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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 GFP+ axon and host astrocyte alignment in GDA- versus GRP- transplanted lesion margins at 8 days after injury. (a) A high-magnification image showing aligned axon growth (green) associated with aligned GFAP+ host astrocytic processes (red) in the caudal margin of a GDA-transplanted lesion. (b) In contrast, GFAP+ astrocytic processes (green) are misaligned in the caudal margin of a GRP-transplanted lesion (red). (c) A high-power confocal image showing GFP+ axons displaying tortuous, misaligned patterns of growth and dystrophic end bulbs (arrowhead) within the astrogliotic caudal margin of a GRP-transplanted lesion. Scale bars: (a) 25 μm; (b,c) 50 μm.
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Figure 5: A comparison of GFP+ axon and host astrocyte alignment in GDA- versus GRP- transplanted lesion margins at 8 days after injury. (a) A high-magnification image showing aligned axon growth (green) associated with aligned GFAP+ host astrocytic processes (red) in the caudal margin of a GDA-transplanted lesion. (b) In contrast, GFAP+ astrocytic processes (green) are misaligned in the caudal margin of a GRP-transplanted lesion (red). (c) A high-power confocal image showing GFP+ axons displaying tortuous, misaligned patterns of growth and dystrophic end bulbs (arrowhead) within the astrogliotic caudal margin of a GRP-transplanted lesion. Scale bars: (a) 25 μm; (b,c) 50 μm.

Mentions: Newly growing axons from the transplanted neurons failed to cross GRP-transplanted injuries (Figures 4c and 5c) or lesions injected with medium (data not shown). In contrast, 53% (s.d. ± 3) of rostrally directed GFP+ axons grew into the center of GDA-transplanted injuries, 62% of axons at the lesion center reached 0.5 mm beyond lesion sites, 42% reached 1.5 mm into rostral white matter, and small numbers of axons extended up to 2 mm beyond the injury site (Figure 4a). Comparison of endogenous BDA+ and GFP+ axons from the two separate experiments (Table 1, experiments 1 and 2) revealed a remarkably similar efficiency of axon growth (66% and 62%, respectively) exiting GDA-filled injuries. Thus, transplantation of GDAs was able to promote axon growth across acute dorsal column injuries, but transplantation of GRP cells (from which GDAs are derived) had no such effect.


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 GFP+ axon and host astrocyte alignment in GDA- versus GRP- transplanted lesion margins at 8 days after injury. (a) A high-magnification image showing aligned axon growth (green) associated with aligned GFAP+ host astrocytic processes (red) in the caudal margin of a GDA-transplanted lesion. (b) In contrast, GFAP+ astrocytic processes (green) are misaligned in the caudal margin of a GRP-transplanted lesion (red). (c) A high-power confocal image showing GFP+ axons displaying tortuous, misaligned patterns of growth and dystrophic end bulbs (arrowhead) within the astrogliotic caudal margin of a GRP-transplanted lesion. Scale bars: (a) 25 μm; (b,c) 50 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC1561531&req=5

Figure 5: A comparison of GFP+ axon and host astrocyte alignment in GDA- versus GRP- transplanted lesion margins at 8 days after injury. (a) A high-magnification image showing aligned axon growth (green) associated with aligned GFAP+ host astrocytic processes (red) in the caudal margin of a GDA-transplanted lesion. (b) In contrast, GFAP+ astrocytic processes (green) are misaligned in the caudal margin of a GRP-transplanted lesion (red). (c) A high-power confocal image showing GFP+ axons displaying tortuous, misaligned patterns of growth and dystrophic end bulbs (arrowhead) within the astrogliotic caudal margin of a GRP-transplanted lesion. Scale bars: (a) 25 μm; (b,c) 50 μm.
Mentions: Newly growing axons from the transplanted neurons failed to cross GRP-transplanted injuries (Figures 4c and 5c) or lesions injected with medium (data not shown). In contrast, 53% (s.d. ± 3) of rostrally directed GFP+ axons grew into the center of GDA-transplanted injuries, 62% of axons at the lesion center reached 0.5 mm beyond lesion sites, 42% reached 1.5 mm into rostral white matter, and small numbers of axons extended up to 2 mm beyond the injury site (Figure 4a). Comparison of endogenous BDA+ and GFP+ axons from the two separate experiments (Table 1, experiments 1 and 2) revealed a remarkably similar efficiency of axon growth (66% and 62%, respectively) exiting GDA-filled injuries. Thus, transplantation of GDAs was able to promote axon growth across acute dorsal column injuries, but transplantation of GRP cells (from which GDAs are derived) had no such effect.

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