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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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Quantification of numbers of regenerating BDA+ axons in GDA-transplanted versus control dorsal column white matter at 8 days after injury and transplantation. BDA-labeled axons were counted in every third sagittally oriented section within the lesion center and at points 0.5 mm, 1.5 mm, and 5 mm rostral to the injury site, up to and including the dorsal column nuclei (DCN). Note that 61% of BDA+ axons had reached the centers of GDA-transplanted lesions and 39% to 0.5 mm beyond injury sites, compared with just 4% (lesion center) and 3.8% (0.5 mm rostral) present in controls. The steady decline in numbers of BDA+ axons within rostral white matter indicates a staggered front of maximum axon growth beyond sites of injury in GDA-transplanted groups at this time point. Note the total absence of axons at 5.0 mm rostral and in dorsal column nuclei in controls. Counts of BDA+ axons labeled in all adjacent sagittally oriented sections in representative GDA-treated and control lesioned cords revealed totals of 372 and 330 axons, respectively, at 0.5 mm caudal to the injury site. Increases in numbers of BDA+ axons in GDA-treated animals compared with controls were statistically significant (p < 0.01) in all rostral spinal cord regions. Error bars indicate ± 1 standard deviation.
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Figure 2: Quantification of numbers of regenerating BDA+ axons in GDA-transplanted versus control dorsal column white matter at 8 days after injury and transplantation. BDA-labeled axons were counted in every third sagittally oriented section within the lesion center and at points 0.5 mm, 1.5 mm, and 5 mm rostral to the injury site, up to and including the dorsal column nuclei (DCN). Note that 61% of BDA+ axons had reached the centers of GDA-transplanted lesions and 39% to 0.5 mm beyond injury sites, compared with just 4% (lesion center) and 3.8% (0.5 mm rostral) present in controls. The steady decline in numbers of BDA+ axons within rostral white matter indicates a staggered front of maximum axon growth beyond sites of injury in GDA-transplanted groups at this time point. Note the total absence of axons at 5.0 mm rostral and in dorsal column nuclei in controls. Counts of BDA+ axons labeled in all adjacent sagittally oriented sections in representative GDA-treated and control lesioned cords revealed totals of 372 and 330 axons, respectively, at 0.5 mm caudal to the injury site. Increases in numbers of BDA+ axons in GDA-treated animals compared with controls were statistically significant (p < 0.01) in all rostral spinal cord regions. Error bars indicate ± 1 standard deviation.

Mentions: Transplantation of GDAs into stab-wound lesions of the dorsal column white matter pathways of adult rat spinal cord (Figure 1a–c) resulted in the growth of the majority of the cut ascending dorsal column axons into the lesion center (Figures 2 and 3a), with 66% of these axons extending further beyond the lesion site into adjacent white matter (Figures 2 and 3a,b,e,f). In order to minimize labeling of spared axons, a discrete population of ascending axons aligned with the lesion site was traced en passage with a single biotinylated dextran amine (BDA) injection caudal to GDA-transplanted or control stab injuries of the right-hand dorsal column cuneate and gracile white matter pathways (Figure 1c; see the Glossary box for an explanation of terms). Previous studies have shown that about 30–40% of ascending dorsal column axons projecting to the dorsal column nuclei arise from postsynaptic dorsal column neurons in spinal laminar 4 and that 25% of ascending dorsal column axons are also propriospinal in origin [43,44]. Indeed, it is thought that only 15% of primary afferents of dorsal root ganglion (DRG) neurons entering the spinal cord at lumbar levels reach the cervical spinal cord and that most leave dorsal column white matter within two to three segments of entering [45]. Therefore our en passage labeling of dorsal column axons at the cervical level included significant proportions of axons from both DRG neurons and CNS spinal neurons.


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)

Quantification of numbers of regenerating BDA+ axons in GDA-transplanted versus control dorsal column white matter at 8 days after injury and transplantation. BDA-labeled axons were counted in every third sagittally oriented section within the lesion center and at points 0.5 mm, 1.5 mm, and 5 mm rostral to the injury site, up to and including the dorsal column nuclei (DCN). Note that 61% of BDA+ axons had reached the centers of GDA-transplanted lesions and 39% to 0.5 mm beyond injury sites, compared with just 4% (lesion center) and 3.8% (0.5 mm rostral) present in controls. The steady decline in numbers of BDA+ axons within rostral white matter indicates a staggered front of maximum axon growth beyond sites of injury in GDA-transplanted groups at this time point. Note the total absence of axons at 5.0 mm rostral and in dorsal column nuclei in controls. Counts of BDA+ axons labeled in all adjacent sagittally oriented sections in representative GDA-treated and control lesioned cords revealed totals of 372 and 330 axons, respectively, at 0.5 mm caudal to the injury site. Increases in numbers of BDA+ axons in GDA-treated animals compared with controls were statistically significant (p < 0.01) in all rostral spinal cord regions. Error bars indicate ± 1 standard deviation.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: Quantification of numbers of regenerating BDA+ axons in GDA-transplanted versus control dorsal column white matter at 8 days after injury and transplantation. BDA-labeled axons were counted in every third sagittally oriented section within the lesion center and at points 0.5 mm, 1.5 mm, and 5 mm rostral to the injury site, up to and including the dorsal column nuclei (DCN). Note that 61% of BDA+ axons had reached the centers of GDA-transplanted lesions and 39% to 0.5 mm beyond injury sites, compared with just 4% (lesion center) and 3.8% (0.5 mm rostral) present in controls. The steady decline in numbers of BDA+ axons within rostral white matter indicates a staggered front of maximum axon growth beyond sites of injury in GDA-transplanted groups at this time point. Note the total absence of axons at 5.0 mm rostral and in dorsal column nuclei in controls. Counts of BDA+ axons labeled in all adjacent sagittally oriented sections in representative GDA-treated and control lesioned cords revealed totals of 372 and 330 axons, respectively, at 0.5 mm caudal to the injury site. Increases in numbers of BDA+ axons in GDA-treated animals compared with controls were statistically significant (p < 0.01) in all rostral spinal cord regions. Error bars indicate ± 1 standard deviation.
Mentions: Transplantation of GDAs into stab-wound lesions of the dorsal column white matter pathways of adult rat spinal cord (Figure 1a–c) resulted in the growth of the majority of the cut ascending dorsal column axons into the lesion center (Figures 2 and 3a), with 66% of these axons extending further beyond the lesion site into adjacent white matter (Figures 2 and 3a,b,e,f). In order to minimize labeling of spared axons, a discrete population of ascending axons aligned with the lesion site was traced en passage with a single biotinylated dextran amine (BDA) injection caudal to GDA-transplanted or control stab injuries of the right-hand dorsal column cuneate and gracile white matter pathways (Figure 1c; see the Glossary box for an explanation of terms). Previous studies have shown that about 30–40% of ascending dorsal column axons projecting to the dorsal column nuclei arise from postsynaptic dorsal column neurons in spinal laminar 4 and that 25% of ascending dorsal column axons are also propriospinal in origin [43,44]. Indeed, it is thought that only 15% of primary afferents of dorsal root ganglion (DRG) neurons entering the spinal cord at lumbar levels reach the cervical spinal cord and that most leave dorsal column white matter within two to three segments of entering [45]. Therefore our en passage labeling of dorsal column axons at the cervical level included significant proportions of axons from both DRG neurons and CNS spinal neurons.

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