kyoto 606-8501, Japan. dezawa@anat2.med.kyoto-u.ac.jp http://www.ncbi.nlm.nih.gov/entrez/q..._uids=16305495
• Kimura H, Yoshikawa M, Matsuda R, Toriumi H, Nishimura F, Hirabayashi H, Nakase H, Kawaguchi S, Ishizaka S and Sakaki T (2005). Transplantation of embryonic stem cell-derived neural stem cells for spinal cord injury in adult mice. Neurol Res 27: 812-9. AIMS: To investigate the efficacy of embryonic stem cell-derived neural stem cells (NSCs) for spinal cord injury (SCI) in mice and whether a combination treatment with thyroid hormone provides a more effective ES cell-based therapy. METHODS: Nestin-positive NSCs were induced from undifferentiated mouse ES cells by a step-by-step culture and used as grafts. Thirty-six mice were subjected to an SCI at Th10 and divided into three groups of 12. Graft cells were transplanted into the injury site 10 days after injury. Group 1 mice were left under observation without receiving graft cells, while mice in Group 2 received 2 x 104 graft cells, and those in Group 3 received 2 x 104 graft cells and were treated with a continuous intraperitoneal injection of thyroxin using osmotic mini-pumps. Behavioral improvement was assessed by a scoring system throughout the experimental period until post-transplantation day (PD) 28. RESULTS: Mice in Groups 2 and 3 demonstrated an improved behavioral function, as compared to those in Group 1 after PD 14. There was no significant difference in behavioral recovery between Groups 2 and 3. CONCLUSIONS: Transplantation of ES-NSCs into the injury site was effective for SCI, while thyroxine did not deliver additional effectiveness. Department of Neurosurgery, Nara Medical University, Nara, Japan. http://www.ncbi.nlm.nih.gov/entrez/q..._uids=16354541
• Pallini R, Vitiani LR, Bez A, Casalbore P, Facchiano F, Di Giorgi Gerevini V, Falchetti ML, Fernandez E, Maira G, Peschle C and Parati E (2005). Homologous transplantation of neural stem cells to the injured spinal cord of mice. Neurosurgery 57: 1014-25; discussion 1014-25. OBJECTIVE: Murine neural stem cells (NSCs) were homografted onto the injured spinal cord (SC) to assess their potential to improve motor behavior, to differentiate as neurons, and to establish synapse-like contacts with the descending axonal paths of the host. In addition, we investigated whether transduced NSCs over-expressing vascular endothelial growth factor might exert any angiogenetic effect in the injured SC. METHODS: NSCs derived from mouse embryos were transduced to express either green fluorescent protein or vascular endothelial growth factor. The cells were engrafted in mice where an extended dorsal funiculotomy had been performed at the T8-T9 level. At intervals from 4 to 12 weeks after grafting, motor behavior was assessed using an open field locomotor scale and footprint analysis. At the same time points, the SC was studied by conventional histology, immunohistochemistry, and fluorescence microscopy. The interactions between the grafted NSCs and descending axonal paths were investigated using anterogradely transported fluorescent axonal tracers. RESULTS: By the 12-week time point, mice engrafted with NSCs significantly improved both their locomotor score on open field test and their base of support on footprint analysis. Histological studies showed that green fluorescent protein-positive NSCs survived as long as 12 weeks after grafting, migrated from the grafting site with a tropism toward the lesion, and either remained undifferentiated or differentiated into the astrocytic phenotype without neuronal or oligodendrocytic differentiation. Interestingly, the NSC-derived astrocytes expressed vimentin, suggesting that these cells differentiated as immature astrocytes. The tips of severed descending axonal paths came adjacent to grafted NSCs without forming synapse-like structures. When genetically engineered to over-express vascular endothelial growth factor, the grafted NSCs significantly increased vessel density in the injured area. CONCLUSION: In the traumatically injured mice SC, NSC grafting improves motor recovery. Although differentiation of engrafted NSCs is restricted exclusively toward the astrocytic phenotype, the NSC-derived astrocytes show features that are typical of the early phase after SC injury when the glial scar is still permissive to regenerating axons. The immature phenotype of the NSC-derived astrocytes suggests that these cells might support neurite outgrowth by the host neurons. Thus, modifying the glial scar with NSCs might enhance axonal regeneration in the injured area. The use of genetically engineered NSCs that express trophic factors appears to be an attractive tool in SC transplantation research. Department of Neurosurgery, Laboratory for Neural Stem Cells, Center for Research on Regeneration of the Nervous System, Catholic University School of Medicine, Rome, Italy. pallini@rm.unicatt.it http://www.ncbi.nlm.nih.gov/entrez/q..._uids=16284571
• Okano H, Okada S, Nakamura M and Toyama Y (2005). Neural stem cells and regeneration of injured spinal cord. Kidney Int 68: 1927-31. Recent progress in the stem cell biology has led much insight into new therapeutic interventions aiming for the regeneration of the damaged central nervous system. The major strategies can be classified into two subgroups: (1) activation of endogenous neural stem cells, and (2) cell transplantation therapies. In either of these strategies, it is crucial to understand the underlying mechanisms of maintenance, activation, and differentiation of neural stem cells and subsequent process, including the migration, survival, and functional maturation of differentiated cells. In this paper, we would like to summarize our recent findings on the therapeutic interventions of the injured spinal cord, especially focusing on the development of treatment for the acute phase of spinal cord injury with anti-interleukin (IL)-6 receptor blocking antibody. Department of Physiology, Keio University School of Medicine, Tokyo, Japan. hidokano@sc.itc.keio.ac.jp http://www.ncbi.nlm.nih.gov/entrez/q..._uids=16221167
• Ferretti P (2004). Neural stem cell plasticity: recruitment of endogenous populations for regeneration. Curr Neurovasc Res 1: 215-29. Lower vertebrates, such as fish and urodele amphibians can regenerate complex body structures including significant portions of their central nervous system by recruiting progenitor cells to repair the damage. Significant ability to regenerate the nervous system is observed also during development in higher vertebrates, for example in the chick spinal cord, though it is not yet clear whether this involves de novo neurogenesis, in addition to axonal re-growth, also at the latest stages of development permissive for regeneration. The mechanisms underlying recruitment of progenitor cells in response to injury, particularly within the nervous system, are still poorly understood. Although it has been suggested that some neurogenesis can be induced even in regions of the adult mammalian brain, this potential is largely lost with evolution and development. Following tail amputation in urodeles, an ependymal tube, resembling a developing neural tube, forms from ependymal cells that migrate from the cord stump towards the terminal vesicle, and elongates by cell proliferation. The new cord might originate from stem cells, with possibly only a subset of ependymal cells displaying such properties, or via a process of dedifferentiation / transdifferentiation of these cells. Data currently available are more supportive of the latter hypothesis. Whereas dedifferentiation is a well demonstrated phenomenon in a broad range of urodele tissues, transdifferentiation seems to occur less widely and in extreme circumstances, and may contribute significantly to regeneration only in a few cases. In higher vertebrates it is even less clear how common and relevant to repair transdifferentiation is, as much work both in favour and against it has recently been published. However, the existence of multipotent neural progenitors in adult mammalian CNS and of a much higher neural cell plasticity, at least in vitro, than previously believed, encourages the view that if we were to better understand progenitor cell recruitment and plasticity in species where it does occur spontaneously, we might then find the way to make it happen effectively in mammals. Developmental Biology Unit, Institute of Child Health, University College London, UK. ferretti@ich.ucl.ac.uk http://www.ncbi.nlm.nih.gov/entrez/q..._uids=16181072
• Chen J, Bernreuther C, Dihne M and Schachner M (2005). Cell adhesion molecule l1-transfected embryonic stem cells with enhanced survival support regrowth of corticospinal tract axons in mice after spinal cord injury. J Neurotrauma 22: 896-906. Previous studies have indicated that the cell adhesion molecule L1 enhances neuronal survival and neurite outgrowth. L1-mediated promotion of neurite outgrowth has been shown to occur also in an inhibitory environment not only in vitro, but also in vivo. To further investigate the effects of L1 in spinal cord injury, we transfected embryonic stem cells with a plasmid encoding the full-length mouse L1 molecule under the control of PGK promoter. An embryonic stem cell line derived from C57BL/6J transgenic mice that express green fluorescent protein under control of the beta-actin promoter was transfected with L1 and injected into the lesion site of 3-month-old C57BL/6J female mice 7 days after compression injury. Non-transfected embryonic stem cells were detectable at the lesion site 3 days after transplantation, but lost their cellular integrity 7 days after transplantation and were barely detectable 1 month after transplantation. In contrast, L1-transfected embryonic stem cells were detected 1 month after transplantation in numbers comparable to those of the injected cells and demonstrated extended processes. Further, in contrast to the few detectable nontransfected stem cells that remained at the injection site 1 month post-transplantation, the L1-transfected embryonic stem cells had migrated rostrally and caudally from the lesion. Anterogradely labeled corticospinal tract axons showed interdigitation with L1-transfected embryonic stem cells and, in contrast to non-transfected stem cells, extended into the lesion site 1 month after transplantation and, in some cases, extended beyond it. Our observations encourage the use of L1-transfected embryonic stem cells that express L1 not only at the cell surface, but also as a soluble and secreted form. Their use could condition the inhibitory environment for homophilic L1-enhanced axon regrowth not only in spinal cord regeneration, but also in other lesion paradigms. Zentrum fur Molekulare Neurobiologie, Universitat Hamburg, Hamburg, Germany. http://www.ncbi.nlm.nih.gov/entrez/q..._uids=16083356
• Goldman S (2005). Stem and progenitor cell-based therapy of the human central nervous system. Nat Biotechnol 23: 862-71. Multipotent neural stem cells, capable of giving rise to both neurons and glia, line the cerebral ventricles of all adult animals, including humans. In addition, distinct populations of nominally glial progenitor cells, which also have the capacity to generate several cell types, are dispersed throughout the subcortical white matter and cortex. A number of approaches have evolved for using neural progenitor cells in cell therapy. Four strategies are especially attractive for clinical translation: first, transplantation of oligodendrocyte progenitor cells as a means of treating the disorders of myelin; second, transplantation of phenotypically restricted neuronal progenitor cells to treat diseases of discrete loss of a single neuronal phenotype, such as Parkinson disease; third, implantation of mixed progenitor pools to treat diseases characterized by the loss of several discrete phenotypes, such as spinal cord injury; and fourth, mobilization of endogenous neural progenitor cells to restore neurons lost as a result of neurodegenerative diseases, in particular Huntington disease. Together, these may present the most compelling strategies and near-term disease targets for cell-based neurological therapy. Division of Cell and Gene Therapy, Department of Neurology, 601 Elmwood Ave., Box 645, University of Rochester Medical Center, Rochester, New York 14642, USA. steven_goldman@urmc.rochester.edu http://www.ncbi.nlm.nih.gov/entrez/q..._uids=16003375
• Wu D, Miyamoto O, Shibuya S, Mori S, Norimatsu H, Janjua NA and Itano T (2005). Co-expression of radial glial marker in macrophages/microglia in rat spinal cord contusion injury model. Brain Res 1051: 183-8. Macrophages/microglia are implicated in spinal cord injury but their precise role in the process is not clear. Our previous studies have reported that radial glia (RG) possess properties of neural stem cells and remerged after central nervous system (CNS) injury which may play an important role in neural repair and regeneration. In the present study, we examined the expression of ED1 (a specific marker for activated macrophages/microglia) and RG in a spinal cord injury (SCI) model and detected the activation at 1, 4, 8, and 12 weeks in both dorsal funiculus and ventral white matter after SCI. For both ED1-positive cells and RG cells, there was a gradual increase in density and in number from 1 to 4 weeks followed by down-regulation up to 12 weeks after injury. The morphologies of macrophages and radial glia were different. However, some ED1-positive cells were also stained by RG marker. These results suggest that macrophages may have some lineage to radial glial cells. Department of Orthopaedic Surgery, School of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kagawa 761-0793, Japan. http://www.ncbi.nlm.nih.gov/entrez/q..._uids=15993386
• Phinney DG and Isakova I (2005). Plasticity and therapeutic potential of mesenchymal stem cells in the nervous system. Curr Pharm Des 11: 1255-65. Mesenchymal stem cells resident in adult bone marrow are best characterized by their capacity to differentiate into connective tissue cell types such as adipocytes, chondrocytes, osteoblasts and hematopoiesis-supporting stroma. Accordingly, these cells are being evaluated in human clinical trials for efficacy in treating genetic diseases of bone, to speed hematopoietic recovery after bone marrow transplantation and reduce the severity of graft versus host disease. In the past few years MSCs have also been reported to exhibit a broad degree of plasticity commensurate with other adult stem cell populations, including the ability to differentiate in vitro and in vivo into non-mesodermal cell types such as neurons and astrocytes. MSCs have also been reported to promote repair and regeneration of nervous tissue within the central and peripheral nervous system, although the mechanism by which this occurs remains indeterminate. Herein, we review evidence purporting the differentiation of MSCs into neural cell lineages and evaluate the utility of MSCs as cellular vectors for treating neurological disorders and spinal cord injury. Based on our analysis of their transcriptome, we also theorize how the varied functions of MSCs and their progeny in bone marrow may extrapolate to a therapeutic benefit in models of neurological disease. Center for Gene Therapy, Tulane University Health Sciences Center, 1430 Tulane Avenue, New Orleans, LA 70112, USA. dphinne@tulane.edu http://www.ncbi.nlm.nih.gov/entrez/q..._uids=15853682
• Xu G, Li X, Bai Y, Bai J, Li L and Shen L (2004). Improving recovery of spinal cord-injured rats by telomerase-driven human neural progenitor cells. Restor Neurol Neurosci 22: 469-76. PURPOSE: Human neural progenitor cells hold great promise for treating a variety of human neurological diseases such as spinal cord injury. One of the issues limiting this technology is how to expand neural progenitor cells in vitro to obtain sufficient number of cells for clinical transplantation. We have established a homogeneous population of human neural progenitor cells (hNPC-TERT) immortalized by the human telomerase reverse transcriptase (hTERT) gene. Then we studied whether these cells could differentiate into neural cells in vivo and improve the recovery of spinal cord-injured rats. METHODS: The hNPC-TERT cells had been transplanted into the injured spinal cord and the functional recovery of the rats with spinal cord contusion injury was evaluated through BBB locomotor scale and Motor Evoked Potentials. Additionally, the differentiation of hNPC-TERT cells was shown by immunocytochemistry. RESULTS: As revealed by this animal model, hNPC-TERT cells developed into functional cells in the injured spinal cord and improved recovery from spinal cord injury in both locomotor scores and electrophysiological parameter in this animal model. CONCLUSIONS: This study is the first demonstration of the use of telomerase-driven human progenitor cells to treat spinal cord injury and should provide a new cell source for research of clinical application. Department of Orthopedics, Peking University Third Hospital, 49 West Garden Road, Beijing, 100083, P.R. China. http://www.ncbi.nlm.nih.gov/entrez/q..._uids=15798365
• Watanabe K, Nakamura M, Iwanami A, Fujita Y, Kanemura Y, Toyama Y and Okano H (2004). Comparison between fetal spinal-cord- and forebrain-derived neural stem/progenitor cells as a source of transplantation for spinal cord injury. Dev Neurosci 26: 275-87. Recently, we have shown that the transplantation of spinal-cord-derived neural stem/progenitor cells (NSPCs) can contribute to the repair of injured spinal cords in adult rats, which may correspond to a behavioral recovery. To apply these results to clinical practice, a system for supplying human NSPCs on a large scale must be established. However, human spinal-cord-derived NSPCs are known to have a low proliferation rate, compared with forebrain-derived NSPCs. This low proliferative potency limits the feasibility of large-scale spinal cord-derived NSPC use. Thus, forebrain-derived NSPCs should be examined as an alternative to spinal-cord-derived NSPCs for the treatment of spinal cord injuries. In this study, we compared spinal-cord- and forebrain-derived NSPCs transplanted into injured spinal cords with respect to their fates in vivo as well as the animals' functional recovery. Both spinal-cord- and forebrain-derived NSPCs promoted functional recovery in rats with spinal cord injuries. While both spinal-cord- and forebrain-derived NSPCs survived, migrated and differentiated into neurons, astrocytes and oligodendrocytes in response to the microenvironment within the injured spinal cord after transplantation, forebrain-derived NSPCs differentiated into more neurons and fewer oligodendrocytes, compared to spinal-cord-derived NSPCs. Neurons that had differentiated from the transplanted forebrain-derived NSPCs were shown to be positive for neurotransmitters like GABA, glutamate and glycine, although authentic glycinergic neurons are not normally present within the forebrain. Thus, at least a subpopulation of the transplanted forebrain-derived NSPCs differentiated into spinal-cord-type neurons. In conclusion, forebrain-derived NSPCs could be used as an alternative to spinal-cord-derived NSPCs as a potential therapeutic agent for spinal cord injuries. Department of Orthopaedic Surgery, Keio University, Tokyo, Japan. http://www.ncbi.nlm.nih.gov/entrez/q..._uids=15711067

[john smith]

Wise;

This one sounds very cool!

Cao Q, Xu XM, Devries WH, Enzmann GU, Ping P, Tsoulfas P, Wood PM, Bunge MB and Whittemore SR (2005). Functional recovery in traumatic spinal cord injury after transplantation of multineurotrophin-expressing glial-restricted precursor cells. J Neurosci 25: 6947-57. Demyelination contributes to the physiological and behavioral deficits after contusive spinal cord injury (SCI). Therefore, remyelination may be an important strategy to facilitate repair after SCI. We show here that rat embryonic day 14 spinal cord-derived glial-restricted precursor cells (GRPs), which differentiate into both oligodendrocytes and astrocytes, formed normal-appearing central myelin around axons of cultured DRG neurons and had enhanced proliferation and survival in the presence of neurotrophin 3 (NT3) and brain-derived neurotrophin factor (BDNF). We infected GRPs with retroviruses expressing the multineurotrophin D15A (with both BDNF and NT3 activities) and then transplanted them into the contused adult thoracic spinal cord at 9 d after injury. Expression of D15A in the injured spinal cord is five times higher in animals receiving D15A-GRP grafts than ones receiving enhanced green fluorescent protein (EGFP)-GRP or DMEM grafts. Six weeks after transplantation, the grafted GRPs differentiated into mature oligodendrocytes expressing both myelin basic protein (MBP) and adenomatus polyposis coli (APC). Ultrastructural analysis showed that the grafted GRPs formed morphologically normal-appearing myelin sheaths around the axons in the ventrolateral funiculus (VLF) of spinal cord. Expression of D15A significantly increased the percentage of APC+ oligodendrocytes of grafted GRPs (15-30%). Most importantly, 8 of 12 rats receiving grafts of D15A-GRPs recovered transcranial magnetic motor-evoked potential responses, indicating that conduction through the demyelinated VLF axons was restored. Such electrophysiological recovery was not observed in rats receiving grafts of EGFP-GRPs, D15A-NIH3T3 cells, or an injection of an adenovirus expressing D15A. Recovery of hindlimb locomotor function was also significantly enhanced only in the D15A-GRP-grafted animals at 4 and 5 weeks after transplantation. Therefore, combined treatment with neurotrophins and GRP grafts can facilitate functional recovery after traumatic SCI and may prove to be a useful therapeutic strategy to repair the injured spinal cord. Kentucky Spinal Cord Injury Research Center, University of Louisville, Louisville, Kentucky 40202, USA. http://www.ncbi.nlm.nih.gov/entrez/q..._uids=16049170

Cherrylips;

There will be a test on the rest tomorrow.

John

[Cherry]

Wise

Woah thanks!

Yeah I realise there are numerous studies annually/monthly, its just I heard that Cummings was particularly successful?

John.....can you expand on this

cheers in advance

[john smith]

Cherrylips;

Just kidding about the test. I too was in awe of Dr. Young's answer to your question. The work I cited is cool because it seems to duplicate and validate similar work done by Keirstead at UC Irvine. Certainly those with incomplete injuries would benefit from regeneration of myelin sheath.

John

[Cherry]

hehe yea i figured that after Id posted