Abstract
In the injured central nervous system (CNS), reactive astrocytes form a glial scar and are considered to be detrimental for axonal regeneration, but their function remains elusive. Here we show that reactive astrocytes have a crucial role in wound healing and functional recovery by using mice with a selective deletion of the protein signal transducer and activator of transcription 3 (Stat3) or the protein suppressor of cytokine signaling 3 (Socs3) under the control of the Nes promoter-enhancer (Nes-Stat3−/−, Nes-Socs3−/−). Reactive astrocytes in Nes-Stat3−/− mice showed limited migration and resulted in markedly widespread infiltration of inflammatory cells, neural disruption and demyelination with severe motor deficits after contusive spinal cord injury (SCI). On the contrary, we observed rapid migration of reactive astrocytes to seclude inflammatory cells, enhanced contraction of lesion area and notable improvement in functional recovery in Nes-Socs3−/− mice. These results suggest that Stat3 is a key regulator of reactive astrocytes in the healing process after SCI, providing a potential target for intervention in the treatment of CNS injury.
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Acknowledgements
This work was supported by grants from Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan, the General Insurance Association in Japan, Terumo Foundation Life Science Foundation (to H.O.), and a Grant-in-Aid for the 21st century COE program, Keio Gijuku Academic Development Funds.
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S.O. performed most of the experiments to characterize mouse phenotypes. M.N. instructed group members about experimental processes. H.K. helped prepare the manuscript. T.M. and T.S. maintained and prepared knockout mice. K.I. and J.Y. prepared spinal cord–injured animals. A.Y. provided Nes-Socs3−/− mice. Y.I. advised experiments by S.O. Y.T. and H.O. designed experiments and prepared the manuscript.
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Supplementary information
Supplementary Fig. 1
Neuronal cell loss and ratio of pStat3 astrocytes. (PDF 501 kb)
Supplementary Fig. 2
Dividing inflammatory cells fill the lesion. (PDF 454 kb)
Supplementary Fig. 3
Generation of Nes-Stat3−/− mice and identification of Cre-mediated cells after SCI. (PDF 190 kb)
Supplementary Fig. 4
The effect of Stat3 on oligodendrocytes after SCI. (PDF 296 kb)
Supplementary Fig. 5
Quantification of regenerative fibers using anti-GAP 43 staining. (PDF 410 kb)
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Okada, S., Nakamura, M., Katoh, H. et al. Conditional ablation of Stat3 or Socs3 discloses a dual role for reactive astrocytes after spinal cord injury. Nat Med 12, 829–834 (2006). https://doi.org/10.1038/nm1425
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DOI: https://doi.org/10.1038/nm1425
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