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Astrocytes derived from glial-restricted precursors promote spinal cord repair.

Davies JE, Huang C, Proschel C, Noble M, Mayer-Proschel M, Davies SJ - J. Biol. (2006)

Bottom Line: We reasoned therefore that pre-differentiation of embryonic neural precursors to astrocytes, which are thought to support axon growth in the injured immature CNS, would be more beneficial for CNS repair.In sharp contrast, undifferentiated GRPs failed to suppress scar formation or support axon growth and locomotor recovery.Pre-differentiation of glial precursors into GDAs before transplantation into spinal cord injuries leads to significantly improved outcomes over precursor cell transplantation, providing both a novel strategy and a highly effective new cell type for repairing CNS injuries.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Neurosurgery, Baylor College of Medicine, 1709 Dryden Street, Suite 750, Houston, Texas 77030, USA. jdavies@bcm.edu

ABSTRACT

Background: Transplantation of embryonic stem or neural progenitor cells is an attractive strategy for repair of the injured central nervous system. Transplantation of these cells alone to acute spinal cord injuries has not, however, resulted in robust axon regeneration beyond the sites of injury. This may be due to progenitors differentiating to cell types that support axon growth poorly and/or their inability to modify the inhibitory environment of adult central nervous system (CNS) injuries. We reasoned therefore that pre-differentiation of embryonic neural precursors to astrocytes, which are thought to support axon growth in the injured immature CNS, would be more beneficial for CNS repair.

Results: Transplantation of astrocytes derived from embryonic glial-restricted precursors (GRPs) promoted robust axon growth and restoration of locomotor function after acute transection injuries of the adult rat spinal cord. Transplantation of GRP-derived astrocytes (GDAs) into dorsal column injuries promoted growth of over 60% of ascending dorsal column axons into the centers of the lesions, with 66% of these axons extending beyond the injury sites. Grid-walk analysis of GDA-transplanted rats with rubrospinal tract injuries revealed significant improvements in locomotor function. GDA transplantation also induced a striking realignment of injured tissue, suppressed initial scarring and rescued axotomized CNS neurons with cut axons from atrophy. In sharp contrast, undifferentiated GRPs failed to suppress scar formation or support axon growth and locomotor recovery.

Conclusion: Pre-differentiation of glial precursors into GDAs before transplantation into spinal cord injuries leads to significantly improved outcomes over precursor cell transplantation, providing both a novel strategy and a highly effective new cell type for repairing CNS injuries.

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GDA transplantation suppresses atrophy of red nucleus neurons and promotes robust behavioral recovery. (a) Injured left-side red nuclei in control rats contained an average of 52% of the neurons counted in uninjured right-side red nuclei at 5 weeks after injury. The numbers of neurons in the injured left-side red nuclei of GDA-transplanted animals, however, was 81% of total neuron numbers in uninjured right-side nuclei (*p < 0.01). (b) Grid-walk analysis of locomotor recovery. Graph showing the average number of mistakes per experimental group at different time points after injury for GDA-transplanted rats versus the control-lesion and sham-operated groups. GDA-transplanted animals (green) performed significantly better than lesioned controls at all post-injury time points (p < 0.05). (c) Transplanted GRPs do not promote locomotor recovery. Graph showing the average number of grid-walk mistakes per experimental group from 1 day before injury (baseline pre-lesion) to 2 weeks after injury for a separate series of matched RST-lesioned rats that received either GRP or GDA transplants versus lesion-only control rats. Note the complete failure of locomotor recovery in GRP-transplanted animals compared with lesion-only controls at all time points and confirmation of significant locomotor recovery in response to GDA transplantation (p < 0.05). cs, cyclosporine.
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Figure 9: GDA transplantation suppresses atrophy of red nucleus neurons and promotes robust behavioral recovery. (a) Injured left-side red nuclei in control rats contained an average of 52% of the neurons counted in uninjured right-side red nuclei at 5 weeks after injury. The numbers of neurons in the injured left-side red nuclei of GDA-transplanted animals, however, was 81% of total neuron numbers in uninjured right-side nuclei (*p < 0.01). (b) Grid-walk analysis of locomotor recovery. Graph showing the average number of mistakes per experimental group at different time points after injury for GDA-transplanted rats versus the control-lesion and sham-operated groups. GDA-transplanted animals (green) performed significantly better than lesioned controls at all post-injury time points (p < 0.05). (c) Transplanted GRPs do not promote locomotor recovery. Graph showing the average number of grid-walk mistakes per experimental group from 1 day before injury (baseline pre-lesion) to 2 weeks after injury for a separate series of matched RST-lesioned rats that received either GRP or GDA transplants versus lesion-only control rats. Note the complete failure of locomotor recovery in GRP-transplanted animals compared with lesion-only controls at all time points and confirmation of significant locomotor recovery in response to GDA transplantation (p < 0.05). cs, cyclosporine.

Mentions: GDA transplants to dorsal lateral funiculus lesions also resulted in a suppression of atrophy of neurons within the injured red nucleus (Figure 9a and Additional data file 4). Atrophy of significant numbers of red nucleus neurons begins 1 week after RST transection [47]. We similarly found that the number of neurons with a cell body diameter greater than 20 μm in the injured left-side red nucleus in rats not receiving GDA transplants fell to 52% of the values in the uninjured right-side nucleus at 5 weeks after injury. Design-based stereological analysis (see Materials and methods) revealed, however, that the injured left-side nucleus in GDA-transplanted animals contained 81% as many large-diameter neurons as found in the uninjured right-side nucleus, effectively an approximately 65% increase in numbers of neurons that had maintained a cell body diameter of greater than 20 μm above that observed for control, injured red nuclei (Figure 9a).


Astrocytes derived from glial-restricted precursors promote spinal cord repair.

Davies JE, Huang C, Proschel C, Noble M, Mayer-Proschel M, Davies SJ - J. Biol. (2006)

GDA transplantation suppresses atrophy of red nucleus neurons and promotes robust behavioral recovery. (a) Injured left-side red nuclei in control rats contained an average of 52% of the neurons counted in uninjured right-side red nuclei at 5 weeks after injury. The numbers of neurons in the injured left-side red nuclei of GDA-transplanted animals, however, was 81% of total neuron numbers in uninjured right-side nuclei (*p < 0.01). (b) Grid-walk analysis of locomotor recovery. Graph showing the average number of mistakes per experimental group at different time points after injury for GDA-transplanted rats versus the control-lesion and sham-operated groups. GDA-transplanted animals (green) performed significantly better than lesioned controls at all post-injury time points (p < 0.05). (c) Transplanted GRPs do not promote locomotor recovery. Graph showing the average number of grid-walk mistakes per experimental group from 1 day before injury (baseline pre-lesion) to 2 weeks after injury for a separate series of matched RST-lesioned rats that received either GRP or GDA transplants versus lesion-only control rats. Note the complete failure of locomotor recovery in GRP-transplanted animals compared with lesion-only controls at all time points and confirmation of significant locomotor recovery in response to GDA transplantation (p < 0.05). cs, cyclosporine.
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Figure 9: GDA transplantation suppresses atrophy of red nucleus neurons and promotes robust behavioral recovery. (a) Injured left-side red nuclei in control rats contained an average of 52% of the neurons counted in uninjured right-side red nuclei at 5 weeks after injury. The numbers of neurons in the injured left-side red nuclei of GDA-transplanted animals, however, was 81% of total neuron numbers in uninjured right-side nuclei (*p < 0.01). (b) Grid-walk analysis of locomotor recovery. Graph showing the average number of mistakes per experimental group at different time points after injury for GDA-transplanted rats versus the control-lesion and sham-operated groups. GDA-transplanted animals (green) performed significantly better than lesioned controls at all post-injury time points (p < 0.05). (c) Transplanted GRPs do not promote locomotor recovery. Graph showing the average number of grid-walk mistakes per experimental group from 1 day before injury (baseline pre-lesion) to 2 weeks after injury for a separate series of matched RST-lesioned rats that received either GRP or GDA transplants versus lesion-only control rats. Note the complete failure of locomotor recovery in GRP-transplanted animals compared with lesion-only controls at all time points and confirmation of significant locomotor recovery in response to GDA transplantation (p < 0.05). cs, cyclosporine.
Mentions: GDA transplants to dorsal lateral funiculus lesions also resulted in a suppression of atrophy of neurons within the injured red nucleus (Figure 9a and Additional data file 4). Atrophy of significant numbers of red nucleus neurons begins 1 week after RST transection [47]. We similarly found that the number of neurons with a cell body diameter greater than 20 μm in the injured left-side red nucleus in rats not receiving GDA transplants fell to 52% of the values in the uninjured right-side nucleus at 5 weeks after injury. Design-based stereological analysis (see Materials and methods) revealed, however, that the injured left-side nucleus in GDA-transplanted animals contained 81% as many large-diameter neurons as found in the uninjured right-side nucleus, effectively an approximately 65% increase in numbers of neurons that had maintained a cell body diameter of greater than 20 μm above that observed for control, injured red nuclei (Figure 9a).

Bottom Line: We reasoned therefore that pre-differentiation of embryonic neural precursors to astrocytes, which are thought to support axon growth in the injured immature CNS, would be more beneficial for CNS repair.In sharp contrast, undifferentiated GRPs failed to suppress scar formation or support axon growth and locomotor recovery.Pre-differentiation of glial precursors into GDAs before transplantation into spinal cord injuries leads to significantly improved outcomes over precursor cell transplantation, providing both a novel strategy and a highly effective new cell type for repairing CNS injuries.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Neurosurgery, Baylor College of Medicine, 1709 Dryden Street, Suite 750, Houston, Texas 77030, USA. jdavies@bcm.edu

ABSTRACT

Background: Transplantation of embryonic stem or neural progenitor cells is an attractive strategy for repair of the injured central nervous system. Transplantation of these cells alone to acute spinal cord injuries has not, however, resulted in robust axon regeneration beyond the sites of injury. This may be due to progenitors differentiating to cell types that support axon growth poorly and/or their inability to modify the inhibitory environment of adult central nervous system (CNS) injuries. We reasoned therefore that pre-differentiation of embryonic neural precursors to astrocytes, which are thought to support axon growth in the injured immature CNS, would be more beneficial for CNS repair.

Results: Transplantation of astrocytes derived from embryonic glial-restricted precursors (GRPs) promoted robust axon growth and restoration of locomotor function after acute transection injuries of the adult rat spinal cord. Transplantation of GRP-derived astrocytes (GDAs) into dorsal column injuries promoted growth of over 60% of ascending dorsal column axons into the centers of the lesions, with 66% of these axons extending beyond the injury sites. Grid-walk analysis of GDA-transplanted rats with rubrospinal tract injuries revealed significant improvements in locomotor function. GDA transplantation also induced a striking realignment of injured tissue, suppressed initial scarring and rescued axotomized CNS neurons with cut axons from atrophy. In sharp contrast, undifferentiated GRPs failed to suppress scar formation or support axon growth and locomotor recovery.

Conclusion: Pre-differentiation of glial precursors into GDAs before transplantation into spinal cord injuries leads to significantly improved outcomes over precursor cell transplantation, providing both a novel strategy and a highly effective new cell type for repairing CNS injuries.

Show MeSH
Related in: MedlinePlus