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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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Reduced astrocytic differentiation in MRL/MpJ injured spinal cord.Sagittal sections of the lesion epicenter at 54 dpi (a–l) and 109 dpi (m–r) labeled for BrdU (green) and lineage markers (red): GFAP (a–f), NG2 (g–l), OX-42 (m–r) in C57BL/6 (a–c, g–i, m–o) and MRL/MpJ (d–f, j–l, p–r) mice. Higher magnifications of cells marked by the arrowheads are shown in boxed inserts. s–v, Graphs represent the quantification of BrdU-labeled cells stained for a specific marker at 54 dpi (s, u) and 109 dpi (t, v) shown as percentage of all BrdU-labeled cells (s, t) and as absolute number of co-stained BrdU-labeled nuclei per mm3 (u, v). At 54 dpi, C57BL/6 mice showed more NG2/BrdU- and GFAP/BrdU-positive cells than MRL/MpJ mice. At 109 dpi, C57BL/6 mice had still more GFAP/BrdU-expressing cells than MRL/MpJ mice; however, OX-42/BrdU-positive cells were only found in MRL/MpJ spinal cord (2.7±0.9%). Asterisks denote significant difference between MRL/MpJ and C57BL/6, P<0.05 (Student's t-test). Scale bar, 100 µm (a–i); 50 µm (p–r); 50 µm for boxed area (a–i); 25 µm for boxed area (p–r).
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pone-0030904-g005: Reduced astrocytic differentiation in MRL/MpJ injured spinal cord.Sagittal sections of the lesion epicenter at 54 dpi (a–l) and 109 dpi (m–r) labeled for BrdU (green) and lineage markers (red): GFAP (a–f), NG2 (g–l), OX-42 (m–r) in C57BL/6 (a–c, g–i, m–o) and MRL/MpJ (d–f, j–l, p–r) mice. Higher magnifications of cells marked by the arrowheads are shown in boxed inserts. s–v, Graphs represent the quantification of BrdU-labeled cells stained for a specific marker at 54 dpi (s, u) and 109 dpi (t, v) shown as percentage of all BrdU-labeled cells (s, t) and as absolute number of co-stained BrdU-labeled nuclei per mm3 (u, v). At 54 dpi, C57BL/6 mice showed more NG2/BrdU- and GFAP/BrdU-positive cells than MRL/MpJ mice. At 109 dpi, C57BL/6 mice had still more GFAP/BrdU-expressing cells than MRL/MpJ mice; however, OX-42/BrdU-positive cells were only found in MRL/MpJ spinal cord (2.7±0.9%). Asterisks denote significant difference between MRL/MpJ and C57BL/6, P<0.05 (Student's t-test). Scale bar, 100 µm (a–i); 50 µm (p–r); 50 µm for boxed area (a–i); 25 µm for boxed area (p–r).

Mentions: We then assessed the phenotype of BrdU-positive cells in injured mice. At 54 dpi, no neurogenesis occurred in either of the strains and most of the surviving proliferating cells exhibited a glial phenotype (Fig. 5). The proportions of BrdU-positive cells co-labeled with NG2 (9.7±2.1% vs 4.7±2.0%), S100b (4.0±2.1% vs 2.9±1.4%) and OX-42 (2.0±1.4% vs 1.6±1.4%) in C57BL/6 versus MRL/MpJ mice were not significantly different (Fig. 5s). Nevertheless, BrdU+/GFAP+ cells were significantly higher in C57BL/6 mice (22.5±0.5%) than in MRL/MpJ animals (16.1±0.8%; p<0.05; Fig. 5s). When we assessed double-labeled cells (absolute numbers) per volume, we found that C57BL/6 mice had almost 3 times more NG2+/BrdU+ cells (Fig. 5g–l) and 2 times more GFAP+/BrdU+ cells (Fig. 5a–f) than MRL/MpJ mice (Fig. 5u; p<0.05), but there was no significant difference between the number of OX-42+/BrdU+ cells. At 109 dpi, the phenotype of BrdU-labeled cells was similar to 54 dpi with C57BL/6 mice, showing still more GFAP+/BrdU+ cells than MRL/MpJ mice (1167.8±172.3 vs 660.9±151.5; p<0.05; Fig. 5t, v). But interestingly, at 109 dpi, OX-42+/BrdU+ cells were absent in C57/BL6 mice, whereas they represented 2.7±0.9% of the MRL/MpJ BrdU-labeled cells (p<0.05; Fig. 5n–r, t, v).


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

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

Reduced astrocytic differentiation in MRL/MpJ injured spinal cord.Sagittal sections of the lesion epicenter at 54 dpi (a–l) and 109 dpi (m–r) labeled for BrdU (green) and lineage markers (red): GFAP (a–f), NG2 (g–l), OX-42 (m–r) in C57BL/6 (a–c, g–i, m–o) and MRL/MpJ (d–f, j–l, p–r) mice. Higher magnifications of cells marked by the arrowheads are shown in boxed inserts. s–v, Graphs represent the quantification of BrdU-labeled cells stained for a specific marker at 54 dpi (s, u) and 109 dpi (t, v) shown as percentage of all BrdU-labeled cells (s, t) and as absolute number of co-stained BrdU-labeled nuclei per mm3 (u, v). At 54 dpi, C57BL/6 mice showed more NG2/BrdU- and GFAP/BrdU-positive cells than MRL/MpJ mice. At 109 dpi, C57BL/6 mice had still more GFAP/BrdU-expressing cells than MRL/MpJ mice; however, OX-42/BrdU-positive cells were only found in MRL/MpJ spinal cord (2.7±0.9%). Asterisks denote significant difference between MRL/MpJ and C57BL/6, P<0.05 (Student's t-test). Scale bar, 100 µm (a–i); 50 µm (p–r); 50 µm for boxed area (a–i); 25 µm for boxed area (p–r).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3278405&req=5

pone-0030904-g005: Reduced astrocytic differentiation in MRL/MpJ injured spinal cord.Sagittal sections of the lesion epicenter at 54 dpi (a–l) and 109 dpi (m–r) labeled for BrdU (green) and lineage markers (red): GFAP (a–f), NG2 (g–l), OX-42 (m–r) in C57BL/6 (a–c, g–i, m–o) and MRL/MpJ (d–f, j–l, p–r) mice. Higher magnifications of cells marked by the arrowheads are shown in boxed inserts. s–v, Graphs represent the quantification of BrdU-labeled cells stained for a specific marker at 54 dpi (s, u) and 109 dpi (t, v) shown as percentage of all BrdU-labeled cells (s, t) and as absolute number of co-stained BrdU-labeled nuclei per mm3 (u, v). At 54 dpi, C57BL/6 mice showed more NG2/BrdU- and GFAP/BrdU-positive cells than MRL/MpJ mice. At 109 dpi, C57BL/6 mice had still more GFAP/BrdU-expressing cells than MRL/MpJ mice; however, OX-42/BrdU-positive cells were only found in MRL/MpJ spinal cord (2.7±0.9%). Asterisks denote significant difference between MRL/MpJ and C57BL/6, P<0.05 (Student's t-test). Scale bar, 100 µm (a–i); 50 µm (p–r); 50 µm for boxed area (a–i); 25 µm for boxed area (p–r).
Mentions: We then assessed the phenotype of BrdU-positive cells in injured mice. At 54 dpi, no neurogenesis occurred in either of the strains and most of the surviving proliferating cells exhibited a glial phenotype (Fig. 5). The proportions of BrdU-positive cells co-labeled with NG2 (9.7±2.1% vs 4.7±2.0%), S100b (4.0±2.1% vs 2.9±1.4%) and OX-42 (2.0±1.4% vs 1.6±1.4%) in C57BL/6 versus MRL/MpJ mice were not significantly different (Fig. 5s). Nevertheless, BrdU+/GFAP+ cells were significantly higher in C57BL/6 mice (22.5±0.5%) than in MRL/MpJ animals (16.1±0.8%; p<0.05; Fig. 5s). When we assessed double-labeled cells (absolute numbers) per volume, we found that C57BL/6 mice had almost 3 times more NG2+/BrdU+ cells (Fig. 5g–l) and 2 times more GFAP+/BrdU+ cells (Fig. 5a–f) than MRL/MpJ mice (Fig. 5u; p<0.05), but there was no significant difference between the number of OX-42+/BrdU+ cells. At 109 dpi, the phenotype of BrdU-labeled cells was similar to 54 dpi with C57BL/6 mice, showing still more GFAP+/BrdU+ cells than MRL/MpJ mice (1167.8±172.3 vs 660.9±151.5; p<0.05; Fig. 5t, v). But interestingly, at 109 dpi, OX-42+/BrdU+ cells were absent in C57/BL6 mice, whereas they represented 2.7±0.9% of the MRL/MpJ BrdU-labeled cells (p<0.05; Fig. 5n–r, t, v).

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