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Enhanced functional recovery in MRL/MpJ mice after spinal cord dorsal hemisection.

Thuret S, Thallmair M, Horky LL, Gage FH - PLoS ONE (2012)

Bottom Line: Furthermore, we observed a reduced astrocytic response and fewer micro-cavities at the injury site, which appear to create a more growth-permissive environment for the injured axons.Our data suggest that the reduced astrocytic response is in part due to a lower lesion-induced increase of cell proliferation post-SCI, and a reduced astrocytic differentiation of the proliferating cells.Interestingly, we also found an increased number of proliferating microglia, which could be involved in the MRL/MpJ spinal cord repair mechanisms.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, California, United States of America. sandrine.1.thuret@kcl.ac.uk

ABSTRACT
Adult MRL/MpJ mice have been shown to possess unique regeneration capabilities. They are able to heal an ear-punched hole or an injured heart with normal tissue architecture and without scar formation. Here we present functional and histological evidence for enhanced recovery following spinal cord injury (SCI) in MRL/MpJ mice. A control group (C57BL/6 mice) and MRL/MpJ mice underwent a dorsal hemisection at T9 (thoracic vertebra 9). Our data show that MRL/MpJ mice recovered motor function significantly faster and more completely. We observed enhanced regeneration of the corticospinal tract (CST). Furthermore, we observed a reduced astrocytic response and fewer micro-cavities at the injury site, which appear to create a more growth-permissive environment for the injured axons. Our data suggest that the reduced astrocytic response is in part due to a lower lesion-induced increase of cell proliferation post-SCI, and a reduced astrocytic differentiation of the proliferating cells. Interestingly, we also found an increased number of proliferating microglia, which could be involved in the MRL/MpJ spinal cord repair mechanisms. Finally, to evaluate the molecular basis of faster spinal cord repair, we examined the difference in gene expression changes in MRL/MpJ and C57BL/6 mice after SCI. Our microarray data support our histological findings and reveal a transcriptional profile associated with a more efficient spinal cord repair in MRL/MpJ mice.

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Enhanced regeneration of corticospinal tract (CST) axons in MRL/MpJ mice after SCI.a, b, Sagittal sections of BDA-labeled CST axons in C57BL/6 (a) and MRL/MpJ (b) mice. Two weeks after tracing, dorsal hemisections were performed. The CST was analyzed at 4 dpi ( = 18 days after tracing). In both mouse strains, axons are visible rostral and caudal from the injury site. No BDA-labeled fibers were found at the injury site, confirming that the CST was completely transected. c, d, Sagittal sections of BDA-labeled CST axons in injured C57BL/6 (c) and MRL/MpJ (d) mice at 54 dpi. Here, BDA tracing was performed right after SCI. C57BL/6 CST axons retracted from the lesion (arrowhead in c). In contrast, some MRL/MpJ CST fibers crossed through the lesion site (arrowhead in (d)). e, f, Montage of sagittal sections of BDA-labeled CST axons in C57BL/6 (e) and MRL/MpJ (f) mice at 109 dpi. Higher magnifications are shown in g (from boxed area in e) and h (from boxed area in f). We found no BDA-positive fibers below the injury site in C57BL/6 spinal cord (e, g), in contrast to MRL/MpJ mice (f, h). i, j, Data represent percentage of fibers and are reported as a function of the distance from the lesion at 54 dpi (i) and 109 dpi (j). MRL/MpJ mice exhibited significantly more regenerating axons at 0.5 mm caudal from the lesion site. Rostral end of the spinal cord is to the left. The arrows point at the injury site. Asterisks denote significant differences between MRL/MpJ and C57BL/6, P<0.02 (two-way ANOVA, Bonferroni Post-hoc). Scale bar, 250 µm (a–d); 300 µm (e, f); 100 µm (g, h).
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pone-0030904-g002: Enhanced regeneration of corticospinal tract (CST) axons in MRL/MpJ mice after SCI.a, b, Sagittal sections of BDA-labeled CST axons in C57BL/6 (a) and MRL/MpJ (b) mice. Two weeks after tracing, dorsal hemisections were performed. The CST was analyzed at 4 dpi ( = 18 days after tracing). In both mouse strains, axons are visible rostral and caudal from the injury site. No BDA-labeled fibers were found at the injury site, confirming that the CST was completely transected. c, d, Sagittal sections of BDA-labeled CST axons in injured C57BL/6 (c) and MRL/MpJ (d) mice at 54 dpi. Here, BDA tracing was performed right after SCI. C57BL/6 CST axons retracted from the lesion (arrowhead in c). In contrast, some MRL/MpJ CST fibers crossed through the lesion site (arrowhead in (d)). e, f, Montage of sagittal sections of BDA-labeled CST axons in C57BL/6 (e) and MRL/MpJ (f) mice at 109 dpi. Higher magnifications are shown in g (from boxed area in e) and h (from boxed area in f). We found no BDA-positive fibers below the injury site in C57BL/6 spinal cord (e, g), in contrast to MRL/MpJ mice (f, h). i, j, Data represent percentage of fibers and are reported as a function of the distance from the lesion at 54 dpi (i) and 109 dpi (j). MRL/MpJ mice exhibited significantly more regenerating axons at 0.5 mm caudal from the lesion site. Rostral end of the spinal cord is to the left. The arrows point at the injury site. Asterisks denote significant differences between MRL/MpJ and C57BL/6, P<0.02 (two-way ANOVA, Bonferroni Post-hoc). Scale bar, 250 µm (a–d); 300 µm (e, f); 100 µm (g, h).

Mentions: To show that the CST was completely transected by our lesion approach (a 0.5 mm dorsal hemisection), intact MRL/MpJ and intact C57BL6 mice were injected with BDA. Two weeks later these mice underwent a dorsal hemisection and the CST was assessed at 4 dpi (i.e., 18 days after tracing). In both mouse strains the dorsal CST was BDA-labeled and fully transected. Axons were observed rostral as well as caudal to the injury site, but there were no BDA-labeled fibers in the injury epicenter (Fig. 2 a, b).


Enhanced functional recovery in MRL/MpJ mice after spinal cord dorsal hemisection.

Thuret S, Thallmair M, Horky LL, Gage FH - PLoS ONE (2012)

Enhanced regeneration of corticospinal tract (CST) axons in MRL/MpJ mice after SCI.a, b, Sagittal sections of BDA-labeled CST axons in C57BL/6 (a) and MRL/MpJ (b) mice. Two weeks after tracing, dorsal hemisections were performed. The CST was analyzed at 4 dpi ( = 18 days after tracing). In both mouse strains, axons are visible rostral and caudal from the injury site. No BDA-labeled fibers were found at the injury site, confirming that the CST was completely transected. c, d, Sagittal sections of BDA-labeled CST axons in injured C57BL/6 (c) and MRL/MpJ (d) mice at 54 dpi. Here, BDA tracing was performed right after SCI. C57BL/6 CST axons retracted from the lesion (arrowhead in c). In contrast, some MRL/MpJ CST fibers crossed through the lesion site (arrowhead in (d)). e, f, Montage of sagittal sections of BDA-labeled CST axons in C57BL/6 (e) and MRL/MpJ (f) mice at 109 dpi. Higher magnifications are shown in g (from boxed area in e) and h (from boxed area in f). We found no BDA-positive fibers below the injury site in C57BL/6 spinal cord (e, g), in contrast to MRL/MpJ mice (f, h). i, j, Data represent percentage of fibers and are reported as a function of the distance from the lesion at 54 dpi (i) and 109 dpi (j). MRL/MpJ mice exhibited significantly more regenerating axons at 0.5 mm caudal from the lesion site. Rostral end of the spinal cord is to the left. The arrows point at the injury site. Asterisks denote significant differences between MRL/MpJ and C57BL/6, P<0.02 (two-way ANOVA, Bonferroni Post-hoc). Scale bar, 250 µm (a–d); 300 µm (e, f); 100 µm (g, h).
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pone-0030904-g002: Enhanced regeneration of corticospinal tract (CST) axons in MRL/MpJ mice after SCI.a, b, Sagittal sections of BDA-labeled CST axons in C57BL/6 (a) and MRL/MpJ (b) mice. Two weeks after tracing, dorsal hemisections were performed. The CST was analyzed at 4 dpi ( = 18 days after tracing). In both mouse strains, axons are visible rostral and caudal from the injury site. No BDA-labeled fibers were found at the injury site, confirming that the CST was completely transected. c, d, Sagittal sections of BDA-labeled CST axons in injured C57BL/6 (c) and MRL/MpJ (d) mice at 54 dpi. Here, BDA tracing was performed right after SCI. C57BL/6 CST axons retracted from the lesion (arrowhead in c). In contrast, some MRL/MpJ CST fibers crossed through the lesion site (arrowhead in (d)). e, f, Montage of sagittal sections of BDA-labeled CST axons in C57BL/6 (e) and MRL/MpJ (f) mice at 109 dpi. Higher magnifications are shown in g (from boxed area in e) and h (from boxed area in f). We found no BDA-positive fibers below the injury site in C57BL/6 spinal cord (e, g), in contrast to MRL/MpJ mice (f, h). i, j, Data represent percentage of fibers and are reported as a function of the distance from the lesion at 54 dpi (i) and 109 dpi (j). MRL/MpJ mice exhibited significantly more regenerating axons at 0.5 mm caudal from the lesion site. Rostral end of the spinal cord is to the left. The arrows point at the injury site. Asterisks denote significant differences between MRL/MpJ and C57BL/6, P<0.02 (two-way ANOVA, Bonferroni Post-hoc). Scale bar, 250 µm (a–d); 300 µm (e, f); 100 µm (g, h).
Mentions: To show that the CST was completely transected by our lesion approach (a 0.5 mm dorsal hemisection), intact MRL/MpJ and intact C57BL6 mice were injected with BDA. Two weeks later these mice underwent a dorsal hemisection and the CST was assessed at 4 dpi (i.e., 18 days after tracing). In both mouse strains the dorsal CST was BDA-labeled and fully transected. Axons were observed rostral as well as caudal to the injury site, but there were no BDA-labeled fibers in the injury epicenter (Fig. 2 a, b).

Bottom Line: Furthermore, we observed a reduced astrocytic response and fewer micro-cavities at the injury site, which appear to create a more growth-permissive environment for the injured axons.Our data suggest that the reduced astrocytic response is in part due to a lower lesion-induced increase of cell proliferation post-SCI, and a reduced astrocytic differentiation of the proliferating cells.Interestingly, we also found an increased number of proliferating microglia, which could be involved in the MRL/MpJ spinal cord repair mechanisms.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, California, United States of America. sandrine.1.thuret@kcl.ac.uk

ABSTRACT
Adult MRL/MpJ mice have been shown to possess unique regeneration capabilities. They are able to heal an ear-punched hole or an injured heart with normal tissue architecture and without scar formation. Here we present functional and histological evidence for enhanced recovery following spinal cord injury (SCI) in MRL/MpJ mice. A control group (C57BL/6 mice) and MRL/MpJ mice underwent a dorsal hemisection at T9 (thoracic vertebra 9). Our data show that MRL/MpJ mice recovered motor function significantly faster and more completely. We observed enhanced regeneration of the corticospinal tract (CST). Furthermore, we observed a reduced astrocytic response and fewer micro-cavities at the injury site, which appear to create a more growth-permissive environment for the injured axons. Our data suggest that the reduced astrocytic response is in part due to a lower lesion-induced increase of cell proliferation post-SCI, and a reduced astrocytic differentiation of the proliferating cells. Interestingly, we also found an increased number of proliferating microglia, which could be involved in the MRL/MpJ spinal cord repair mechanisms. Finally, to evaluate the molecular basis of faster spinal cord repair, we examined the difference in gene expression changes in MRL/MpJ and C57BL/6 mice after SCI. Our microarray data support our histological findings and reveal a transcriptional profile associated with a more efficient spinal cord repair in MRL/MpJ mice.

Show MeSH
Related in: MedlinePlus