oeg and stem cell

DA · 05-04-2003, 08:45 AM

a few years back, dr young, you posted that stem cells implanted into spinal cord turned into nothing helpful.(long story short). so why in nasal mucosa transplants are you not giving credit to the oeg when pass results showed stem cells aren't helpful.

Wise Young · 05-04-2003, 08:14 PM

DA,

What I said was that stem cells have been shown to remyelinate the spinal cord but they have not yet been shown to regenerate the spinal cord. There was no evidence that stem cells regenerate the spinal cord. However, that situation has changed. The Keio University group in Japan has now published a number of papers showing that fetal neural stem cells are beneficial and stimulate recovery in rats after spinal cord injury.

Lu's papers in Brain and Spine are interesting and I really hope that nasal mucosa transplants or stem cells from the nasal mucosa help restore function, whether through regeneration or remyelination. We are all anxiously awaiting the results of both the Lisbon and Brisbane trial.

Wise.

larwatson · 05-05-2003, 10:01 AM

In addition to the fetal stem cells in japan we also now have the reports from minnesota and Neuronyx indicating that asc's are following closely behind.

This is great stuff.

DA · 05-05-2003, 10:27 AM

dr young are you saying their is some evidence that stem cells REGENERATE axons in the spinal cord? ----------

Wise Young · 05-05-2003, 10:49 AM

Yes. Here are some examples... I have deliberately excluded embryonic stem cells although some of these studies used fetal neural stem cells.

• Cao Q, Benton RL and Whittemore SR (2002). Stem cell repair of central nervous system injury. J Neurosci Res 68:501-10. Summary: Neural stem cells (NSCs) have great potential as a therapeutic tool for the repair of a number of CNS disorders. NSCs can either be isolated from embryonic and adult brain tissue or be induced from both mouse and human ES cells. These cells proliferate in vitro through many passages without losing their multipotentiality. Following engraftment into the adult CNS, NSCs differentiate mainly into glia, except in neurogenic areas. After engraftment into the injured and diseased CNS, their differentiation is further retarded. In vitro manipulation of NSC fate prior to transplantation and/or modification of the host environment may be necessary to control the terminal lineage of the transplanted cells to obtain functionally significant numbers of neurons. NSCs and a few types of glial precursors have shown the capability to differentiate into oligodendrocytes and to remyeliate the demyelinated axons in the CNS, but the functional extent of remyelination achieved by these transplants is limited. Manipulation of endogenous neural precursors may be an alternative therapy or a complimentary therapy to stem cell transplantation for neurodegenerative disease and CNS injury. However, this at present is challenging and so far has been unsuccessful. Understanding mechanisms of NSC differentiation in the context of the injured CNS will be critical to achieving these therapeutic strategies. Kentucky Spinal Cord Injury Research Center, University of Louisville School of Medicine, Louisville, Kentucky, USA.

• Cao QL, Howard RM, Dennison JB and Whittemore SR (2002). Differentiation of engrafted neuronal-restricted precursor cells is inhibited in the traumatically injured spinal cord. Exp Neurol 177:349-59. Summary: Differentiation of pluripotent neural stem cells engrafted into the adult normal and injured spinal cord is restricted to the glial lineage, suggesting that in vitro induction toward a neuronal lineage prior to transplantation and/or modification of the host environment may be necessary to initiate and increase the differentiation of neurons. In the present study, we investigated the differentiation of neuronal-restricted precursors (NRPs) grafted into the normal and contused adult rat spinal cord. NRPs proliferated through multiple passages in the presence of FGF2 and NT3 and differentiated into only neurons in vitro in the presence of retinoic acid and the absence of FGF2. Differentiated NRPs expressed GABA, glycine, glutamate, and ChAT. Two weeks to 2 months after engraftment of undifferentiated NRPs into adult normal spinal cord, large numbers of surviving cells were seen in all of the animals. The majority differentiated into betaIII-tubulin-positive neurons. Some transplanted NRPs expressed GABA and small numbers were glutamate- and ChAT-positive. NRPs were also transplanted into the epicenter of the contused adult rat spinal cord. Two weeks to 2 months after transplantation, some engrafted NRPs remained undifferentiated nestin-positive cells. Small numbers were MAP2- or betaIII-tubulin-positive neurons. However, the expression of GABA, glutamate, or ChAT was not observed. These results show that NRPs can differentiate into different types of neurons in the normal adult rat spinal cord, but that such differentiation is inhibited in the injured spinal cord. Manipulation of the microenvironment in the injured spinal cord will likely be necessary to facilitate neuronal replacement. Kentucky Spinal Cord Injury Research Center, University of Louisville School of Medicine, Louisville, Kentucky 40202, USA.

• Galvin KA and Jones DG (2002). Adult human neural stem cells for cell-replacement therapies in the central nervous system. Med J Aust 177:316-8. Summary: Human neural stem cells (HNSCs) can be isolated from both the developing and adult central nervous system (CNS). HNSCs can be successfully grown in culture, are self-renewable, and can generate mature neuronal and glial progeny. Embryonic HNSCs can be induced to differentiate into specific neuronal phenotypes. HNSCs successfully integrate into the host environment after transplantation into the developing or adult CNS. HNSCs transplanted into animal models of Parkinson's disease and spinal cord injury have induced functional recovery. The risks associated with stem cell transplantation trials are difficult to assess, but have not become overtly apparent throughout preclinical investigations. Major hurdles remain to be overcome before human clinical trials can be embarked upon. Department of Anatomy and Structural Biology, University of Otago, Dunedin, New Zealand.

• Han SS, Kang DY, Mujtaba T, Rao MS and Fischer I (2002). Grafted lineage-restricted precursors differentiate exclusively into neurons in the adult spinal cord. Exp Neurol 177:360-75. Summary: Multipotent neural stem cells (NSCs) have the potential to differentiate into neuronal and glial cells and are therefore candidates for cell replacement after CNS injury. Their phenotypic fate in vivo is dependent on the engraftment site, suggesting that the environment exerts differential effects on neuronal and glial lineages. In particular, when grafted into the adult spinal cord, NSCs are restricted to the glial lineage, indicating that the host spinal cord environment is not permissive for neuronal differentiation. To identify the stage at which neuronal differentiation is inhibited we examined the survival, differentiation, and integration of neuronal restricted precursor (NRP) cells, derived from the embryonic spinal cord of transgenic alkaline phosphatase rats, after transplantation into the adult spinal cord. We found that grafted NRP cells differentiate into mature neurons, survive for at least 1 month, appear to integrate within the host spinal cord, and extend processes in both the gray and white matter. Conversely, grafted glial restricted precursor cells did not differentiate into neurons. We did not observe glial differentiation from the grafted NRP cells, indicating that they retained their neuronal restricted properties in vivo. We conclude that the adult nonneurogenic CNS environment does not support the transition of multipotential NSCs to the neuronal commitment stage, but does allow the survival, maturation, and integration of NRP cells. Department of Neurobiology and Anatomy, Drexel University College of Medicine, 2900 Queen Lane, Philadelphia, Pennsylvania 19129, USA [corrected].

• Nakamura M and Toyama Y (2003). [Transplantation of neural stem cells into spinal cord after injury]. Nippon Rinsho 61:463-8. Summary: Recovery from central nervous system damage in adult mammals is hindered by their limited ability to replace lost cells and damaged myelin, and reestablish functional neural connections. However, recent progresses in stem cell biology are making it feasible to induce the regeneration of injured axons after spinal cord injury. Transplantation of in vitro expanded neural stem cells into rat spinal cord 9 days after contusion injury induced their differentiation into neurons and oligodendrocytes, and the functional recovery of skilled forelimb movement. It was partly because the microenvironment within the injured spinal cord at 9 days after injury was more favorable for grafted neural stem cells in terms of their survival and differentiation. Department of Orthopedic Surgery, School of Medicine, Keio University.

• Ogawa Y, Sawamoto K, Miyata T, Miyao S, Watanabe M, Nakamura M, Bregman BS, Koike M, Uchiyama Y, Toyama Y and Okano H (2002). Transplantation of in vitro-expanded fetal neural progenitor cells results in neurogenesis and functional recovery after spinal cord contusion injury in adult rats. J Neurosci Res 69:925-33. Summary: Neural progenitor cells, including neural stem cells, are a potential expandable source of graft material for transplantation aimed at repairing the damaged CNS. Here we present the first evidence that in vitro-expanded fetus-derived neurosphere cells were able to generate neurons in vivo and improve motor function upon transplantation into an adult rat spinal-cord-contusion injury model. As the source of graft material, we used a neural stem cell-enriched population that was derived from rat embryonic spinal cord (E14.5) and expanded in vitro by neurosphere formation. Nine days after contusion injury, these neurosphere cells were transplanted into adult rat spinal cord at the injury site. Histological analysis 5 weeks after the transplantation showed that mitotic neurogenesis occurred from the transplanted donor progenitor cells within the adult rat spinal cord, a nonneurogenic region; that these donor-derived neurons extended their processes into the host tissues; and that the neurites formed synaptic structures. Furthermore, analysis of motor behavior using a skilled reaching task indicated that the treated rats showed functional recovery. These results indicate that in vitro-expanded neurosphere cells derived from the fetal spinal cord are a potential source for transplantable material for treatment of spinal cord injury. Department of Physiology, Keio University School of Medicine, Tokyo, Japan. hidokano@sc.itc.keio.ac.jp

• Teng YD, Lavik EB, Qu X, Park KI, Ourednik J, Zurakowski D, Langer R and Snyder EY (2002). Functional recovery following traumatic spinal cord injury mediated by a unique polymer scaffold seeded with neural stem cells. Proc Natl Acad Sci U S A 99:3024-9. Summary: To better direct repair following spinal cord injury (SCI), we designed an implant modeled after the intact spinal cord consisting of a multicomponent polymer scaffold seeded with neural stem cells. Implantation of the scaffold-neural stem cells unit into an adult rat hemisection model of SCI promoted long-term improvement in function (persistent for 1 year in some animals) relative to a lesion-control group. At 70 days postinjury, animals implanted with scaffold-plus-cells exhibited coordinated, weight-bearing hindlimb stepping. Histology and immunocytochemical analysis suggested that this recovery might be attributable partly to a reduction in tissue loss from secondary injury processes as well as in diminished glial scarring. Tract tracing demonstrated corticospinal tract fibers passing through the injury epicenter to the caudal cord, a phenomenon not present in untreated groups. Together with evidence of enhanced local GAP-43 expression not seen in controls, these findings suggest a possible regeneration component. These results may suggest a new approach to SCI and, more broadly, may serve as a prototype for multidisciplinary strategies against complex neurological problems. Department of Neurology, Harvard Medical School, Boston, MA 02115, USA.

• Tzeng SF (2002). Neural progenitors isolated from newborn rat spinal cords differentiate into neurons and astroglia. J Biomed Sci 9:10-6. Summary: Permanent functional deficit in patients with spinal cord injury (SCI) is in part due to severe neural cell death. Therefore, cell replacement using stem cells and neural progenitors that give rise to neurons and glia is thought to be a potent strategy to promote tissue repair after SCI. Many studies have shown that stem cells and neural progenitors can be isolated from embryonic, postnatal and adult spinal cords. Recently, we isolated neural progenitors from newborn rat spinal cords. In general, the neural progenitors grew as spheres in culture, and showed immunoreactivity to a neural progenitor cellular marker, nestin. They were found to proliferate and differentiate into glial fibrillary acidic protein-positive astroglia and multiple neuronal populations, including GABAergic and cholinergic neurons. Neurotrophin 3 and neurotrophin 4 enhanced the differentiation of neural progenitors into neurons. Furthermore, the neural progenitors that were transplanted into contusive spinal cords were found to survive and have migrated in the spinal cord rostrally and caudally over 8 mm to the lesion center 7 days after injury. Thus, the neural progenitors isolated from newborn rat spinal cords in combination with neurotrophic factors may provide a tool for cell therapy in SCI patients. Department of Biology, National Cheng-Kung University, Tainan, Taiwan, ROC. stzeng@mail.ncku.edu.tw

Wise Young · 05-06-2003, 06:59 AM

DA, stem cells may have the following beneficial effects for spinal cord injury:

1. Bridging. They may provide a permissive bridge at the injury site that allow axonal growth. Many stem cells have been shown to produce astrocytes that may be permissive. Of course, one of the problems with stem cells is that we do not know yet how to control what they become after transplantation. That is one of the reasons why OEG's are so attractive. We don't know what nasal mucosal stem cells become when they are transplanted into the spinal cord. Perhaps they will make olfactory mucosa cells. Look, this may sound funny but Doug Anderson transplanted nasal mucosa into a cat spinal cord in 1989. I remember seeing sheets of hairy nasal mucosal cells in the spinal cord. Not a pretty sight.

2. Growth factors. Stem cells secrete growth factors and cell adhesion molecules that may facilitate axonal growth. They can be genetically modified to produce growth factors and cell adhesion molecules to promote regeneration. Some cells will also migrate in the spinal cord and may be able to facilitate growth of axons not only at the injury site but in the surrounding cord. By the way, many cells (such as fibroblasts and Schwann cells) do not migrate in the spinal cord.

3. Cell replacement. Stem cells may be able to replace neurons that have been lost at the injury area. This may be useful for reversing atrophy and also for reducing neuropathic pain. They will also be able to replace oligodendroglia to remyelinate the spinal cord. Everybody assumes that bone marrow and umbilical cord blood cells can be easily turned into neurons or astrocytes. This is not true. I would dearly love to know how to make a stem cell produce olfactory ensheathing glia. After all, they are being made in the nasal mucosa all throughout adult life.

Wise.

DA · 05-06-2003, 08:50 AM

dr young...has anyone did a gene study in the difference between all stem cells?

can you take oeg cells and mix them with stem cells and then use same method to grow numbers of oeg. the stem cells will copy the oeg by changing into oeg.

how about taking oeg cells, introducing the cancer gene, grow a few billion cells, then take away cancer gene. outside the body ofcourse.

Wise Young · 05-06-2003, 09:06 AM

DA, all that has been done.

1. OEG Cell line. There is an OEG cell line has been immortalized with the T-oncogene and has been transplanted into the spinal cord. Removing the gene is, however, a lot of trouble. An alternative is to find the OEG precursor/progenitor cell. We tried for many months to find the OEG precursor/progenitor cell and did not succeed. The lack of such a cell line is of course why we are still struggling to find a feasible source of human OEG for transplantation.

2. Mixing OEG and stem cells. There was a recent study suggesting that mixing mesenchymal stem cells and OEG actually promotes the ability of OEG to remyelinate the spinal cord. We are very interested in doing that, particularly with umbilical cord blood cells.

3. Gene studies of stem cells. I have not been posting the flood of papers that are being published daily concerning the genes that regulate stem cells and how they differentiate into different cells. This is probably one of the hottest areas of research. I believe that the field will soon know what genes make a stem cell. It will happen probably within a year. This, unfortunately, will not make embryonic stem cells moot. I think that it will be some years before we will understand in detail how cells differentiate. In order to do that, we have have access to embryonic and fetal stem cells. Also, there are sufficient species differences that the studies must be carried out in human stem cells.

Wise.

05-04-2003, 08:45 AM	#1
DA Senior Member Join Date: Jul 2001 Location: beaumont tx usa Posts: 32,390	oeg and stem cell a few years back, dr young, you posted that stem cells implanted into spinal cord turned into nothing helpful.(long story short). so why in nasal mucosa transplants are you not giving credit to the oeg when pass results showed stem cells aren't helpful.

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05-04-2003, 08:14 PM	#2
Wise Young Administrator Join Date: Jul 2001 Location: New Brunswick, NJ, USA Posts: 37,975	DA, What I said was that stem cells have been shown to remyelinate the spinal cord but they have not yet been shown to regenerate the spinal cord. There was no evidence that stem cells regenerate the spinal cord. However, that situation has changed. The Keio University group in Japan has now published a number of papers showing that fetal neural stem cells are beneficial and stimulate recovery in rats after spinal cord injury. Lu's papers in Brain and Spine are interesting and I really hope that nasal mucosa transplants or stem cells from the nasal mucosa help restore function, whether through regeneration or remyelination. We are all anxiously awaiting the results of both the Lisbon and Brisbane trial. Wise.

05-05-2003, 10:01 AM	#3
larwatson Senior Member Join Date: Jul 2002 Posts: 1,110	In addition to the fetal stem cells in japan we also now have the reports from minnesota and Neuronyx indicating that asc's are following closely behind. This is great stuff.

05-05-2003, 10:27 AM	#4
DA Senior Member Join Date: Jul 2001 Location: beaumont tx usa Posts: 32,390	dr young are you saying their is some evidence that stem cells REGENERATE axons in the spinal cord? ----------

05-05-2003, 10:49 AM	#5
Wise Young Administrator Join Date: Jul 2001 Location: New Brunswick, NJ, USA Posts: 37,975	Yes. Here are some examples... I have deliberately excluded embryonic stem cells although some of these studies used fetal neural stem cells. • Cao Q, Benton RL and Whittemore SR (2002). Stem cell repair of central nervous system injury. J Neurosci Res 68:501-10. Summary: Neural stem cells (NSCs) have great potential as a therapeutic tool for the repair of a number of CNS disorders. NSCs can either be isolated from embryonic and adult brain tissue or be induced from both mouse and human ES cells. These cells proliferate in vitro through many passages without losing their multipotentiality. Following engraftment into the adult CNS, NSCs differentiate mainly into glia, except in neurogenic areas. After engraftment into the injured and diseased CNS, their differentiation is further retarded. In vitro manipulation of NSC fate prior to transplantation and/or modification of the host environment may be necessary to control the terminal lineage of the transplanted cells to obtain functionally significant numbers of neurons. NSCs and a few types of glial precursors have shown the capability to differentiate into oligodendrocytes and to remyeliate the demyelinated axons in the CNS, but the functional extent of remyelination achieved by these transplants is limited. Manipulation of endogenous neural precursors may be an alternative therapy or a complimentary therapy to stem cell transplantation for neurodegenerative disease and CNS injury. However, this at present is challenging and so far has been unsuccessful. Understanding mechanisms of NSC differentiation in the context of the injured CNS will be critical to achieving these therapeutic strategies. Kentucky Spinal Cord Injury Research Center, University of Louisville School of Medicine, Louisville, Kentucky, USA. • Cao QL, Howard RM, Dennison JB and Whittemore SR (2002). Differentiation of engrafted neuronal-restricted precursor cells is inhibited in the traumatically injured spinal cord. Exp Neurol 177:349-59. Summary: Differentiation of pluripotent neural stem cells engrafted into the adult normal and injured spinal cord is restricted to the glial lineage, suggesting that in vitro induction toward a neuronal lineage prior to transplantation and/or modification of the host environment may be necessary to initiate and increase the differentiation of neurons. In the present study, we investigated the differentiation of neuronal-restricted precursors (NRPs) grafted into the normal and contused adult rat spinal cord. NRPs proliferated through multiple passages in the presence of FGF2 and NT3 and differentiated into only neurons in vitro in the presence of retinoic acid and the absence of FGF2. Differentiated NRPs expressed GABA, glycine, glutamate, and ChAT. Two weeks to 2 months after engraftment of undifferentiated NRPs into adult normal spinal cord, large numbers of surviving cells were seen in all of the animals. The majority differentiated into betaIII-tubulin-positive neurons. Some transplanted NRPs expressed GABA and small numbers were glutamate- and ChAT-positive. NRPs were also transplanted into the epicenter of the contused adult rat spinal cord. Two weeks to 2 months after transplantation, some engrafted NRPs remained undifferentiated nestin-positive cells. Small numbers were MAP2- or betaIII-tubulin-positive neurons. However, the expression of GABA, glutamate, or ChAT was not observed. These results show that NRPs can differentiate into different types of neurons in the normal adult rat spinal cord, but that such differentiation is inhibited in the injured spinal cord. Manipulation of the microenvironment in the injured spinal cord will likely be necessary to facilitate neuronal replacement. Kentucky Spinal Cord Injury Research Center, University of Louisville School of Medicine, Louisville, Kentucky 40202, USA. • Galvin KA and Jones DG (2002). Adult human neural stem cells for cell-replacement therapies in the central nervous system. Med J Aust 177:316-8. Summary: Human neural stem cells (HNSCs) can be isolated from both the developing and adult central nervous system (CNS). HNSCs can be successfully grown in culture, are self-renewable, and can generate mature neuronal and glial progeny. Embryonic HNSCs can be induced to differentiate into specific neuronal phenotypes. HNSCs successfully integrate into the host environment after transplantation into the developing or adult CNS. HNSCs transplanted into animal models of Parkinson's disease and spinal cord injury have induced functional recovery. The risks associated with stem cell transplantation trials are difficult to assess, but have not become overtly apparent throughout preclinical investigations. Major hurdles remain to be overcome before human clinical trials can be embarked upon. Department of Anatomy and Structural Biology, University of Otago, Dunedin, New Zealand. • Han SS, Kang DY, Mujtaba T, Rao MS and Fischer I (2002). Grafted lineage-restricted precursors differentiate exclusively into neurons in the adult spinal cord. Exp Neurol 177:360-75. Summary: Multipotent neural stem cells (NSCs) have the potential to differentiate into neuronal and glial cells and are therefore candidates for cell replacement after CNS injury. Their phenotypic fate in vivo is dependent on the engraftment site, suggesting that the environment exerts differential effects on neuronal and glial lineages. In particular, when grafted into the adult spinal cord, NSCs are restricted to the glial lineage, indicating that the host spinal cord environment is not permissive for neuronal differentiation. To identify the stage at which neuronal differentiation is inhibited we examined the survival, differentiation, and integration of neuronal restricted precursor (NRP) cells, derived from the embryonic spinal cord of transgenic alkaline phosphatase rats, after transplantation into the adult spinal cord. We found that grafted NRP cells differentiate into mature neurons, survive for at least 1 month, appear to integrate within the host spinal cord, and extend processes in both the gray and white matter. Conversely, grafted glial restricted precursor cells did not differentiate into neurons. We did not observe glial differentiation from the grafted NRP cells, indicating that they retained their neuronal restricted properties in vivo. We conclude that the adult nonneurogenic CNS environment does not support the transition of multipotential NSCs to the neuronal commitment stage, but does allow the survival, maturation, and integration of NRP cells. Department of Neurobiology and Anatomy, Drexel University College of Medicine, 2900 Queen Lane, Philadelphia, Pennsylvania 19129, USA [corrected]. • Nakamura M and Toyama Y (2003). [Transplantation of neural stem cells into spinal cord after injury]. Nippon Rinsho 61:463-8. Summary: Recovery from central nervous system damage in adult mammals is hindered by their limited ability to replace lost cells and damaged myelin, and reestablish functional neural connections. However, recent progresses in stem cell biology are making it feasible to induce the regeneration of injured axons after spinal cord injury. Transplantation of in vitro expanded neural stem cells into rat spinal cord 9 days after contusion injury induced their differentiation into neurons and oligodendrocytes, and the functional recovery of skilled forelimb movement. It was partly because the microenvironment within the injured spinal cord at 9 days after injury was more favorable for grafted neural stem cells in terms of their survival and differentiation. Department of Orthopedic Surgery, School of Medicine, Keio University. • Ogawa Y, Sawamoto K, Miyata T, Miyao S, Watanabe M, Nakamura M, Bregman BS, Koike M, Uchiyama Y, Toyama Y and Okano H (2002). Transplantation of in vitro-expanded fetal neural progenitor cells results in neurogenesis and functional recovery after spinal cord contusion injury in adult rats. J Neurosci Res 69:925-33. Summary: Neural progenitor cells, including neural stem cells, are a potential expandable source of graft material for transplantation aimed at repairing the damaged CNS. Here we present the first evidence that in vitro-expanded fetus-derived neurosphere cells were able to generate neurons in vivo and improve motor function upon transplantation into an adult rat spinal-cord-contusion injury model. As the source of graft material, we used a neural stem cell-enriched population that was derived from rat embryonic spinal cord (E14.5) and expanded in vitro by neurosphere formation. Nine days after contusion injury, these neurosphere cells were transplanted into adult rat spinal cord at the injury site. Histological analysis 5 weeks after the transplantation showed that mitotic neurogenesis occurred from the transplanted donor progenitor cells within the adult rat spinal cord, a nonneurogenic region; that these donor-derived neurons extended their processes into the host tissues; and that the neurites formed synaptic structures. Furthermore, analysis of motor behavior using a skilled reaching task indicated that the treated rats showed functional recovery. These results indicate that in vitro-expanded neurosphere cells derived from the fetal spinal cord are a potential source for transplantable material for treatment of spinal cord injury. Department of Physiology, Keio University School of Medicine, Tokyo, Japan. hidokano@sc.itc.keio.ac.jp • Teng YD, Lavik EB, Qu X, Park KI, Ourednik J, Zurakowski D, Langer R and Snyder EY (2002). Functional recovery following traumatic spinal cord injury mediated by a unique polymer scaffold seeded with neural stem cells. Proc Natl Acad Sci U S A 99:3024-9. Summary: To better direct repair following spinal cord injury (SCI), we designed an implant modeled after the intact spinal cord consisting of a multicomponent polymer scaffold seeded with neural stem cells. Implantation of the scaffold-neural stem cells unit into an adult rat hemisection model of SCI promoted long-term improvement in function (persistent for 1 year in some animals) relative to a lesion-control group. At 70 days postinjury, animals implanted with scaffold-plus-cells exhibited coordinated, weight-bearing hindlimb stepping. Histology and immunocytochemical analysis suggested that this recovery might be attributable partly to a reduction in tissue loss from secondary injury processes as well as in diminished glial scarring. Tract tracing demonstrated corticospinal tract fibers passing through the injury epicenter to the caudal cord, a phenomenon not present in untreated groups. Together with evidence of enhanced local GAP-43 expression not seen in controls, these findings suggest a possible regeneration component. These results may suggest a new approach to SCI and, more broadly, may serve as a prototype for multidisciplinary strategies against complex neurological problems. Department of Neurology, Harvard Medical School, Boston, MA 02115, USA. • Tzeng SF (2002). Neural progenitors isolated from newborn rat spinal cords differentiate into neurons and astroglia. J Biomed Sci 9:10-6. Summary: Permanent functional deficit in patients with spinal cord injury (SCI) is in part due to severe neural cell death. Therefore, cell replacement using stem cells and neural progenitors that give rise to neurons and glia is thought to be a potent strategy to promote tissue repair after SCI. Many studies have shown that stem cells and neural progenitors can be isolated from embryonic, postnatal and adult spinal cords. Recently, we isolated neural progenitors from newborn rat spinal cords. In general, the neural progenitors grew as spheres in culture, and showed immunoreactivity to a neural progenitor cellular marker, nestin. They were found to proliferate and differentiate into glial fibrillary acidic protein-positive astroglia and multiple neuronal populations, including GABAergic and cholinergic neurons. Neurotrophin 3 and neurotrophin 4 enhanced the differentiation of neural progenitors into neurons. Furthermore, the neural progenitors that were transplanted into contusive spinal cords were found to survive and have migrated in the spinal cord rostrally and caudally over 8 mm to the lesion center 7 days after injury. Thus, the neural progenitors isolated from newborn rat spinal cords in combination with neurotrophic factors may provide a tool for cell therapy in SCI patients. Department of Biology, National Cheng-Kung University, Tainan, Taiwan, ROC. stzeng@mail.ncku.edu.tw

05-06-2003, 06:59 AM	#6
Wise Young Administrator Join Date: Jul 2001 Location: New Brunswick, NJ, USA Posts: 37,975	DA, stem cells may have the following beneficial effects for spinal cord injury: 1. Bridging. They may provide a permissive bridge at the injury site that allow axonal growth. Many stem cells have been shown to produce astrocytes that may be permissive. Of course, one of the problems with stem cells is that we do not know yet how to control what they become after transplantation. That is one of the reasons why OEG's are so attractive. We don't know what nasal mucosal stem cells become when they are transplanted into the spinal cord. Perhaps they will make olfactory mucosa cells. Look, this may sound funny but Doug Anderson transplanted nasal mucosa into a cat spinal cord in 1989. I remember seeing sheets of hairy nasal mucosal cells in the spinal cord. Not a pretty sight. 2. Growth factors. Stem cells secrete growth factors and cell adhesion molecules that may facilitate axonal growth. They can be genetically modified to produce growth factors and cell adhesion molecules to promote regeneration. Some cells will also migrate in the spinal cord and may be able to facilitate growth of axons not only at the injury site but in the surrounding cord. By the way, many cells (such as fibroblasts and Schwann cells) do not migrate in the spinal cord. 3. Cell replacement. Stem cells may be able to replace neurons that have been lost at the injury area. This may be useful for reversing atrophy and also for reducing neuropathic pain. They will also be able to replace oligodendroglia to remyelinate the spinal cord. Everybody assumes that bone marrow and umbilical cord blood cells can be easily turned into neurons or astrocytes. This is not true. I would dearly love to know how to make a stem cell produce olfactory ensheathing glia. After all, they are being made in the nasal mucosa all throughout adult life. Wise.

05-06-2003, 08:50 AM	#7
DA Senior Member Join Date: Jul 2001 Location: beaumont tx usa Posts: 32,390	dr young...has anyone did a gene study in the difference between all stem cells? can you take oeg cells and mix them with stem cells and then use same method to grow numbers of oeg. the stem cells will copy the oeg by changing into oeg. how about taking oeg cells, introducing the cancer gene, grow a few billion cells, then take away cancer gene. outside the body ofcourse.

05-06-2003, 09:06 AM	#8
Wise Young Administrator Join Date: Jul 2001 Location: New Brunswick, NJ, USA Posts: 37,975	DA, all that has been done. 1. OEG Cell line. There is an OEG cell line has been immortalized with the T-oncogene and has been transplanted into the spinal cord. Removing the gene is, however, a lot of trouble. An alternative is to find the OEG precursor/progenitor cell. We tried for many months to find the OEG precursor/progenitor cell and did not succeed. The lack of such a cell line is of course why we are still struggling to find a feasible source of human OEG for transplantation. 2. Mixing OEG and stem cells. There was a recent study suggesting that mixing mesenchymal stem cells and OEG actually promotes the ability of OEG to remyelinate the spinal cord. We are very interested in doing that, particularly with umbilical cord blood cells. 3. Gene studies of stem cells. I have not been posting the flood of papers that are being published daily concerning the genes that regulate stem cells and how they differentiate into different cells. This is probably one of the hottest areas of research. I believe that the field will soon know what genes make a stem cell. It will happen probably within a year. This, unfortunately, will not make embryonic stem cells moot. I think that it will be some years before we will understand in detail how cells differentiate. In order to do that, we have have access to embryonic and fetal stem cells. Also, there are sufficient species differences that the studies must be carried out in human stem cells. Wise.