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Thread: Jerry Silver and Other Discussion from ChinaSCINet Update

  1. #181
    Quote Originally Posted by NowhereMan View Post
    None of these are "convincing" evidence of efficacy of the treatment.

    1st link -- this was using olfactory ensheathing cells, not umbilical cord blood cells. They are not homogenous just because they happen to both be stem cells. I'm not even sure UCB cells are stem cells. I also can't find the paper online to see images of axon regeneration in the dogs.

    2nd link -- this was in an acute model, not chronic. It was also in an incomplete injury model. Even then, BBB scores increased from 11 to 13.5. That doesn't impress me at all.

    3rd link -- this was in a incomplete model. I assume it was also in an acute model as well, but I'm not sure as the abstract did not say.

    4th link -- this was in an acute model. It did not regenerate any axons but prevented secondary axon damage. Big difference.

    5th link -- from what I heard, I think Dr. Young was showing how the UCB cells that they implanted migrated into the injury site, he wasn't showing axons growing into the injury site.

    This is a chronic injury and complete injury trial. There are NO animal studies, that I am aware of, showing robust axon growth using Umbilical cord blood cells in a complete/chronic model. I understand that it is impossible to test HLA matching cells on animals, but that does not mean that animal studies showing efficacy exist. Again, wait until the results are published and the scientific community has a chance to respond before you are so certain of the results.
    All of the studies above are published in journals because they contain convincing evidence of efficacy of treatment. Those were the first three listed related to UCBMC treatment in animal SCI. Here's another one published 9 1/2 years ago.

    Quote Originally Posted by jsilver View Post
    Would it not be possible that a 10 year post chronic spinal cord may have made changes over time to breakdown a portion of the gilia scar barrier that was originally developed?

    Yes, indeed, the scar does change over time. It becomes thinner and its associated inhibitory proteoglycan extracellular matrices become more restricted to the cell surfaces.
    What if on a cellular level acute SCI is more challenging to fix than chronic SCI? You can't say for sure that it isn't, but you probably will anyways.

    You say studies on efficacy of stem cell treatment in animal SCI don't exist (there are easily hundreds of articles posted online), you aren't sure whether umbilical cord blood mononuclear cells are stem cells or not, and you seem to be suggesting that once injected into the spinal cord, stem cells (if they are stem cells) differentiate not into axons, but into migratory stem cell non-axonal superfreaks. Ok.

    I respect your concerns about waiting til the study is published to be certain of the results. It doesn't mean we can't look to animal models to get an idea if it might work or not. If UCBMC have helped animals get better, UCBMC could help humans get better. If UCBMC helps humans get better, it's possible that DTI's of their spinal cord might show substantial axonal regrowth.
    Last edited by crabbyshark; 01-10-2013 at 05:24 PM.

  2. #182
    Quote Originally Posted by NowhereMan View Post
    None of these are "convincing" evidence of efficacy of the treatment.

    1st link -- this was using olfactory ensheathing cells, not umbilical cord blood cells. They are not homogenous just because they happen to both be stem cells. I'm not even sure UCB cells are stem cells. I also can't find the paper online to see images of axon regeneration in the dogs.

    2nd link -- this was in an acute model, not chronic. It was also in an incomplete injury model. Even then, BBB scores increased from 11 to 13.5. That doesn't impress me at all.

    3rd link -- this was in a incomplete model. I assume it was also in an acute model as well, but I'm not sure as the abstract did not say.

    4th link -- this was in an acute model. It did not regenerate any axons but prevented secondary axon damage. Big difference.

    5th link -- from what I heard, I think Dr. Young was showing how the UCB cells that they implanted migrated into the injury site, he wasn't showing axons growing into the injury site.


    This is a chronic injury and complete injury trial. There are NO animal studies, that I am aware of, showing robust axon growth using Umbilical cord blood cells in a complete/chronic model. I understand that it is impossible to test HLA matching cells on animals, but that does not mean that animal studies showing efficacy exist. Again, wait until the results are published and the scientific community has a chance to respond before you are so certain of the results.
    you are on the ball.....

  3. #183
    Quote Originally Posted by crabbyshark View Post
    All of the studies above are published in journals because they contain convincing evidence of efficacy of treatment. Those were the first three listed related to UCBMC treatment in animal SCI. Here's another one published 9 1/2 years ago.


    What if on a cellular level acute SCI is more challenging to fix than chronic SCI? You can't say for sure that it isn't, but you probably will anyways.

    You say studies on efficacy of stem cell treatment in animal SCI don't exist (there are easily hundreds of articles posted online), you aren't sure whether umbilical cord blood mononuclear cells are stem cells or not, and you seem to be suggesting that once injected into the spinal cord, stem cells (if they are stem cells) differentiate not into axons, but into migratory stem cell non-axonal superfreaks. Ok.

    I respect your concerns about waiting til the study is published to be certain of the results. It doesn't mean we can't look to animal models to get an idea if it might work or not. If UCBMC have helped animals get better, UCBMC could help humans get better. If UCBMC helps humans get better, it's possible that DTI's of their spinal cord might show substantial axonal regrowth.
    One of your mistakes, and it is a large one, is not comprehending the difference between acute and chronic spinal cord injury. They can almost be viewed as two completely different injuries. Most acute treatments in development attempt to preserve axons from dying, not to regenerate them. Night and day difference. Other acute treatments being developed do attempt to regenerate axons so they are relevant to a chronic injury. No link that you provided shows/proves the UCB regenerated axons across the injury site.

    In the acute rat studies you provided, I saw no evidence of axon growth across the injury site. If you look at the PTEN study, you will see nice images of axons growing across the injury site. Show me just one UCB study that has photographic evidence of axon growth.
    http://www.ncbi.nlm.nih.gov/pubmed/20694004

    Most importantly, If you are convinced that UCB cells will work in human chronic SCI (because they show efficacy in acute, incomplete animal models), where are the studies that show efficacy in Chronic animal models?

  4. #184
    I am sorry that I am in China and don't have the time answer in detail. I have posted many time on the subject. I will briefly summarize the justification for the clinical trial.

    Before I do so, let me say that people should not be calling umbilical cord blood mononuclear cells "my" therapy. In fact, as all of you have noticed, most of the preclinical studies were done by other investigators and not by my group at Rutgers. ChinaSCINet tests what its investigators consider to be the most promising and feasible therapies. In 2006, we reviewed the literature and found that umbilical cord blood cells were the most promising cell transplants for spinal cord injury for the following reasons:
    1. The cells are available in a well-vetted GMP source (i.e. Stemcyte) that adheres to rigorous standards of sterility, quality, and immune-compatibility.
    2. The cells have been reported by multiple independent laboratories to be beneficial in large and small animal spinal cord injury models.
    3. The cells have a strong safety record of use in both large and small animals.
    4. The cells are likely to be approved by regulatory authorities in China, U.S., Europe, and India.

    No other cell source fulfilled these criteria.

    Umbilical cord blood is available from a number of sources and we selected the best of these, i.e. Stemcyte, a commercial company with the largest and most diverse collection of cord blood in the world and a strong record of safe transplant of such cells in humans. We considered autologous bone marrow cells, fetal olfactory ensheathing cells, autologous nasal mucosa cells, fetal neural stem cells, embryonic stem cells, induced pluripotent stem cells, and many other sources. No other cells fulfilled GMP standards.

    Even in 2006, four independent laboratories had reported beneficial effects of umbilical cord blood on animal spinal cord injury models. Many additional studies have been published since 2006 confirming the original studies. Over a dozen independent laboratories have reported the beneficial effect so umbilical cord blood mononuclear cells on rat and dog models of spinal cord injury. It is true that few of them had been on "chronic" spinal cord injury but several have been in both dogs and rats at 1 week after injury.

    Umbilical cord blood cells been transplanted into over 30,000 people over the past 25 years with no evidence of forming tumors or other problems. They are HLA-matchable and therefore can be immune-compatible. Finally, we developed a method of isolating the cells so that they would fall under the criterion of "minimally manipulated", which would greatly ease regulatory approval of the cells if we show safety and efficacy.

    Lithium has been reported by two independent groups to have beneficial effects on animal spinal cord injury, i.e. Wu's laboratory at HKU and Dill, et al. at the University of Texas. One group (in China) has reported that the combination of UCBMC and lithium is more effective than UCBMC. We have shown that the combination of the two therapies resulted in greater neurotrophin expression at the injury site when we do not use cyclosporin therapy. Unfortunately, we found that if we use cyclosporin, it cancelled out the effects of lithium on umbilical cord blood. We proposed to test the two individual therapies first individually and then in combination. In phase I and II trials, we have shown that lithium can be safely given to patients with chronic spinal cord injury. We are now conducting Phase II trials to assess the escalating doses of umbilical cord blood.

    References

    1. Saporta S, Kim JJ, Willing AE, Fu ES, Davis CD and Sanberg PR (2003). Human umbilical cord blood stem cells infusion in spinal cord injury: engraftment and beneficial influence on behavior. J Hematother Stem Cell Res 12: 271-8. Center for Aging and Brain Repair and Department of Anatomy, University of South Florida College of Medicine, Tampa, FL 33612, USA. ssaporta@hsc.usf.edu. The use of human umbilical cord blood (hUCB)--a rich source of nonembryonic or adult stem cells--has recently been reported to ameliorate behavioral consequences of stroke. In this study, we tested whether human cord blood leukocytes also ameliorate behavioral impairments of spinal cord injury. Rats were divided into five groups: (1) laminectomy (without spinal cord injury) only; (2) laminectomy + cord blood infusion; (3) spinal cord injury + cord blood infused 1 day post injury; (4) spinal cord injury + cord blood infused 5 days post injury; and (5) spinal cord injury only. Spinal cord injury was induced by compressing the spinal cord for 1 min with an aneurysm clip calibrated to a closing pressure of 55 g. Open-field behavior was assessed 1, 2, and 3 weeks after intravenous injection of prelabeled human cord blood cells. Open-field test scores of spinal cord injured rats treated with human cord blood at 5 days were significantly improved as compared to scores of rats similarly injured but treated at day 1 as well as the otherwise untreated injured group. The results suggest that cord blood stem cells are beneficial in reversing the behavioral effects of spinal cord injury, even when infused 5 days after injury. Human cord blood-derived cells were observed in injured areas, but not in noninjured areas, of rat spinal cords, and were never seen in corresponding areas of spinal cord of noninjured animals. The results are consistent with the hypothesis that cord blood-derived stem cells migrate to and participate in the healing of neurological defects caused by traumatic assault.
    2. Zhao ZM, Li HJ, Liu HY, Lu SH, Yang RC, Zhang QJ and Han ZC (2004). Intraspinal transplantation of CD34+ human umbilical cord blood cells after spinal cord hemisection injury improves functional recovery in adult rats. Cell Transplant 13: 113-22. National Research Center for Stem Cell Engineering & Technology, State Key Laboratory of Experimental Hematology, Institute of Hematology, Chinese Academy of Medical Sciences, Peking Union Medical College, Tianjin, People's Republic of China. The present study was designed to compare the functional outcome of the intraspinal transplantation of CD34+ human umbilical cord blood (CB) cells with that of human bone marrow stromal (BMS) cells in adult rats with spinal cord injury. Sixty adult Wistar rats were subjected to left spinal cord hemisection, and then divided into three groups randomly. The control group received an injection of PBS without cells, while the two other groups of rats received a transplantation of 5 x 10(5) CD34+ CB or BMS cells, respectively. Functional outcome was measured using the modified Tarlov score at days 1, 7, 14, 21, and 28 after transplantation. A statistically significant improvement in functional outcome and survival rate in the experimental groups of rats was observed compared with the control group. Rats that received CD34+ CB cells achieved a better improvement in functional score than those that received BMS cells at days 7 and 14 after transplantation. Histological evaluation revealed that bromodeoxyuridine (BrdU)-labeled CD34+ CB and BMS cells survived and migrated into the injured area. Some of these cells expressed glial fibriliary acidic protein (GFAP) or neuronal nuclear antigen (NeuN). Our data demonstrate for the first time that intraspinal transplantation of human CD34+ CB cells provides benefit in function recovery after spinal cord hemisection in rats and suggest that CD34+ CB cells may be an excellent choice of cells as routine starting material of allogenic and autologous transplantations for the treatment of spinal cord injury.
    3. 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 Neurochirurgica 147: 985-92; discussion 992. Department of Neurosurgery, Yonsei University College of Medicine, Seoul, Korea. 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 immunofluorescence 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.
    4. Roussos I, Rodriguez M, Villan D, Ariza A, Rodriguez L and Garcia J (2005). Development of a rat model of spinal cord injury and cellular transplantation. Transplant Proc 37: 4127-30. Departament de Neurocirurgia, Hospital Germans Trias i Pujol, Badalona, Spain. BACKGROUND AND PURPOSE: Intravenously or intraspinally delivered human umbilical cord blood (UCB) cells and mesenchymal stem cells have been previously shown to improve the functional recovery of spinal cord-injured rats. Obtaining an animal model in the laboratory setting is critical for the development of experimental therapies. We have established a rat model of spinal cord injury (SCI) with basic histological and functional evaluations, ready to use for cell transplantation experiments. METHODS: In the first phase 10 Sprague-Dawley (SD) rats were used to standardize the laminectomy at D9-D10 without secondary lesions. In a second phase, 28 SD rats were laminectomized and injured at D9 by spinal cord compression for 3 to 5 seconds with an aneurysmal clip. Open-field behavior was assessed at days 2 and 7 postoperatively, and weekly until their sacrifice, using the Basso, Beattie, and Bresnahan locomotor rating scale. Two weeks postinjury, 14 immunosuppressed rats received a double intraspinal cell transplant of previously frozen UCB mononuclear cells (MNCs). Using a Hamilton syringe, 2.5 x 10(5) unlabelled MNCs in 10 microL medium were transplanted, rostrally and caudally to the lesion site. Rats were sacrificed at 4 weeks posttransplant by transcardial perfusion with 4% paraformaldehyde, and spinal cords were dissected and further fixated for histological analysis. RESULTS: No wound infections were observed. Thirteen rats developed urinary tract infections and two animals showed autophagia grade 3. We observed a common spontaneous mobility improvement until a certain limit, depending on the degree of lesion and intrinsic characteristics of the animal. CONCLUSIONS: An animal model of SCI has been established. Critical parameters in the survival and correct functional analysis are continuous animal care postinjury, urinary tract infections, autophagia, and weight loss. In addition, electrophysiological measures might be necessary to properly assess functional modifications.
    5. Nishio Y, Koda M, Kamada T, Someya Y, Yoshinaga K, Okada S, Harada H, Okawa A, Moriya H and Yamazaki M (2006). The use of hemopoietic stem cells derived from human umbilical cord blood to promote restoration of spinal cord tissue and recovery of hindlimb function in adult rats. J Neurosurg Spine 5: 424-33. Department of Orthopaedic Surgery, Chiba University Graduate School of dicine, Tougane Chiba Prefecture Hospital, Chiba, Japan. OBJECT: The use of human umbilical cord blood (HUCB) cells has been reported to improve functional recovery in cases of central nervous system injuries such as stroke, traumatic brain injury, and spinal cord injury (SCI). The authors investigated the effects of hemopoietic stem cells that were derived from HUCB and transplanted into the injured spinal cords of rats. METHODS: One week after injury, an HUCB fraction enriched in CD34-positive cells was transplanted into the experimental group. In control animals, vehicle (Matrigel) was transplanted. Recovery of motor functions was assessed using the Basso-Beattie-Bresnahan Locomotor Scale, and immunohistochemical examinations were performed. Cells from HUCB that were CD34 positive improved functional recovery, reduced the area of the cystic cavity at the site of injury, increased the volume of residual white matter, and promoted the regeneration or sparing of axons in the injured spinal cord. Immunohistochemical examination revealed that transplanted CD34-positive cells survived in the host spinal cord for at least 3 weeks after transplantation but had disappeared by 5 weeks. The transplanted cells were not positive for neural markers, but they were positive for hemopoietic markers. There was no evidence of an immune reaction at the site of injury in either group. CONCLUSIONS: These results suggest that transplantation of a CD34-positive fraction from HUCB may have therapeutic effects for SCI. The results of this study provide important preclinical data regarding HUCB stem cell-based therapy for SCI.
    6. Dasari VR, Spomar DG, Gondi CS, Sloffer CA, Saving KL, Gujrati M, Rao JS and Dinh DH (2007). Axonal remyelination by cord blood stem cells after spinal cord injury. J Neurotrauma 24: 391-410. Program of Cancer Biology, Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine at Peoria, Peoria, Illinois 61605, USA. Human umbilical cord blood stem cells (hUCB) hold great promise for therapeutic repair after spinal cord injury (SCI). Here, we present our preliminary investigations on axonal remyelination of injured spinal cord by transplanted hUCB. Adult male rats were subjected to moderate SCI using NYU Impactor, and hUCB were grafted into the site of injury one week after SCI. Immunohistochemical data provides evidence of differentiation of hUCB into several neural phenotypes including neurons, oligodendrocytes and astrocytes. Ultrastructural analysis of axons reveals that hUCB form morphologically normal appearing myelin sheaths around axons in the injured areas of spinal cord. Colocalization studies prove that oligodendrocytes derived from hUCB secrete neurotrophic hormones neurotrophin-3 (NT3) and brain-derived neurotrophic factor (BDNF). Cord blood stem cells aid in the synthesis of myelin basic protein (MBP) and proteolipid protein (PLP) of myelin in the injured areas, thereby facilitating the process of remyelination. Elevated levels of mRNA expression were observed for NT3, BDNF, MBP and PLP in hUCB-treated rats as revealed by fluorescent in situ hybridization (FISH) analysis. Recovery of hind limb locomotor function was also significantly enhanced in the hUCB-treated rats based on Basso-Beattie-Bresnahan (BBB) scores assessed 14 days after transplantation. These findings demonstrate that hUCB, when transplanted into the spinal cord 7 days after weight-drop injury, survive for at least 2 weeks, differentiate into oligodendrocytes and neurons, and enable improved locomotor function. Therefore, hUCB facilitate functional recovery after moderate SCI and may prove to be a useful therapeutic strategy to repair the injured spinal cord.
    7. Lim JH, Byeon YE, Ryu HH, Jeong YH, Lee YW, Kim WH, Kang KS and Kweon OK (2007). Transplantation of canine umbilical cord blood-derived mesenchymal stem cells in experimentally induced spinal cord injured dogs. J Vet Sci 8: 275-82. Department of Veterinary Surgery, College of Veterinary Medicine, Seoul National University, Seoul 151-742, Korea. This study was to determine the effects of allogenic umbilical cord blood (UCB)-derived mesenchymal stem cells (MSCs) and recombinant methionyl human granulocyte colony-stimulating factor (rmhGCSF) on a canine spinal cord injury model after balloon compression at the first lumbar vertebra. Twenty-five adult mongrel dogs were assigned to five groups according to treatment after a spinal cord injury: no treatment (CN); saline treatment (CP); rmhGCSF treatment (G); UCB-MSCs treatment (UCB-MSC); co-treatment (UCBG). The UCBMSCs isolated from cord blood of canine fetuses were prepared as 10(6) cells/150 microl saline. The UCB-MSCs were directly injected into the injured site of the spinal cord and rmhGCSF was administered subcutaneously 1 week after the induction of spinal cord injury. The Olby score, magnetic resonance imaging, somatosensory evoked potentials and histopathological examinations were used to evaluate the functional recovery after transplantation. The Olby scores of all groups were zero at the 0-week evaluation. At 2 week after the transplantation, the Olby scores in the groups with the UCB-MSC and UCBG were significantly higher than in the CN and CP groups. However, there were no significant differences between the UCB-MSC and UCBG groups, and between the CN and CP groups. These comparisons remained stable at 4 and 8 week after transplantation. There was significant improvement in the nerve conduction velocity based on the somatosensory evoked potentials. In addition, a distinct structural consistency of the nerve cell bodies was noted in the lesion of the spinal cord of the UCB-MSC and UCBG groups. These results suggest that transplantation of the UCB-MSCs resulted in recovery of nerve function in dogs with a spinal cord injury and may be considered as a therapeutic modality for spinal cord injury.
    8. Chen CT, Foo NH, Liu WS and Chen SH (2008). Infusion of human umbilical cord blood cells ameliorates hind limb dysfunction in experimental spinal cord injury through anti-inflammatory, vasculogenic and neurotrophic mechanisms. Pediatr neonatol 49: 77-83. Department of Pediatrics and Stem Cell Lab, Chi Mei Medical Center, Yung Kung City, Tainan, Taiwan. BACKGROUND: Human umbilical cord blood cells (HUCBCs) were used to investigate the mechanisms underlying the beneficial effects of cord blood cells in spinal cord injury (SCI). METHODS: Rats were divided into three groups: (1) sham operation (laminectomy only); (2) Laminectomy+SCI+human adult peripheral blood mononucleocytes (PBMCs) (5 x 10(6)/0.3 mL); and (3) Laminectomy+SCi+HUCBCs (5 x 10(6)/0.3 mL). SCI was induced by compressing the spinal cord for 1 minute with an aneurysm clip calibrated to 55 g closing pressure. HUCBCs were infused immediately after SCI via the tail vein. Behavioral function tests measuring the maximal angle at which an animal could hold onto the inclined plane were conducted on days 1, 4 and 7 after SCI. Serum levels of tumor necrosis factor (TNF)-alpha and interleukin (IL)-10, were assayed. Furthermore, to determine if glial cell line-derived neurotrophic factor (GDNF) or vascular endothelial growth factor (VEGF) could be detected in the spinal cord injured area after systemic HUCBC infusion, analysis of these two molecules was conducted by immunofluorescence. RESULTS: Systemic HUCBC infusion significantly attenuated SCI-induced hind limb dysfunction. The serum IL-10 levels were increased, but TNF-alpha levels were decreased after HUCBC infusion. Both VEGF and GDNF could be detected in the injured spinal cord after transplantation of HUCBC, but not PBMC, cells. CONCLUSION: Our results demonstrate that HUCBC therapy may be beneficial for the recovery of SCI-induced hind limb dysfunction by increasing serum levels of IL-10, VEGF and GDNF in SCI rats.
    9. Cho SR, Yang MS, Yim SH, Park JH, Lee JE, Eom YW, Jang IK, Kim HE, Park JS, Kim HO, Lee BH, Park CI and Kim YJ (2008). Neurally induced umbilical cord blood cells modestly repair injured spinal cords. Neuroreport 19: 1259-63. Department and Research Institute of Rehabilitation Medicine, Brain Research Institute and Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea. srcho918@yumc.yonsei.ac.kr. Umbilical cord blood (UCB) is known to have stem/progenitor cells. We earlier showed that novel progenitors could be isolated from cryopreserved human UCB with high efficiency. The multipotent progenitor cells were induced to differentiate into neural-lineage cells under the appropriate condition. In this study, we confirmed these neurally induced progenitor cells (NPCs), containing higher quantities of nerve growth factor, promoted functional recovery in rats with spinal cord injury (SCI). Sprague-Dawley rats with SCI achieved a modest improvement in locomotor rating scale until 10 weeks after transplantation of the NPCs. SCI rats treated with NPCs also showed somatosensory-evoked potentials were recovered, and grafted cells especially exhibited oligodendrocytic phenotype around the necrotic cavity. These findings suggest that UCB-NPCs might be a therapeutic resource to repair damaged spinal cords.
    10. Dasari VR, Spomar DG, Li L, Gujrati M, Rao JS and Dinh DH (2008). Umbilical cord blood stem cell mediated downregulation of fas improves functional recovery of rats after spinal cord injury. Neurochem Res 33: 134-49. Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine, Peoria, IL, 61656, USA. Human umbilical cord blood stem cells (hUCB), due to their primitive nature and ability to develop into nonhematopoietic cells of various tissue lineages, represent a potentially useful source for cell-based therapies after spinal cord injury (SCI). To evaluate their therapeutic potential, hUCB were stereotactically transplanted into the injury epicenter, one week after SCI in rats. Our results show the presence of a substantial number of surviving hUCB in the injured spinal cord up to five weeks after transplantation. Three weeks after SCI, apoptotic cells were found especially in the dorsal white matter and gray matter, which are positive for both neuron and oligodendrocyte markers. Expression of Fas on both neurons and oligodendrocytes was efficiently downregulated by hUCB. This ultimately resulted in downregulation of caspase-3 extrinsic pathway proteins involving increased expression of FLIP, XIAP and inhibition of PARP cleavage. In hUCB-treated rats, the PI3K/Akt pathway was also involved in antiapoptotic actions. Further, structural integrity of the cytoskeletal proteins alpha-tubulin, MAP2A&2B and NF-200 has been preserved in hUCB treatments. The behavioral scores of hind limbs of hUCB-treated rats improved significantly than those of the injured group, showing functional recovery. Taken together, our results indicate that hUCB-mediated downregulation of Fas and caspases leads to functional recovery of hind limbs of rats after SCI.
    11. Kao CH, Chen SH, Chio CC and Lin MT (2008). Human umbilical cord blood-derived CD34+ cells may attenuate spinal cord injury by stimulating vascular endothelial and neurotrophic factors. Shock 29: 49-55. Center for General Education, Southern Taiwan University of Technology, Taiwan. Human umbilical cord blood-derived CD34(+) cells were used to elucidate the mechanisms underlying the beneficial effects exerted by cord blood cells in spinal cord injury (SCI). Rats were divided into four groups: (1) sham operation (laminectomy only); (2) laminectomy + SCI + CD34(-) cells (5 x 10(5) human cord blood lymphocytes and monocytes that contained <0.2% CD34(+) cells); (3) laminectomy + SCI + CD34(+) cells (5 x 10(5) human cord blood lymphocytes and monocytes that contained approximately 95% CD34(+) cells); and (4) laminectomy + SCI + saline (0.3 mL). Spinal cord injury was induced by compressing the spinal cord for 1 min with an aneurysm clip calibrated to a closing pressure of 55 g. CD34 cells or saline was administered immediately after SCI via the tail vein. Behavioral tests of motor function measured by maximal angle an animal could hold to the inclined plane were conducted at days 1 to 7 after SCI. The triphenyltetrazolium chloride staining and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end labeling assay were also conducted after SCI to evaluate spinal cord infarction and apoptosis, respectively. To elucidate whether glial cell line-derived neurotrophic factor (GDNF) or vascular endothelial growth factor (VEGF) can be secreted in spinal cord-injured area by the i.v. transplanted CD34(+) cells, analysis of spinal cord homogenate supernatants by specific enzyme-linked immunosorbent assay for GDNF or immunofluorescence for VEGF was conducted. It was found that systemic administration of CD34(+), but not CD34(-), cells significantly attenuated the SCI-induced hind limb dysfunction and spinal cord infarction and apoptosis. Both GDNF and VEGF could be detected in the injured spinal cord after transplantation of CD34(+), but not CD34(-), cells. The results indicate that CD34(+) cell therapy may be beneficial in reversing the SCI-induced spinal cord infarction and apoptosis and hindlimb dysfunction by stimulating the production of both VEGF and GDNF in a spinal cord compression model.
    12. Dasari VR, Veeravalli KK, Tsung AJ, Gondi CS, Gujrati M, Dinh DH and Rao JS (2009). Neuronal apoptosis is inhibited by cord blood stem cells after spinal cord injury. J Neurotrauma 26: 2057-69. Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine at Peoria, Peoria, Illinois 61656, USA. Spinal cord injury (SCI) induces a series of endogenous biochemical changes that lead to secondary damage involving apoptosis as one of the major events. To understand the molecular basis of apoptosis after spinal cord injury, we subjected male rats to spinal cord injury using a weight drop device (NYU impactor) and evaluated the therapeutic potential of human umbilical cord blood stem cells (hUCB), which were stereotactically transplanted into the injury epicenter 1 week after SCI. We identified genes that render the adult-injured spinal cord nonconducive and the hUCB-treated spinal cord conducive to regeneration and repair at 3 weeks post-injury using an RT-PCR microarray by analyzing 84 apoptotic genes. Genes involved in inflammation and apoptosis were upregulated in injured spinal cords of rats, whereas genes involved in neuroprotection were upregulated in the hUCB-treated rats. Quantitative RT-PCR verified mRNA changes in the apoptotic genes of TNF-alpha, TNFR1, TNFR2, Fas, Lta, and CD40. Based on these results, we evaluated the role of TNF-alpha and its related apoptotic genes in neuronal death after SCI. Changes in the expression of TNF-alpha, TNFR1, and TNFR2 were observed over a period of 3 weeks post-SCI and after treatment with hUCB. Expression of P50 and P65 on neurons after SCI was efficiently downregulated by hUCB. These results were confirmed by the evaluation of apoptotic proteins of co-cultures of spinal neurons with hUCB under in-vitro conditions. The results of this study suggest that hUCB have therapeutic potential in inhibiting neuronal apoptosis during the repair of injured spinal cord.
    13. Lee JH, Chang HS, Kang EH, Chung DJ, Choi CB, Hwang SH, Han H and Kim HY (2009). Percutaneous transplantation of human umbilical cord blood-derived multipotent stem cells in a canine model of spinal cord injury. J Neurosurg Spine 11: 749-57. Department of Veterinary Surgery, Konkuk University, Seoul, Republic of Korea. OBJECT: The authors describe a method for percutaneous transplantation of human umbilical cord blood (hUCB)-derived multipotent stem cells (MSCs) under fluoroscopic guidance. The investigators then tested whether percutaneous transplantation of hUCB-derived MSCs improved neurological functional recovery after acute spinal cord injury (SCI). METHODS: The authors induced SCI in 10 dogs by percutaneous balloon compression. The 10 injured dogs were assigned randomly to the following groups (2 dogs each): Group 1, evaluated 2 weeks after sham transplantation; Group 2, evaluated 2 weeks after transplantation; Group 3, evaluated 4 weeks after sham transplantation; Group 4, evaluated 4 weeks after transplantation; and Group 5, evaluated 4 weeks after multispot transplantations. The dogs with sham transplantation (Groups 1 and 3) received the same volume of saline, as a control. A spinal needle was advanced into the spinal canal, and the investigators confirmed that the end of the spinal needle was located in the ventral part of spinal cord parenchyma by using contrast medium under fluoroscopic guidance. The hUCB-derived MSCs were transplanted into the cranial end of the injured segment in 6 injured dogs at 7 days after SCI. RESULTS: Two dogs in Group 2 showed no improvement until 2 weeks after transplantation. Three of 4 dogs (Groups 4 and 5) that received cellular transplants exhibited gradual improvement in hindlimb locomotion from 3 weeks after cell transplantation. The CM-DiI-labeled hUCB-derived MSCs were observed in the spinal cord lesions at 4 weeks posttransplantation and exerted a significant beneficial effect by reducing cyst and injury size. The transplanted cells were positive for NeuN, glial fibrillary acidic protein, and von Willebrand factor. CONCLUSIONS: The percutaneous transplantation technique described here can be easily performed, and it differs from previous techniques by avoiding surgical exposure and allowing cells to be more precisely transplanted into the spinal cord. This technique has many potential applications in the treatment of human SCI by cell transplantation. The results also suggest that transplantation of hUCB-derived MSCs may have therapeutic effects that decrease cavitation for acute SCI.
    14. Veeravalli KK, Dasari VR, Tsung AJ, Dinh DH, Gujrati M, Fassett D and Rao JS (2009). Stem cells downregulate the elevated levels of tissue plasminogen activator in rats after spinal cord injury. Neurochem Res 34: 1183-94. Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine at Peoria, One Illini Drive, Peoria, IL 61605, USA. We investigated the involvement of tPA after SCI in rats and effect of treatment with human umbilical cord blood derived stem cells. tPA expression and activity were determined in vivo after SCI in rats and in vitro in rat embryonic spinal neurons in response to injury with staurosporine, hydrogen peroxide and glutamate. The activity and/or expression of tPA increased after SCI and reached peak levels on day 21 post-SCI. Notably, the tPA mRNA activity was upregulated by 310-fold compared to controls on day 21 post-SCI. As expected, MBP expression is minimal at the time of peak tPA activity and vice versa. Implantation of hUCB after SCI resulted in the downregulation of elevated tPA activity/expression in vivo in rats as well as in vitro in spinal neurons. Our results demonstrated the involvement of tPA in the secondary pathogenesis after SCI as well as the therapeutic potential of hUCB.
    15. Veeravalli KK, Dasari VR, Tsung AJ, Dinh DH, Gujrati M, Fassett D and Rao JS (2009). Human umbilical cord blood stem cells upregulate matrix metalloproteinase-2 in rats after spinal cord injury. Neurobiol Dis 36: 200-12. Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine at Peoria, Peoria, IL 61605, USA. Matrix metalloproteinases (MMPs) are a large family of proteolytic enzymes involved in inflammation, wound healing and other pathological processes after neurological disorders. MMP-2 promotes functional recovery after spinal cord injury (SCI) by regulating the formation of a glial scar. In the present study, we aimed to investigate the expression and/or activity of several MMPs, after SCI and human umbilical cord blood mesenchymal stem cell (hUCB) treatment in rats with a special emphasis on MMP-2. Treatment with hUCB after SCI altered the expression of several MMPs in rats. MMP-2 is upregulated after hUCB treatment in spinal cord injured rats and in spinal neurons injured either with staurosporine or hydrogen peroxide. Further, hUCB induced upregulation of MMP-2 reduced formation of the glial scar at the site of injury along with reduced immunoreactivity to chondroitin sulfate proteoglycans. Blockade of MMP-2 activity in hUCB cocultured injured spinal neurons reduced the protection offered by hUCB which indicated the involvement of MMP-2 in the neuroprotection offered by hUCB. Based on these results, we conclude that hUCB treatment after SCI upregulates MMP-2 levels and reduces the formation of the glial scar thereby creating an environment suitable for endogenous repair mechanisms.
    16. Chua SJ, Bielecki R, Yamanaka N, Fehlings MG, Rogers IM and Casper RF (2010). The effect of umbilical cord blood cells on outcomes after experimental traumatic spinal cord injury. Spine (Phila Pa 1976) 35: 1520-6. From the *Samuel Lunenfeld Research Institute, Mt. Sinai Hospital, Toronto, Ontario, Canada; daggerInstitute of Medical Sciences, University of Toronto, Ontario, Canada; double daggerToronto Western Research Institute, Spinal Program, Krembil Neuroscience Centre, Ontario, Canada; and section signDepartment of Surgery, University of Toronto, Ontario, Canada. STUDY DESIGN.: A cytokine expression profile of umbilical cord blood (UCB) derived multipotential stem cells (MPSC) was produced. We then transplanted MPSCs into a rat model of spinal cord injury (SCI) and assessed neurologic function as well as spinal cord histology. OBJECTIVE.: To determine if MPSCs transplanted into a rat model of acute SCI would lead to a beneficial neurologic effect. SUMMARY OF BACKGROUND DATA.: Conditioned medium from UCB contains factors that could promote healing of endogenous neural tissues. Previously, our laboratory has demonstrated that UCB hematopoietic cells can develop into MPSCs capable of differentiating into multiple cell types including oligodendrocyte-like cells. METHODS.: We cultured MPSCs from UCB cells using fibroblast growth factor 4, stem cell factor and fms-like tyrosine kinase receptor-3 ligand supplemented serum-free medium. Using a cytokine antibody array, we produced a cytokines expression profile of MPSCs. We then transplanted MPSCs into an immunosuppressed rat model of SCI and assessed neurologic function weekly for 6 weeks by the Basso, Beattie, and Bresnahan locomotor test. The spinal cords were examined histologically and lesion areas quantified. RESULTS.: We detected elevated levels of cytokines and growth factors with known neuroprotective, angiogenic, and anti-inflammatory effects in the MPSC conditioned media. The SCI rats treated with MPSCs showed a significant improvement in Basso, Beattie, and Bresnahan scores after 6 weeks compared with the group that received vehicle only. Immunohistochemistry revealed transplanted human cells were present in the injured spinal cord after 1 week, but were no longer present by 6 weeks. There was a trend for the lesion size in treated rats to be smaller than that of the control group. CONCLUSION.: We conclude that UCB MPSCs improve neurologic function of rats with acute SCI, possibly by the release of factors that reduce secondary injury.
    17. Deng XY, Zhou RP, Lu KW and Jin DD (2010). [Lithium chloride combined with human umbilical cord blood mesenchymal stem cell transplantation for treatment of spinal cord injury in rats]. Nan fang yi ke da xue xue bao = Journal of Southern Medical University 30: 2436-9. Department of Spinal Surgery, Third Affiliated Hospital of Southern Medical University, Guangzhou 510630, China. dengxuyong@tom.com. OBJECTIVE: To observe the effects of lithium chloride combined with human umbilical cord blood mesenchymal stem cell (hUCB-SCs) transplantation in the treatment of spinal cord injury in rats. METHODS: Eighty female SD rats with complete T9 spinal cord transaction were randomized into 4 groups (n=20), namely the control group (group A), lithium chloride group (group B), hUCB-SCs group (group C) and hUCB-SCs(+) lithium chloride group (group D). On days 1 and 3 and the last days of the following weeks postoperatively, the motor function of the hindlimb of the rats were evaluated according to the BBB scores. At 8 weeks, all the rats were sacrificed and the spinal cords were taken for morphological observation. The spinal cord tissues at the injury site were observed with Brdu nuclear labeling to identify the survival and migration of the transplanted SCs. The regeneration and distribution of the spinal nerve fibers were observed with fluorescent-gold (FG) spinal cord retrograde tracing. RESULTS: Brdu labeling showed that the transplanted hUCB-SCs survived and migrated in the spinal cord 8 weeks postoperatively in groups C and D. FG retrograde tracing identified a small amount of pyramidal cells that migrated across the injury site in groups C and D. The BBB scores of the hindlimb motor function 8 weeks postoperatively were 4.11-/+0.14, 4.50-/+0.15, 8.31-/+0.11 and 11.15-/+0.18 in groups A, B, C and D, respectively. CONCLUSION: Lithium chloride can promote the survival and differentiation of hUCB-SCs into neural cells at the injury site. Lithium chloride combined with hUCB-SCs transplantation may accelerate functional recovery of the hindlimbs in rats with complete transection of the spinal cord.
    18. Ichim TE, Solano F, Lara F, Paris E, Ugalde F, Rodriguez JP, Minev B, Bogin V, Ramos F, Woods EJ, Murphy MP, Patel AN, Harman RJ and Riordan NH (2010). Feasibility of combination allogeneic stem cell therapy for spinal cord injury: a case report. Int Arch Med 3: 30. Medistem Inc, San Diego, USA. nhriordan@gmail.com. ABSTRACT: Cellular therapy for spinal cord injury (SCI) is overviewed focusing on bone marrow mononuclear cells, olfactory ensheathing cells, and mesenchymal stem cells. A case is made for the possibility of combining cell types, as well as for allogeneic use. We report the case of 29 year old male who suffered a crush fracture of the L1 vertebral body, lacking lower sensorimotor function, being a score A on the ASIA scale. Stem cell therapy comprised of intrathecal administration of allogeneic umbilical cord blood ex-vivo expanded CD34 and umbilical cord matrix MSC was performed 5 months, 8 months, and 14 months after injury. Cell administration was well tolerated with no adverse effects observed. Neuropathic pain subsided from intermittent 10/10 to once a week 3/10 VAS. Recovery of muscle, bowel and sexual function was noted, along with a decrease in ASIA score to "D". This case supports further investigation into allogeneic-based stem cell therapies for SCI.
    19. Kaner T, Karadag T, Cirak B, Erken HA, Karabulut A, Kiroglu Y, Akkaya S, Acar F, Coskun E, Genc O and Colakoglu N (2010). The effects of human umbilical cord blood transplantation in rats with experimentally induced spinal cord injury. J Neurosurg Spine 13: 543-51. Department of Neurosurgery, Pendik State Hospital, Istanbul, Turkey. OBJECT: Even though there have been many efforts to recover neuronal dysfunction following spinal cord injuries, there are limitations to the treatment of these injuries. The purpose of this laboratory investigation was to determine the clinical and neurophysiological effects of human umbilical cord blood (HUCB) transplantation in a rat hemisection model of spinal cord injury. METHODS: In this study, experimental hemisection of the thoracic spinal cord was performed in rats. The rats were divided into 4 groups (6 rats in each group). One group of rats (Group 1) underwent thoracic laminectomy only. Rats in Group 2 underwent laminectomy and right hemisection of the thoracic spinal cord. Rats in Group 3 underwent right hemisection and implantation of freshly obtained HUCB on Day 0 postinjury. Rats in Group 4 underwent hemisection and implantation of freshly obtained HUCB on Day 4 postinjury. Clinical evaluations of rat motor function included the following: neurological examination, Rotarod performance, and inclined plane tests. Rats also underwent reflex evaluation. RESULTS: The neurological examinations revealed that the frequency of plegic rats was 70.8% at the beginning of the study across all 4 groups; this value decreased to 20.8% by the end of the study. The percentage of rats with a normal examination increased from 25% to 50%. The results of Rotarod performance and 8-week inclined plane performance tests showed statistical significance (p < 0.05) in an overall group comparison across all time points. At the end of the 8 weeks, a statistically significant difference was found in the inclined plane test results between rats in Groups 1 and 2. There were no statistically significant differences between Groups 1, 3, and 4 (p < 0.05). When the reflex responses of the hemisectioned sides were compared, statistically significant differences were detected between groups (p < 0.05). All groups were significantly different with regard to the right-side reflex response score (p < 0.05). Spinal cord preparations of rats in all groups were examined for histopathological changes. CONCLUSIONS: Human umbilical cord blood is stem cell rich and easily available, and it carries less risk of inducing a graft-versus-host reaction in the recipient. Human umbilical cord blood serum is also noted to contain stem cell-promoting factors, which is why cell isolation was not used in this study. Freshly obtained cord blood was also used because storage of cord blood has been reported to have some negative effects on stem cells. Transplantation of freshly obtained HUCB into the hemisectioned spinal cord experimental model demonstrated clinical and neurophysiological improvement.
    20. Lee JH, Chung WH, Kang EH, Chung DJ, Choi CB, Chang HS, Hwang SH, Han H, Choe BY and Kim HY (2011). Schwann cell-like remyelination following transplantation of human umbilical cord blood (hUCB)-derived mesenchymal stem cells in dogs with acute spinal cord injury. J Neurol Sci 300: 86-96. Department of Veterinary Surgery, College of Veterinary Medicine, Konkuk University, Seoul, 143-701, Republic of Korea. Human umbilical cord blood derived mesenchymal stem cells (hUCB-MSCs) have significant therapeutic potential in cell-based therapies following spinal cord injury (SCI). To evaluate this potential, we conducted our preliminary investigations on the remyelination of injured spinal cords with hUCB-MSC transplantations and we observed its long term effects on dogs with SCI. Of the ten injured dogs, seven were transplanted with hUCB-MSCs 1 week after SCI, whereas the remaining three dogs were not transplanted. Two transplanted dogs died over the first month after transplantation because of urinary tract infection, bedsores and sepsis. The SCI dogs showed no improvement in motor and sensory functions and their urinary dysfunction persisted until they were euthanized (from 3 months to 1 year) while hind-limb recovery in 4 dogs among the five transplanted dogs was significantly improved. In the recovered dogs, functional recovery was sustained for three years following transplantation. Histological results from five transplanted dogs showed that many axons were remyelinated by P0-positive myelin sheaths after transplantation. Our results suggest that transplantation of hUCB-derived MSCs may have beneficial therapeutic effects. Furthermore, histological results provided the first in vivo evidence that hUCB-MSCs are able to enhance the remyelination of peripheral-type myelin sheaths following SCI.
    21. Park DH, Lee JH, Borlongan CV, Sanberg PR, Chung YG and Cho TH (2011). Transplantation of umbilical cord blood stem cells for treating spinal cord injury. Stem Cell Rev 7: 181-94. Department of Neurosurgery, Korea University Medical Center, Anam Hospital, Korea University College of Medicine, #126, 5-GA, Anam-Dong, Sungbuk-Ku, Seoul 136-705, Korea. doctorns@korea.com. Spinal cord injury (SCI) develops primary and secondary damage to neural tissue and this often results in permanent disability of the motor and sensory functions. However, there is currently no effective treatment except methylprednisolone, and the use of methylprednisolone has also been questioned due to its moderate efficacy and the drug's downside. Regenerative medicine has remarkably developed since the discovery of stem cells, and many studies have suggested the potential of cell-based therapies for neural injury. Especially, the therapeutic potential of human umbilical cord blood cells (hUCB cells) for intractable neurological disorders has been demonstrated using in vitro and vivo models. The hUCB cells are immune naive and they are able to differentiate into other phenotypes, including the neural lineage. Their ability to produce several neurotropic factors and to modulate immune and inflammatory reactions has also been noted. Recent evidence has emerged suggesting alternative pathways of graft-mediated neural repair that involve neurotrophic effects. These effects are caused by the release of various growth factors that promote cell survival, angiogenesis and anti-inflammation, and this is all aside from a cell replacement mechanism. In this review, we present the recent findings on the stemness properties and the therapeutic potential of hUCB as a safe, feasible and effective cellular source for transplantation in SCI. These multifaceted protective and restorative effects from hUCB grafts may be interdependent and they act in harmony to promote therapeutic benefits for SCI. Nevertheless, clinical studies with hUCB are still rare because of the concerns about safety and efficiency. Among these concerns, the major histocompatibility in allogeneic transplantation is an important issue to be addressed in future clinical trials for treating SCI.
    22. Park SS, Byeon YE, Ryu HH, Kang BJ, Kim Y, Kim WH, Kang KS, Han HJ and Kweon OK (2011). Comparison of canine umbilical cord blood-derived mesenchymal stem cell transplantation times: Involvement of astrogliosis, inflammation, intracellular actin cytoskeleton pathways, and neurotrophin. Cell Transplant Department of Veterinary Surgery, Laboratory of Stem cell and Tumor Biology, Department of Veterinary Public Health, College of Veterinary Medicine, Seoul National University, Seoul 151-742, Korea, ohkweon@snu.ac.kr. Canine mesenchymal stem cells (cMSCs) derived from umbilical cord blood represent a potentially useful source of stem cells for therapy. The aim of this study was to compare the effects of different transplantation times of cMSCs after spinal cord injury (SCI). A total of 21 dogs were subjected to SCI by balloon-induced compression of the first lumbar vertebrae for 12 hrs. Of the 21 dogs, 12 were divided into four groups of three according to the time of stem cell (1X10(6)) transplantation at the injury site: control no treatment, 12 hr, 1 wk, and 2 wk. The remaining 9 animals were negative harvest (HA) time controls for each treatment group (n =3). Olby and Tarlov scores were used to evaluate functional recovery of the hind limbs. Markers for neuronal regeneration (Tuj-1, nestin, MAP2, and NF-M), astrogliosis (GALC, GFAP, and pSTAT3), signal molecules for actin cytoskeleton (RhoA, Cdc42, and Rac1), inflammation (COX-2), and neurotrophins (NT-3) were evaluated by Western blot analysis. Scores of the 1 wk transplantation group showed significant improvement compared to controls. Hematoxylin and eosin (H & E) staining revealed less fibrosis at the injury site in the 1wk transplantation group compared to other groups and immunohistochemistry showed increased expression of neuronal markers. Furthermore, in both 1 wk and 2 wk transplantation groups, Tuj-1, nestin, MAP2, NF-M, NT-3, and GFAP increased, but pSTAT3, GALC, and COX2 decreased. RhoA decreased and Rac1 and Cdc42 increased in the 1 wk transplantation group. In conclusion, transplantation of cMSCs one week after SCI was more effective in improving clinical signs and neuronal regeneration and reducing fibrosis formation compared to the other transplantation times evaluated. Subsequently, these data may contribute to the optimization of timing for MSC transplantation used as a therapeutic modality.
    23. Park SI, Lim JY, Jeong CH, Kim SM, Jun JA, Jeun SS and Oh WI (2012). Human umbilical cord blood-derived mesenchymal stem cell therapy promotes functional recovery of contused rat spinal cord through enhancement of endogenous cell proliferation and oligogenesis. Journal of biomedicine & biotechnology 2012: 362473. Institute of Catholic Integrative Medicine (ICIM), Incheon St. Mary's Hospital, The Catholic University of Korea, Incheon, Republic of Korea. Numerous studies have shown the benefits of mesenchymal stem cells (MSCs) on the repair of spinal cord injury (SCI) model and on behavioral improvement, but the underlying mechanisms remain unclear. In this study, to investigate possible mechanisms by which MSCs contribute to the alleviation of neurologic deficits, we examined the potential effect of human umbilical cord blood-derived MSCs (hUCB-MSCs) on the endogenous cell proliferation and oligogenesis after SCI. SCI was injured by contusion using a weight-drop impactor and hUCB-MSCs were transplanted into the boundary zone of the injured site. Animals received a daily injection of bromodeoxyuridine (BrdU) for 7 days after treatment to identity newly synthesized cells of ependymal and periependymal cells that immunohistochemically resembled stem/progenitor cells was evident. Behavior analysis revealed that locomotor functions of hUCB-MSCs group were restored significantly and the cavity volume was smaller in the MSCs-transplanted rats compared to the control group. In MSCs-transplanted group, TUNEL-positive cells were decreased and BrdU-positive cells were significantly increased rats compared with control group. In addition, more of BrdU-positive cells expressed neural stem/progenitor cell nestin and oligo-lineage cell such as NG2, CNPase, MBP and glial fibrillary acidic protein typical of astrocytes in the MSC-transplanted rats. Thus, endogenous cell proliferation and oligogenesis contribute to MSC-promoted functional recovery following SCI.
    24. Rodrigues LP, Iglesias D, Nicola FC, Steffens D, Valentim L, Witczak A, Zanatta G, Achaval M, Pranke P and Netto CA (2012). Transplantation of mononuclear cells from human umbilical cord blood promotes functional recovery after traumatic spinal cord injury in Wistar rats. Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas / Sociedade Brasileira de Biofisica ... [et al.] 45: 49-57. Programa de Pos-Graduacao em Neurociencias, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brasil. lpro@terra.com.br. Cell transplantation is a promising experimental treatment for spinal cord injury. The aim of the present study was to evaluate the efficacy of mononuclear cells from human umbilical cord blood in promoting functional recovery when transplanted after a contusion spinal cord injury. Female Wistar rats (12 weeks old) were submitted to spinal injury with a MASCIS impactor and divided into 4 groups: control, surgical control, spinal cord injury, and one cell-treated lesion group. Mononuclear cells from umbilical cord blood of human male neonates were transplanted in two experiments: a) 1 h after surgery, into the injury site at a concentration of 5 x 10(6) cells diluted in 10 microL 0.9% NaCl (N = 8-10 per group); b) into the cisterna magna, 9 days after lesion at a concentration of 5 x 10(6) cells diluted in 150 microL 0.9% NaCl (N = 12-14 per group). The transplanted animals were immunosuppressed with cyclosporin-A (10 mg/kg per day). The BBB scale was used to evaluate motor behavior and the injury site was analyzed with immunofluorescent markers to label human transplanted cells, oligodendrocytes, neurons, and astrocytes. Spinal cord injury rats had 25% loss of cord tissue and cell treatment did not affect lesion extension. Transplanted cells survived in the injured area for 6 weeks after the procedure and both transplanted groups showed better motor recovery than the untreated ones (P < 0.05). The transplantation of mononuclear cells from human umbilical cord blood promoted functional recovery with no evidence of cell differentiation.
    25. Ryu HH, Kang BJ, Park SS, Kim Y, Sung GJ, Woo HM, Kim WH and Kweon OK (2012). Comparison of Mesenchymal Stem Cells Derived from Fat, Bone Marrow, Wharton's Jelly, and Umbilical Cord Blood for Treating Spinal Cord Injuries in Dogs. The Journal of veterinary medical science / the Japanese Society of Veterinary Science Department of Veterinary Surgery, College of Veterinary Medicine, Seoul National University. Previous animal studies have shown that transplantation of mesenchymal stem cells (MSCs) into spinal cord lesions enhances axonal regeneration and promotes functional recovery. We isolated the MSCs derived from fat, bone marrow, Wharton's jelly and umbilical cord blood (UCB) positive for MSC markers and negative for hematopoietic cell markers. Their effects on the regeneration of injured canine spinal cords were compared. Spinal cord injury was induced by balloon catheter compression. Dogs with injured spinal cords were treated with only matrigel or matrigel mixed with each type of MSCs. Olby and modified Tarlov scores, immunohistochemistry, ELISA and Western blot analysis were used to evaluate the therapeutic effects. The different MSC groups showed significant improvements in locomotion at 8 weeks after transplantation (P<0.05). This recovery was accompanied by increased numbers of surviving neuron and neurofilament-positive fibers in the lesion site. Compared to the control, the lesion sizes were smaller, and fewer microglia and reactive astrocytes were found in the spinal cord epicenter of all MSC groups. Although there were no significant differences in functional recovery among the MSCs groups, UCB-derived MSCs (UCSCs) induced more nerve regeneration and anti-inflammation activity (P<0.05). Transplanted MSCs survived for 8 weeks and reduced IL-6 and COX-2 levels, which may have promoted neuronal regeneration in the spinal cord. Our data suggest that transplantation of MSCs promotes functional recovery after SCI. Furthermore, application of UCSCs led to more nerve regeneration, neuroprotection and less inflammation compared to other MSCs.
    26. Schira J, Gasis M, Estrada V, Hendricks M, Schmitz C, Trapp T, Kruse F, Kogler G, Wernet P, Hartung HP and Muller HW (2012). Significant clinical, neuropathological and behavioural recovery from acute spinal cord trauma by transplantation of a well-defined somatic stem cell from human umbilical cord blood. Brain : a journal of neurology 135: 431-46. Molecular Neurobiology Laboratory, Department of Neurology, Heinrich-Heine-University Medical Centre Dusseldorf, Moorenstr. 5, 40223 Dusseldorf, Germany. Stem cell therapy is a potential treatment for spinal cord injury and different stem cell types have been grafted into animal models and humans suffering from spinal trauma. Due to inconsistent results, it is still an important and clinically relevant question which stem cell type will prove to be therapeutically effective. Thus far, stem cells of human sources grafted into spinal cord mostly included barely defined heterogeneous mesenchymal stem cell populations derived from bone marrow or umbilical cord blood. Here, we have transplanted a well-defined unrestricted somatic stem cell isolated from human umbilical cord blood into an acute traumatic spinal cord injury of adult immune suppressed rat. Grafting of unrestricted somatic stem cells into the vicinity of a dorsal hemisection injury at thoracic level eight resulted in hepatocyte growth factor-directed migration and accumulation within the lesion area, reduction in lesion size and augmented tissue sparing, enhanced axon regrowth and significant functional locomotor improvement as revealed by three behavioural tasks (open field Basso-Beattie-Bresnahan locomotor score, horizontal ladder walking test and CatWalk gait analysis). To accomplish the beneficial effects, neither neural differentiation nor long-lasting persistence of the grafted human stem cells appears to be required. The secretion of neurite outgrowth-promoting factors in vitro further suggests a paracrine function of unrestricted somatic stem cells in spinal cord injury. Given the highly supportive functional characteristics in spinal cord injury, production in virtually unlimited quantities at GMP grade and lack of ethical concerns, unrestricted somatic stem cells appear to be a highly suitable human stem cell source for clinical application in central nervous system injuries.

  5. #185
    Quote Originally Posted by Wise Young View Post
    I am sorry that I am in China and don't have the time answer in detail. I have posted many time on the subject. I will briefly summarize the justification for the clinical trial.

    Before I do so, let me say that people should not be calling umbilical cord blood mononuclear cells "my" therapy. In fact, as all of you have noticed, most of the preclinical studies were done by other investigators and not by my group at Rutgers. ChinaSCINet tests what its investigators consider to be the most promising and feasible therapies. In 2006, we reviewed the literature and found that umbilical cord blood cells were the most promising cell transplants for spinal cord injury for the following reasons:
    1. The cells are available in a well-vetted GMP source (i.e. Stemcyte) that adheres to rigorous standards of sterility, quality, and immune-compatibility.
    2. The cells have been reported by multiple independent laboratories to be beneficial in large and small animal spinal cord injury models.
    3. The cells have a strong safety record of use in both large and small animals.
    4. The cells are likely to be approved by regulatory authorities in China, U.S., Europe, and India.

    No other cell source fulfilled these criteria.

    Umbilical cord blood is available from a number of sources and we selected the best of these, i.e. Stemcyte, a commercial company with the largest and most diverse collection of cord blood in the world and a strong record of safe transplant of such cells in humans. We considered autologous bone marrow cells, fetal olfactory ensheathing cells, autologous nasal mucosa cells, fetal neural stem cells, embryonic stem cells, induced pluripotent stem cells, and many other sources. No other cells fulfilled GMP standards.

    Even in 2006, four independent laboratories had reported beneficial effects of umbilical cord blood on animal spinal cord injury models. Many additional studies have been published since 2006 confirming the original studies. Over a dozen independent laboratories have reported the beneficial effect so umbilical cord blood mononuclear cells on rat and dog models of spinal cord injury. It is true that few of them had been on "chronic" spinal cord injury but several have been in both dogs and rats at 1 week after injury.
    You don't need to justify the trial to me, it is already underway and I do hope for the best. I can wait patiently for the results. I am merely responding to another poster and pointing out that there are no animal studies proving efficacy in a chronic setting, let alone a chronic and complete setting. None that I have seen.

    I'm curious, in the list of references are there any publications with imaging showing severed axons growing across the injury site?

    Thank You

  6. #186
    Quote Originally Posted by NowhereMan View Post
    One of your mistakes, and it is a large one, is not comprehending the difference between acute and chronic spinal cord injury. They can almost be viewed as two completely different injuries. Most acute treatments in development attempt to preserve axons from dying, not to regenerate them. Night and day difference.
    I comprehend. You're saying acute SCI could be harder to repair than chronic SCI. I agree.

    Quote Originally Posted by NowhereMan View Post
    Other acute treatments being developed do attempt to regenerate axons so they are relevant to a chronic injury. No link that you provided shows/proves the UCB regenerated axons across the injury site.
    Except that they all improved.

    Quote Originally Posted by NowhereMan View Post
    In the acute rat studies you provided, I saw no evidence of axon growth across the injury site. If you look at the PTEN study, you will see nice images of axons growing across the injury site. Show me just one UCB study that has photographic evidence of axon growth.
    http://www.ncbi.nlm.nih.gov/pubmed/20694004
    Ok

    Quote Originally Posted by NowhereMan View Post
    Most importantly, If you are convinced that UCB cells will work in human chronic SCI (because they show efficacy in acute, incomplete animal models), where are the studies that show efficacy in Chronic animal models?
    I'm willing to bet you $100 that the DTI's Wise Young has seen suggesting robust axonal growth resulting from the UCBMC treatment are real.
    Last edited by crabbyshark; 01-11-2013 at 05:58 AM.

  7. #187
    Take the bet now. Mind you I doubt it will ever be finalized as the argument could go on forever.

    This thread was started because there were posts that were off topic in the ChinaSCINet thread. Well isn't the same happening here? (as if it really matters).

    This thread started out as "Jerry Silver and Other Discussion from ChinaSCINet" but is turning into ChinaSCINet thread number two.

  8. #188
    Quote Originally Posted by crabbyshark View Post
    I comprehend. You're saying acute SCI could be harder to repair than chronic SCI. I agree.
    I can't say with 100% certainty which would be harder because neither have been repaired yet. However, I think most neuroscientists would argue that acute injury is an easier puzzle to solve and fix than chronic injury is. Mammals don't regenerate their spinal cord. It makes sense that it would be easier to preserve the tissue in the first place than it is to regenerate it.

    Also, I don't understand why you would think that. In all the links you provided showing that UCB cells helped recovery, they were all done in acute injury animals. None were in chronic. Why then would you argue acute SCI could be harder to repair than chronic? That makes no sense.


    Quote Originally Posted by crabbyshark View Post
    Except that they all improved.
    Just because animals that received treatment during an acute injury recovered slightly more than control animals does not mean that axons regenerated across the injury site. It is most likely caused by preservation of more axons and/or remylination of preserved axons. I don't think you appreciate the magnitude of the challenge of getting axons to regenerate in a mammal spinal cord.



    Which figure in this publication shows axons growing across the injury site?


    Quote Originally Posted by crabbyshark View Post
    I'm willing to bet you $100 that the DTI's Wise Young has seen suggesting robust axonal growth resulting from the UCBMC treatment are real.
    I'd gladly take you up on that but there is no one authoritative figure who would have final say. I forsee different scientists having different opinions.

  9. #189
    Quote Originally Posted by NowhereMan View Post
    One of your mistakes, and it is a large one, is not comprehending the difference between acute and chronic spinal cord injury. They can almost be viewed as two completely different injuries. Most acute treatments in development attempt to preserve axons from dying, not to regenerate them. Night and day difference. Other acute treatments being developed do attempt to regenerate axons so they are relevant to a chronic injury. No link that you provided shows/proves the UCB regenerated axons across the injury site.

    In the acute rat studies you provided, I saw no evidence of axon growth across the injury site. If you look at the PTEN study, you will see nice images of axons growing across the injury site. Show me just one UCB study that has photographic evidence of axon growth.
    http://www.ncbi.nlm.nih.gov/pubmed/20694004

    Most importantly, If you are convinced that UCB cells will work in human chronic SCI (because they show efficacy in acute, incomplete animal models), where are the studies that show efficacy in Chronic animal models?

    NowhereMan. What is your background? Are you are scientist? You're asking many excellent questions that suggests you have in depth knowledge of spinal cord injury research.

  10. #190
    Quote Originally Posted by jsilver View Post
    NowhereMan. What is your background? Are you are scientist? You're asking many excellent questions that suggests you have in depth knowledge of spinal cord injury research.
    No, I'm no scientist, just have a degree in accounting. I have learned a lot just by reading this forum and watching videos posted from W2W. After a year or so it seeps in.

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