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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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A comparison of the ability of GDA versus GRP transplants to promote axon growth across dorsal column injuries from adjacent microtransplanted adult sensory neurons at 8 days after injury and transplantation. (a) A montaged, confocal image scanned from a single 75-μm thick sagittally oriented section showing GFP+ axons (green) entering and exiting a dorsal column lesion bridged with hPAP+(red) GDAs. (b) In two cases in which GDA transplants did not adequately fill the injury site or migrate into lesion margins, GFP+sensory axons failed to cross the caudal lesion margin and instead formed dystrophic endings identical to those in control untreated injuries. LC, lesion center. (c) Confocal montage showing the complete failure of transplanted GRPs to support the growth of GFP axons across a dorsal column injury. Note that, despite the ability of transplanted GRPs to span the injury site, the majority of GFP+ axons have formed dystrophic endings within the caudal lesion margin. Scale bars: (a) 300 μm; (b) 100 μm; (c) 200 μm.
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Figure 4: A comparison of the ability of GDA versus GRP transplants to promote axon growth across dorsal column injuries from adjacent microtransplanted adult sensory neurons at 8 days after injury and transplantation. (a) A montaged, confocal image scanned from a single 75-μm thick sagittally oriented section showing GFP+ axons (green) entering and exiting a dorsal column lesion bridged with hPAP+(red) GDAs. (b) In two cases in which GDA transplants did not adequately fill the injury site or migrate into lesion margins, GFP+sensory axons failed to cross the caudal lesion margin and instead formed dystrophic endings identical to those in control untreated injuries. LC, lesion center. (c) Confocal montage showing the complete failure of transplanted GRPs to support the growth of GFP axons across a dorsal column injury. Note that, despite the ability of transplanted GRPs to span the injury site, the majority of GFP+ axons have formed dystrophic endings within the caudal lesion margin. Scale bars: (a) 300 μm; (b) 100 μm; (c) 200 μm.

Mentions: To further demonstrate the capacity of transplanted GDAs to support axon growth in an adult rat model of spinal cord injury that eliminates the possibility of axon sparing, we examined the ability of axons growing from adjacent transplants of adult DRG sensory neurons to cross identical spinal cord stab injuries bridged with GDAs. In these experiments, immediately after injury rats received microtransplants of adult mouse sensory neurons expressing green fluorescent protein (GFP) within dorsal column white matter 400–500 μm caudal to GDA-transplanted stab injuries (Figures 1c and 4a) or control stab injuries injected with media alone. In these experiments we also examined the ability of transplantation of GRP cells themselves to promote regeneration (Figures 1c and 4c).


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)

A comparison of the ability of GDA versus GRP transplants to promote axon growth across dorsal column injuries from adjacent microtransplanted adult sensory neurons at 8 days after injury and transplantation. (a) A montaged, confocal image scanned from a single 75-μm thick sagittally oriented section showing GFP+ axons (green) entering and exiting a dorsal column lesion bridged with hPAP+(red) GDAs. (b) In two cases in which GDA transplants did not adequately fill the injury site or migrate into lesion margins, GFP+sensory axons failed to cross the caudal lesion margin and instead formed dystrophic endings identical to those in control untreated injuries. LC, lesion center. (c) Confocal montage showing the complete failure of transplanted GRPs to support the growth of GFP axons across a dorsal column injury. Note that, despite the ability of transplanted GRPs to span the injury site, the majority of GFP+ axons have formed dystrophic endings within the caudal lesion margin. Scale bars: (a) 300 μm; (b) 100 μm; (c) 200 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
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Figure 4: A comparison of the ability of GDA versus GRP transplants to promote axon growth across dorsal column injuries from adjacent microtransplanted adult sensory neurons at 8 days after injury and transplantation. (a) A montaged, confocal image scanned from a single 75-μm thick sagittally oriented section showing GFP+ axons (green) entering and exiting a dorsal column lesion bridged with hPAP+(red) GDAs. (b) In two cases in which GDA transplants did not adequately fill the injury site or migrate into lesion margins, GFP+sensory axons failed to cross the caudal lesion margin and instead formed dystrophic endings identical to those in control untreated injuries. LC, lesion center. (c) Confocal montage showing the complete failure of transplanted GRPs to support the growth of GFP axons across a dorsal column injury. Note that, despite the ability of transplanted GRPs to span the injury site, the majority of GFP+ axons have formed dystrophic endings within the caudal lesion margin. Scale bars: (a) 300 μm; (b) 100 μm; (c) 200 μm.
Mentions: To further demonstrate the capacity of transplanted GDAs to support axon growth in an adult rat model of spinal cord injury that eliminates the possibility of axon sparing, we examined the ability of axons growing from adjacent transplants of adult DRG sensory neurons to cross identical spinal cord stab injuries bridged with GDAs. In these experiments, immediately after injury rats received microtransplants of adult mouse sensory neurons expressing green fluorescent protein (GFP) within dorsal column white matter 400–500 μm caudal to GDA-transplanted stab injuries (Figures 1c and 4a) or control stab injuries injected with media alone. In these experiments we also examined the ability of transplantation of GRP cells themselves to promote regeneration (Figures 1c and 4c).

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