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Thread: Dr.Young

  1. #1
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    Dr.Young

    Dr.Young:
    I do not know if you remember me.I am from Mexico SCI 10 years post.I have seen how science have moved in these years.I have been to many places and meet many scientists.I do PT 2 hours a day 5 days a week and I can tell you that from when I had Dr.Kao surgery 8 years ago with shwann cells till today very little progress has been made.I remember asking him about OEC'S 8 years ago when they first were publisled.He said they where of no use,he said that in his case with shwann cells he had moved 10 years a head of science.And I think he wasn't all that wrong by saying that.
    Up until a couple of years ago OECS have been used in humans with out any success sofar,that means that OECS of today would be equal as shwann cells of the post.NO CURE.
    Now there are ESC and ASC a group of scientist support one and another group other,each group explaning why.But in neither case coming with a cure.
    As time goes by I think we would not see a CURE in the next 50 years.Now almost all scientist have shorten the definition of CURE by not meaning total CURE,but some-cure.Because they see how difficult that task is.Even if there was a semi-total cure in which paras could walk they will never be able to play sports or do simple tasks because they have many discs fused.As when a walking person damages one disk and get two vertebraes fused the Doc tells him not to jogor lift heavy weight.But back to experiments,as you have mencioned before the cure will have to be a combination therapy and as I asked you before I will ask again.It's there any lab doing experiments combination therapies using complete chronic injuered animals?
    If the answer is the same as before NO then we are not getting any where.
    Best regards
    "Elli,Elli lama Sabactani"

  2. #2
    Quote Originally Posted by pla9302
    Dr.Young:
    I do not know if you remember me.I am from Mexico SCI 10 years post.I have seen how science have moved in these years.I have been to many places and meet many scientists.I do PT 2 hours a day 5 days a week and I can tell you that from when I had Dr.Kao surgery 8 years ago with shwann cells till today very little progress has been made.I remember asking him about OEC'S 8 years ago when they first were publisled.He said they where of no use,he said that in his case with shwann cells he had moved 10 years a head of science.And I think he wasn't all that wrong by saying that.
    Up until a couple of years ago OECS have been used in humans with out any success sofar,that means that OECS of today would be equal as shwann cells of the post.NO CURE.
    Now there are ESC and ASC a group of scientist support one and another group other,each group explaning why.But in neither case coming with a cure.
    As time goes by I think we would not see a CURE in the next 50 years.Now almost all scientist have shorten the definition of CURE by not meaning total CURE,but some-cure.Because they see how difficult that task is.Even if there was a semi-total cure in which paras could walk they will never be able to play sports or do simple tasks because they have many discs fused.As when a walking person damages one disk and get two vertebraes fused the Doc tells him not to jogor lift heavy weight.But back to experiments,as you have mencioned before the cure will have to be a combination therapy and as I asked you before I will ask again.It's there any lab doing experiments combination therapies using complete chronic injuered animals?
    If the answer is the same as before NO then we are not getting any where.
    Best regards
    "Elli,Elli lama Sabactani"
    pla9302,

    I am not sure that the situation is as dire as you have painted. If you are expecting miracles, you won't find one. But, if you look for improvements, there are plenty of examples. Let's start with humans.

    Dobkin, et al. (2006) has now shown that 80-90% of people who are "incomplete" after spinal cord injury can recover locomotor function, compared to 40% in the past. This recovery occurs in both people who have received intensive weight-supported treadmill training and those who received defined standing and overground walking exercises.

    Several clinical investigations have reported minor improvements in patients who have been treated with cell transplants. While there have been some scientists who question these results because the studies were not controlled (i.e. compared against patients who received another therapy or placeo/no treatment) and some who have questioned the rigor of the study (Source), the results nevertheless have been fairly consistent and the results suggest that transplantation is relatively safe. On average, the patients have recovered multiple sensory levels and 1-2 motor levels.
    • Lima (see http://sci.rutgers.edu/forum/showthread.php?t=64995) reported the results of the first seven patients that transplanted nasal mucosa into
    • Huang (see http://sci.rutgers.edu/forum/showthread.php?t=62858&) recently published papers reporting results in chronic spinal cord injury patients who have received fetal olfactory ensheathing glial transplants.
    • Park, et al. (2005)) treated 6 complete spinal cord injury patients shortly after injury with autologous bone marrow transplants and reported significant improvements.
    • Rabinovich, et al. (2003) reported the results of transplanting 15 patients with a mixture of fetal nervous and hematopoietic tissues, claiming that 6 of 11 patients recovered from a ASIA classification of A to C.


    Unfortunately, Kao has not published his results. As you know, his results have been mixed. These are what I have referred to as "first generation" transplant studies. They have produced some recovery in some patients. The second generation transplant therapies are just beginning. These include Raisman's announced clinical trials to transplant purified olfactory ensheathing glia and the planned ChinaSCINet to transplant umbilical cord blood cells with lithium. We need controlled clinical trials with combination therapies.

    With regard to animal studies, I don't have the time to review the hundreds of animal studies that have reported improvements in function. But, let me just list some examples of bone marrow and mesenchymal stem cells transplants from the past 2 years. This is by no means a comprehensive list.
    • Shi E, Kazui T, Jiang X, Washiyama N, Yamashita K, Terada H and Bashar AH (2006). Intrathecal injection of bone marrow stromal cells attenuates neurologic injury after spinal cord ischemia. Ann Thorac Surg 81: 2227-33; discussion 2233-4. BACKGROUND: It has been shown that transplantation of bone marrow stromal cells (MSCs) into the ischemic brain improves functional outcome. We sought to investigate whether intrathecal injection of MSCs can attenuate neurologic injury of spinal cord ischemia. METHODS: Rabbit MSCs were expanded in vitro and were pre-labeled with bromodeoxyuridine. Spinal cord ischemia was induced in rabbits by infrarenal aortic occlusion. Group A and control A were subjected to a 20-minute ischemia and the ischemic duration was extended to 30 minutes in group B and control B. Two days before spinal cord ischemia, 1 x 10(8) MSCs were intrathecally injected into groups A and B, whereas vehicle alone was injected into the control groups. Hind-limb motor function was assessed during a 14-day recovery period with Tarlov criteria, and then histologic examination was performed. RESULTS: Marrow stromal cells survived and engrafted into the spinal cord 2 days after transplantation, and more MSCs were found in the lumbar spinal cord (ischemic segment) than in the thoracic spinal cord (nonischemic segment) at 14 days. Compared with their respective control groups, Tarlov scores were significantly higher in both groups A and B (p < 0.05, group A vs control A, at 2, 7, and 14 days; p < 0.05, group B vs control B, at 1, 2, 7, and 14 days, respectively). The number of intact motor neurons was much higher in the two experimental groups (p < 0.01 vs the corresponding control groups, respectively). CONCLUSIONS: Intrathecal injection of MSCs attenuates ischemic injury of spinal cord. First Department of Surgery, Hamamatsu University School of Medicine, Hamamatsu, Japan. http://www.ncbi.nlm.nih.gov/entrez/q..._uids=16731159

    • Zurita M and Vaquero J (2006). Bone marrow stromal cells can achieve cure of chronic paraplegic rats: Functional and morphological outcome one year after transplantation. Neurosci Lett 402: 51-6. Chronic paraplegia resulting from severe spinal cord injury (SCI) is considered to be an irreversible condition. Nevertheless, recent studies utilizing adult stem cells appear to offer promise in the treatment of this and other neurological diseases. Here, we show that progressive functional motor recovery is achieved over the course of the year following the administration of bone marrow stromal cells (BMSC) in traumatic central spinal cord cavities of adult rats with chronic paraplegia. At this time, functional recovery is almost complete and associated with evident nervous tissue regeneration in the previously injured spinal cord. Neuroscience Research Unit of the Mapfre-Medicine Foundation, Neurosurgical Service, Puerta de Hierro Hospital, Autonomus University, San Martin de Porres 4, 28035 Madrid, Spain. http://www.ncbi.nlm.nih.gov/entrez/q..._uids=16713677
    • Himes BT, Neuhuber B, Coleman C, Kushner R, Swanger SA, Kopen GC, Wagner J, Shumsky JS and Fischer I (2006). Recovery of function following grafting of human bone marrow-derived stromal cells into the injured spinal cord. Neurorehabil Neural Repair 20: 278-96. This study evaluates functional recovery after transplanting human bone marrow-derived stromal cells (BMSCs) into contusion models of spinal cord injury (SCI). The authors used a high-throughput process to expand BMSCs and characterized them by flow cytometry, ELISA, and gene expression. They found that BMSCs secrete neurotrophic factors and cytokines with therapeutic potential for cell survival and axon growth. In adult immune-suppressed rats, mild, moderate, or severe contusions were generated using the MASCIS impactor. One week following injury, 0.5 to 1 x 106 BMSCs were injected into the lesioned spinal cord; control animals received vehicle injection. Biweekly behavioral tests included the Basso, Beattie, and Bresnahan Locomotor Rating Scale (BBB), exploratory rearing, grid walking, and thermal sensitivity. Animals receiving moderate contusions followed by BMSC grafts showed significant behavioral recovery in BBB and rearing tests when compared to controls. Animals receiving BMSC grafts after mild or severe contusion showed trends toward improved recovery. Immunocytochemistry identified numerous axons passing through the injury in animals with BMSC grafts but few in controls. BMSCS were detected at 2 weeks after transplantation; however, at 11 weeks very few grafted cells remained. The authors conclude that BMSCs show potential for repairing SCI. However, the use of carefully characterized BMSCs improved transplantation protocols ensuring BMSC, survival, and systematic motor and sensory behavioral testing to identify robust recovery is imperative for further improvement. Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA 19129, USA. http://www.ncbi.nlm.nih.gov/entrez/q..._uids=16679505
    • Sykova E, Jendelova P, Urdzikova L, Lesny P and Hejcl A (2006). Bone Marrow Stem Cells and Polymer Hydrogels-Two Strategies for Spinal Cord Injury Repair. Cell Mol Neurobiol 1. Emerging clinical studies of treating brain and spinal cord injury (SCI) led us to examine the effect of autologous adult stem cell transplantation as well as the use of polymer scaffolds in spinal cord regeneration. We compared an intravenous injection of mesenchymal stem cells (MSCs) or the injection of a freshly prepared mononuclear fraction of bone marrow cells (BMCs) on the treatment of an acute or chronic balloon-induced spinal cord compression lesion in rats. Based on our experimental studies, autologous BMC implantation has been used in a Phase I/II clinical trial in patients (n=20) with a transversal spinal cord lesion.2. MSCs were isolated from rat bone marrow by their adherence to plastic, labeled with iron-oxide nanoparticles and expanded in vitro. Macroporous hydrogels based on derivatives of 2-hydroxyethyl methacrylate (HEMA) or 2-hydroxypropyl methacrylamide (HPMA) were prepared, then modified by their copolymerization with a hydrolytically degradable crosslinker, N,O-dimethacryloylhydroxylamine, or by different surface electric charges. Hydrogels or hydrogels seeded with MSCs were implanted into rats with hemisected spinal cords.3. Lesioned animals grafted with MSCs or BMCs had smaller lesions 35 days postgrafting and higher scores in BBB testing than did control animals and also showed a faster recovery of sensitivity in their hind limbs using the plantar test. The functional improvement was more pronounced in MSC-treated rats. In MR images, the lesion populated by grafted cells appeared as a dark hypointense area and was considerably smaller than in control animals. Morphometric measurements showed an increase in the volume of spared white matter in cell-treated animals. In the clinical trial, we compared intraarterial (via a. vertebralis, n=6) versus intravenous administration of BMCs (n=14) in a group of subacute (10-33 days post-SCI, n=8) and chronic patients (2-18 months, n=12). For patient follow-up we used MEP, SEP, MRI, and the ASIA score. Our clinical study revealed that the implantation of BMCs into patients is safe, as there were no complications following cell administration. Partial improvement in the ASIA score and partial recovery of MEP or SEP have been observed in all subacute patients who received cells via a. vertebralis (n=4) and in one out of four subacute patients who received cells intravenously. Improvement was also found in one chronic patient who received cells via a. vertebralis. A much larger population of patients is needed before any conclusions can be drawn. The implantation of hydrogels into hemisected rat spinal cords showed that cellular ingrowth was most pronounced in copolymers of HEMA with a positive surface electric charge. Although most of the cells had the morphological properties of connective tissue elements, we found NF-160-positive axons invading all the implanted hydrogels from both the proximal and distal stumps. The biodegradable hydrogels degraded from the border that was in direct contact with the spinal cord tissue. They were resorbed by macrophages and replaced by newly formed tissue containing connective tissue elements, blood vessels, GFAP-positive astrocytic processes, and NF-160-positive neurofilaments. Additionally, we implanted hydrogels seeded with nanoparticle-labeled MSCs into hemisected rat spinal cords. Hydrogels seeded with MSCs were visible on MR images as hypointense areas, and subsequent Prussian blue histological staining confirmed positively stained cells within the hydrogels.4. We conclude that treatment with different bone marrow cell populations had a positive effect on behavioral outcome and histopathological assessment after SCI in rats; this positive effect was most pronounced following MSC treatment. Our clinical study suggests a possible positive effect in patients with SCI. Bridging the lesion cavity can be an approach for further improving regeneration. Our preclinical studies showed that macroporous polymer hydrogels based on derivatives of HEMA or HPMA are suitable materials for bridging cavities after SCI; their chemical and physical properties can be modified to a specific use, and 3D implants seeded with different cell types may facilitate the ingrowth of axons. Institute of Experimental Medicine ASCR, Videnska, 1083 142 20, Prague 4, Czech Republic. http://www.ncbi.nlm.nih.gov/entrez/q..._uids=16633897
    • Enzmann GU, Benton RL, Talbott JF, Cao Q and Whittemore SR (2006). Functional considerations of stem cell transplantation therapy for spinal cord repair. J Neurotrauma 23: 479-95. Stem cells hold great promise for therapeutic repair after spinal cord injury (SCI). This review compares the current experimental approaches taken towards a stem cell-based therapy for SCI. It critically evaluates stem cell sources, injury paradigms, and functional measurements applied to detect behavioral changes after transplantation into the spinal cord. Many of the documented improvements do not exclusively depend on lineage-specific cellular differentiation. In most of the studies, the functional tests used cannot unequivocally demonstrate how differentiation of the transplanted cells contributes to the observed effects. Standardized cell isolation and transplantation protocols could facilitate the assessment of the true contribution of various experimental parameters on recovery. We conclude that at present embryonic stem (ES)-derived cells hold the most promise for therapeutic utility, but that non-neural cells may ultimately be optimal if the mechanism of possible transdifferentiation can be elucidated. Kentucky Spinal Cord Injury Research Center, Louisville, Kentucky 40202, USA. http://www.ncbi.nlm.nih.gov/entrez/q..._uids=16629631
    • Bakshi A, Barshinger AL, Swanger SA, Madhavani V, Shumsky JS, Neuhuber B and Fischer I (2006). Lumbar puncture delivery of bone marrow stromal cells in spinal cord contusion: a novel method for minimally invasive cell transplantation. J Neurotrauma 23: 55-65. Cell transplantation as a treatment for spinal cord injury is a promising therapeutic strategy whose effective clinical application would be facilitated by non-invasive delivery protocols. Cells derived from the bone marrow are particularly attractive because they can be obtained easily, expanded to large numbers and potentially used for autologous as well as allogeneic transplantation. In this study we tested the feasibility of a novel minimally invasive method--lumbar puncture (LP)--for transplanting bone marrow stromal stem cells (MSC) into a clinically relevant spinal cord contusion model. We further sought to determine optimal protocols for performing such minimally invasive cell transplantation. Sprague-Dawley rats received a moderate contusion injury at the midthoracic level followed by LP transplantation of MSC derived from transgenic rats that express the human placental alkaline phosphatase (AP) reporter gene. The recipients were analyzed histologically to evaluate the extent of cell delivery and survival at the injury site. We found that MSC delivered by LP reached the contused spinal cord tissues and exerted a significant beneficial effect by reducing cyst and injury size. Transplantation within 14 days of injury provided significantly greater grafting efficiency than more delayed delivery, and increasing MSC dosage improved cell engraftment. The techniques described here can easily be translated to patients, thus accelerating clinical application of stem cell therapies. Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, Pennsylvania 19129, USA. http://www.ncbi.nlm.nih.gov/entrez/q..._uids=16430372
    • Vaquero J, Zurita M, Oya S and Santos M (2006). Cell therapy using bone marrow stromal cells in chronic paraplegic rats: systemic or local administration? Neurosci Lett 398: 129-34. Recent studies showed the therapeutic effect of bone marrow stromal cells (BMSC) after spinal cord injury (SCI). In the present study, we compared the effect of systemic and local administration of BMSC in adult Wistar rats suffering chronic paraplegia as consequence of severe SCI. Adult Wistar rats were subjected to a weight-drop impact causing complete paraplegia, and 3 months later, all the animals remained without signs of functional recovery. At this moment, 3 x 10(6) BMSC were injected intravenously (n: 20) or into traumatic spinal cord cavity (n: 20). Outcome was evaluated until sacrifice of the animals, 6 months later, using the Basso-Beattie-Bresnehan (BBB) score, the cold spray test, and measuring the thigh perimeter. After sacrifice, samples of spinal cord tissue were studied histologically. The results showed that intravenous administration of BMSC achieves some degree of functional recovery when compared to controls. Nevertheless, administration of BMSC into postraumatic spinal cord cavity promotes a clear and progressive functional recovery, significantly superior to the recovery obtained by means of the intravenous administration. This effect is associated to long-term presence of BMSC in the injured spinal cord tissue, with images suggesting neuronal differentiation and spinal cord reconstruction. Neuroscience Research Unit of the Mapfre-Medicine Foundation, Neurosurgical and Experimental Surgery Services, Puerta de Hierro Hospital, Autonomous University, San Martin de Porres, 4, 28035 Madrid, Spain. jvaqueroc@telefonica.net http://www.ncbi.nlm.nih.gov/entrez/q..._uids=16423458
    • Koda M, Okada S, Nakayama T, Koshizuka S, Kamada T, Nishio Y, Someya Y, Yoshinaga K, Okawa A, Moriya H and Yamazaki M (2005). Hematopoietic stem cell and marrow stromal cell for spinal cord injury in mice. Neuroreport 16: 1763-7. We compared the effects of hematopoietic stem cell and marrow stromal cell transplantation for spinal cord injury in mice. From green fluorescent protein transgenic mouse bone marrow, lineage-negative, c-kit- and Sca-1-positive cells were sorted as hematopoietic stem cells and plastic-adherent cells were cultured as marrow stromal cells. One week after injury, hematopoietic stem cells or marrow stromal cells were injected into the lesioned site. Functional recovery was assessed and immunohistochemistry was performed. In the hematopoietic stem cell group, a portion of green fluorescent protein-positive cells expressed glial marker. In the marrow stem cell group, a number of green fluorescent protein and fibronectin-double positive cells were observed. No significant difference was observed in the recovery between both groups. Both hematopoietic stem cells and marrow stromal cells have the potential to restore the injured spinal cord and to promote functional recovery. Department of Orthopaedic Surgery, Chiba University Graduate School of Medicine, Chiba University Hospital, 1-8-1 Inohana, Chuo-ku, Chiba, Japan. m-koda@nifty.com http://www.ncbi.nlm.nih.gov/entrez/q..._uids=16237323
    • Deng YB, Yuan QT, Liu XG, Liu XL, Liu Y, Liu ZG and Zhang C (2005). Functional recovery after rhesus monkey spinal cord injury by transplantation of bone marrow mesenchymal-stem cell-derived neurons. Chin Med J (Engl) 118: 1533-41. BACKGROUND: The treatment of spinal cord injury is still a challenge. This study aimed at evaluating the therapeutical effectiveness of neurons derived form mesenchymal stem cells (MSCs) for spinal cord injury. METHODS: In this study, rhesus MSCs were isolated and induced by cryptotanshinone in vitro and then a process of RT-PCR was used to detect the expression of glutamic acid decarboxylase (GAD) gene. The induced MSCs were tagged with Hoechst 33342 and injected into the injury site of rhesus spinal cord made by the modified Allen method. Following that, behavior analysis was made after 1 week, 1 month, 2 months and 3 months. After 3 months, true blue chloride retrograde tracing study was also used to evaluate the re-establishment of axons pathway and the hematoxylin-eosin (HE) staining and immunohistochemistry were performed after the animals had been killed. RESULTS: In this study, the expression of mRNA of GAD gene could be found in the induced MSCs but not in primitive MSCs and immunohistochemistry could also confirm that rhesus MSCs could be induced and differentiated into neurons. Behavior analysis showed that the experimental animals restored the function of spinal cord up to grade 2-3 of Tarlov classification. Retrograde tracing study showed that true blue chollide could be found in the rostral thoracic spinal cords, red nucleus and sensory-motor cortex. CONCLUSIONS: These results suggest that the transplantation is safe and effective. Department of Pathophysiology, Zhongshan Medical College, Sun Yat-sen University, Guangzhou 510080, China. albert@gzsums.edu.cn http://www.ncbi.nlm.nih.gov/entrez/q..._uids=16232330
    • 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
    • Mansilla E, Marin GH, Sturla F, Drago HE, Gil MA, Salas E, Gardiner MC, Piccinelli G, Bossi S, Petrelli L, Iorio G, Ramos CA and Soratti C (2005). Human mesenchymal stem cells are tolerized by mice and improve skin and spinal cord injuries. Transplant Proc 37: 292-4. INTRODUCTION: We sought to use human mesenchymal stem cells (HMSC) for skin and spinal cord repair in mice. MATERIALS AND METHODS: Human bone marrow obtained from a young healthy donor was used to separate and culture human mesenchymal stem cells (HMSC). Ten mice were included in each of four groups. A full-thickness skin defect was surgically performed on all mice in groups 1 and 2. A transverse complete medullar section was performed in groups 3 and 4. Groups 1 and 3 received HMSC IV infusion and local HMSC polymer implant. Groups 2 and 4 received only the IV HMSC infusion. Five control animals from each group went through the same lesions but they didn't receive treatment. RESULTS: After local administration of HMSC into the fibrin polymer combined with the IV infusion of HMSC, there was no immune rejection; all skin defects healed without scar or retraction at a median time of 14 days. Sixty percent of the animals treated with IV infusion and polymer with HMSC simultaneously had improved neurological activities, while all control mice with spinal cord injury experiments died or perpetuated their paralysis with worsening muscular atrophy and increasing propensity to skin damage. CONCLUSIONS: HMSC are not immunologically reactive and can trespass species defense barriers. Animals treated with these cells repaired injuries better than controls. In this way we propose that universal HMSC from donors can be cultured, expanded, and cryopreserved to be used in human organ or tissue regeneration. National University of La Plata, La Plata, Argentina. http://www.ncbi.nlm.nih.gov/entrez/q..._uids=15808623
    • 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
    • Kamada T, Koda M, Dezawa M, Yoshinaga K, Hashimoto M, Koshizuka S, Nishio Y, Moriya H and Yamazaki M (2005). Transplantation of bone marrow stromal cell-derived Schwann cells promotes axonal regeneration and functional recovery after complete transection of adult rat spinal cord. J Neuropathol Exp Neurol 64: 37-45. The aim of this study was to evaluate whether transplantation of Schwann cells derived from bone marrow stromal cells (BMSC-SCs) promotes axonal regeneration and functional recovery in completely transected spinal cord in adult rats. Bone marrow stromal cells (BMSCs) were induced to differentiate into Schwann cells in vitro. A 4-mm segment of rat spinal cord was removed completely at the T7 level. An ultra-filtration membrane tube, filled with a mixture of Matrigel (MG) and BMSC-SCs (BMSC-SC group) or Matrigel alone (MG group), was grafted into the gap. In the BMSC-SC group, the number of neurofilament- and tyrosine hydroxylase-immunoreactive nerve fibers was significantly higher compared to the MG group, although 5-hydroxytryptamine- or calcitonin gene-related peptide-immunoreactive fibers were rarely detectable in both groups. In the BMSC-SC group, significant recovery of the hindlimb function was recognized, which was abolished by retransection of the graft 6 weeks after transplantation. These results demonstrate that transplantation of BMSC-SCs promotes axonal regeneration of lesioned spinal cord, resulting in recovery of hindlimb function in rats. Transplantation of BMSC-SCs is a potentially useful treatment for spinal cord injury. Department of Orthopaedic Surgery, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8677, Japan. http://www.ncbi.nlm.nih.gov/entrez/q..._uids=15715083
    • Neuhuber B, Timothy Himes B, Shumsky JS, Gallo G and Fischer I (2005). Axon growth and recovery of function supported by human bone marrow stromal cells in the injured spinal cord exhibit donor variations. Brain Res 1035: 73-85. Bone marrow stromal cells (MSC) are non-hematopoietic support cells that can be easily derived from bone marrow aspirates. Human MSC are clinically attractive because they can be expanded to large numbers in culture and reintroduced into patients as autografts or allografts. We grafted human MSC derived from aspirates of four different donors into a subtotal cervical hemisection in adult female rats and found that cells integrated well into the injury site, with little migration away from the graft. Immunocytochemical analysis demonstrated robust axonal growth through the grafts of animals treated with MSC, suggesting that MSC support axonal growth after spinal cord injury (SCI). However, the amount of axon growth through the graft site varied considerably between groups of animals treated with different MSC lots, suggesting that efficacy may be donor-dependent. Similarly, a battery of behavioral tests showed partial recovery in some treatment groups but not others. Using ELISA, we found variations in secretion patterns of selected growth factors and cytokines between different MSC lots. In a dorsal root ganglion explant culture system, we tested efficacy of conditioned medium from three donors and found that average axon lengths increased for all groups compared to control. These results suggest that human MSC produce factors important for mediating axon outgrowth and recovery after SCI but that MSC lots from different donors vary considerably. To qualify MSC lots for future clinical application, such notable differences in donor or lot-lot efficacy highlight the need for establishing adequate characterization, including the development of relevant efficacy assays. Department of Neurobiology and Anatomy, Drexel University College of Medicine, 2900 Queen Lane, Philadelphia, PA 19129, USA. http://www.ncbi.nlm.nih.gov/entrez/q..._uids=15713279
    • 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
    • Ankeny DP, McTigue DM and Jakeman LB (2004). Bone marrow transplants provide tissue protection and directional guidance for axons after contusive spinal cord injury in rats. Exp Neurol 190: 17-31. Contusive spinal cord injury (SCI) produces large fluid-, debris- and inflammatory cell-filled cystic cavities that lack structure to support significant axonal regeneration. The recent discovery of stem cells capable of generating central nervous system (CNS) tissues, coupled with success in neurotransplantation strategies, has renewed hope that repair and recovery from CNS trauma is possible. Based on results from several studies using bone marrow stromal cells (MSCs) to promote CNS repair, we transplanted MSCs into the rat SCI lesion cavity to further investigate their effects on functional recovery, lesion morphology, and axonal growth. We found that transplanted MSCs induced hindlimb airstepping--a spontaneous locomotor movement associated with activation of the stepping control circuitry--but did not alter the time course or extent of overground locomotor recovery. Using stereological techniques to describe spinal cord anatomy, we show that MSC transplants occupied the lesion cavity and were associated with preservation of host tissue and white matter (myelin), demonstrating that these cells exert neuroprotective effects. The tissue matrix formed by MSC grafts supported greater axonal growth than that found in specimens without grafts. Moreover, uniform random sampling of axon profiles revealed that the majority of neurites in MSC grafts were oriented with their long axis parallel to that of the spinal cord, suggesting longitudinally directed growth. Together, these studies support further investigation of marrow stromal cells as a potential SCI repair strategy. Department of Physiology and Cell Biology, The Ohio State University, 333 West 10th Avenue, Columbus, OH 43210, USA. Ankeny.3@osu.edu http://www.ncbi.nlm.nih.gov/entrez/q..._uids=15473977
    • Lu P, Yang H, Jones LL, Filbin MT and Tuszynski MH (2004). Combinatorial therapy with neurotrophins and cAMP promotes axonal regeneration beyond sites of spinal cord injury. J Neurosci 24: 6402-9. Previous attempts to promote regeneration after spinal cord injury have succeeded in stimulating axonal growth into or around lesion sites but rarely beyond them. We tested whether a combinatorial approach of stimulating the neuronal cell body with cAMP and the injured axon with neurotrophins would propel axonal growth into and beyond sites of spinal cord injury. A preconditioning stimulus to sensory neuronal cell bodies was delivered by injecting cAMP into the L4 dorsal root ganglion, and a postinjury stimulus to the injured axon was administered by injecting neurotrophin-3 (NT-3) within and beyond a cervical spinal cord lesion site grafted with autologous bone marrow stromal cells. One to 3 months later, long-projecting dorsal-column sensory axons regenerated into and beyond the lesion. Regeneration beyond the lesion did not occur after treatment with cAMP or NT-3 alone. Thus, clear axonal regeneration beyond spinal cord injury sites can be achieved by combinatorial approaches that stimulate both the neuronal soma and the axon, representing a major advance in strategies to enhance spinal cord repair. Department of Neurosciences, University of California at San Diego, La Jolla, California 92093-0626, USA. http://www.ncbi.nlm.nih.gov/entrez/q..._uids=15254096

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