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Astrocyte scar formation aids central nervous system axon regeneration

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  • Mark A. Anderson

    (David Geffen School of Medicine, University of California
    †Present addresses: School of Life Sciences, Swiss Federal Institute of Technology (EPFL), SV BMI UPCourtine, Station 19, CH-1015 Lausanne, Switzerland (M.A.A); Department of Spine Surgery, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China (Y.R.).)

  • Joshua E. Burda

    (David Geffen School of Medicine, University of California)

  • Yilong Ren

    (David Geffen School of Medicine, University of California
    †Present addresses: School of Life Sciences, Swiss Federal Institute of Technology (EPFL), SV BMI UPCourtine, Station 19, CH-1015 Lausanne, Switzerland (M.A.A); Department of Spine Surgery, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China (Y.R.).)

  • Yan Ao

    (David Geffen School of Medicine, University of California)

  • Timothy M. O’Shea

    (David Geffen School of Medicine, University of California)

  • Riki Kawaguchi

    (David Geffen School of Medicine, University of California)

  • Giovanni Coppola

    (David Geffen School of Medicine, University of California)

  • Baljit S. Khakh

    (David Geffen School of Medicine, University of California)

  • Timothy J. Deming

    (Chemistry and Biochemistry, University of California Los Angeles)

  • Michael V. Sofroniew

    (David Geffen School of Medicine, University of California)

Abstract

Transected axons fail to regrow in the mature central nervous system. Astrocytic scars are widely regarded as causal in this failure. Here, using three genetically targeted loss-of-function manipulations in adult mice, we show that preventing astrocyte scar formation, attenuating scar-forming astrocytes, or ablating chronic astrocytic scars all failed to result in spontaneous regrowth of transected corticospinal, sensory or serotonergic axons through severe spinal cord injury (SCI) lesions. By contrast, sustained local delivery via hydrogel depots of required axon-specific growth factors not present in SCI lesions, plus growth-activating priming injuries, stimulated robust, laminin-dependent sensory axon regrowth past scar-forming astrocytes and inhibitory molecules in SCI lesions. Preventing astrocytic scar formation significantly reduced this stimulated axon regrowth. RNA sequencing revealed that astrocytes and non-astrocyte cells in SCI lesions express multiple axon-growth-supporting molecules. Our findings show that contrary to the prevailing dogma, astrocyte scar formation aids rather than prevents central nervous system axon regeneration.

Suggested Citation

  • Mark A. Anderson & Joshua E. Burda & Yilong Ren & Yan Ao & Timothy M. O’Shea & Riki Kawaguchi & Giovanni Coppola & Baljit S. Khakh & Timothy J. Deming & Michael V. Sofroniew, 2016. "Astrocyte scar formation aids central nervous system axon regeneration," Nature, Nature, vol. 532(7598), pages 195-200, April.
    • Handle: RePEc:nat:nature:v:532:y:2016:i:7598:d:10.1038_nature17623
    DOI: 10.1038/nature17623
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    Cited by:

    1. Christina Koupourtidou & Veronika Schwarz & Hananeh Aliee & Simon Frerich & Judith Fischer-Sternjak & Riccardo Bocchi & Tatiana Simon-Ebert & Xianshu Bai & Swetlana Sirko & Frank Kirchhoff & Martin Di, 2024. "Shared inflammatory glial cell signature after stab wound injury, revealed by spatial, temporal, and cell-type-specific profiling of the murine cerebral cortex," Nature Communications, Nature, vol. 15(1), pages 1-22, December.
    2. Xiaojing Shi & Longlong Luo & Jixian Wang & Hui Shen & Yongfang Li & Muyassar Mamtilahun & Chang Liu & Rubing Shi & Joon-Hyuk Lee & Hengli Tian & Zhijun Zhang & Yongting Wang & Won-Suk Chung & Yaohui , 2021. "Stroke subtype-dependent synapse elimination by reactive gliosis in mice," Nature Communications, Nature, vol. 12(1), pages 1-19, December.
    3. Valentina Cigliola & Adam Shoffner & Nutishia Lee & Jianhong Ou & Trevor J. Gonzalez & Jiaul Hoque & Clayton J. Becker & Yanchao Han & Grace Shen & Timothy D. Faw & Muhammad M. Abd-El-Barr & Shyni Var, 2023. "Spinal cord repair is modulated by the neurogenic factor Hb-egf under direction of a regeneration-associated enhancer," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    4. Wenlu Li & Emiri T. Mandeville & Violeta Durán-Laforet & Norito Fukuda & Zhanyang Yu & Yi Zheng & Aaron Held & Ji-Hyun Park & Takafumi Nakano & Masayoshi Tanaka & Jingfei Shi & Elga Esposito & Wanting, 2022. "Endothelial cells regulate astrocyte to neural progenitor cell trans-differentiation in a mouse model of stroke," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    5. Floriane Bretheau & Adrian Castellanos-Molina & Dominic Bélanger & Maxime Kusik & Benoit Mailhot & Ana Boisvert & Nicolas Vallières & Martine Lessard & Matthias Gunzer & Xiaoyu Liu & Éric Boilard & Ni, 2022. "The alarmin interleukin-1α triggers secondary degeneration through reactive astrocytes and endothelium after spinal cord injury," Nature Communications, Nature, vol. 13(1), pages 1-22, December.
    6. Wei Li & Jian Chen & Shujie Zhao & Tianhe Huang & Huiyan Ying & Claudia Trujillo & Giuseppina Molinaro & Zheng Zhou & Tao Jiang & Wei Liu & Linwei Li & Yuancheng Bai & Peng Quan & Yaping Ding & Jouni , 2022. "High drug-loaded microspheres enabled by controlled in-droplet precipitation promote functional recovery after spinal cord injury," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    7. Yuyan Cheng & Yuqin Yin & Alice Zhang & Alexander M. Bernstein & Riki Kawaguchi & Kun Gao & Kyra Potter & Hui-Ya Gilbert & Yan Ao & Jing Ou & Catherine J. Fricano-Kugler & Jeffrey L. Goldberg & Zhigan, 2022. "Transcription factor network analysis identifies REST/NRSF as an intrinsic regulator of CNS regeneration in mice," Nature Communications, Nature, vol. 13(1), pages 1-22, December.
    8. T. M. O’Shea & Y. Ao & S. Wang & A. L. Wollenberg & J. H. Kim & R. A. Ramos Espinoza & A. Czechanski & L. G. Reinholdt & T. J. Deming & M. V. Sofroniew, 2022. "Lesion environments direct transplanted neural progenitors towards a wound repair astroglial phenotype in mice," Nature Communications, Nature, vol. 13(1), pages 1-22, December.

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