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Required growth facilitators propel axon regeneration across complete spinal cord injury

Author

Listed:
  • Mark A. Anderson

    (David Geffen School of Medicine, University of California, Los Angeles
    School of Life Sciences, Swiss Federal Institute of Technology (EPFL))

  • Timothy M. O’Shea

    (David Geffen School of Medicine, University of California, Los Angeles)

  • Joshua E. Burda

    (David Geffen School of Medicine, University of California, Los Angeles)

  • Yan Ao

    (David Geffen School of Medicine, University of California, Los Angeles)

  • Sabry L. Barlatey

    (School of Life Sciences, Swiss Federal Institute of Technology (EPFL))

  • Alexander M. Bernstein

    (David Geffen School of Medicine, University of California, Los Angeles)

  • Jae H. Kim

    (David Geffen School of Medicine, University of California, Los Angeles)

  • Nicholas D. James

    (School of Life Sciences, Swiss Federal Institute of Technology (EPFL))

  • Alexandra Rogers

    (David Geffen School of Medicine, University of California, Los Angeles)

  • Brian Kato

    (David Geffen School of Medicine, University of California, Los Angeles)

  • Alexander L. Wollenberg

    (Chemistry and Biochemistry, University of California, Los Angeles)

  • Riki Kawaguchi

    (University of California, Los Angeles)

  • Giovanni Coppola

    (University of California, Los Angeles)

  • Chen Wang

    (Children’s Hospital, Harvard Medical School)

  • Timothy J. Deming

    (Chemistry and Biochemistry, University of California, Los Angeles)

  • Zhigang He

    (Children’s Hospital, Harvard Medical School)

  • Gregoire Courtine

    (School of Life Sciences, Swiss Federal Institute of Technology (EPFL))

  • Michael V. Sofroniew

    (David Geffen School of Medicine, University of California, Los Angeles)

Abstract

Transected axons fail to regrow across anatomically complete spinal cord injuries (SCI) in adults. Diverse molecules can partially facilitate or attenuate axon growth during development or after injury1–3, but efficient reversal of this regrowth failure remains elusive4. Here we show that three factors that are essential for axon growth during development but are attenuated or lacking in adults—(i) neuron intrinsic growth capacity2,5–9, (ii) growth-supportive substrate10,11 and (iii) chemoattraction12,13—are all individually required and, in combination, are sufficient to stimulate robust axon regrowth across anatomically complete SCI lesions in adult rodents. We reactivated the growth capacity of mature descending propriospinal neurons with osteopontin, insulin-like growth factor 1 and ciliary-derived neurotrophic factor before SCI14,15; induced growth-supportive substrates with fibroblast growth factor 2 and epidermal growth factor; and chemoattracted propriospinal axons with glial-derived neurotrophic factor16,17 delivered via spatially and temporally controlled release from biomaterial depots18,19, placed sequentially after SCI. We show in both mice and rats that providing these three mechanisms in combination, but not individually, stimulated robust propriospinal axon regrowth through astrocyte scar borders and across lesion cores of non-neural tissue that was over 100-fold greater than controls. Stimulated, supported and chemoattracted propriospinal axons regrew a full spinal segment beyond lesion centres, passed well into spared neural tissue, formed terminal-like contacts exhibiting synaptic markers and conveyed a significant return of electrophysiological conduction capacity across lesions. Thus, overcoming the failure of axon regrowth across anatomically complete SCI lesions after maturity required the combined sequential reinstatement of several developmentally essential mechanisms that facilitate axon growth. These findings identify a mechanism-based biological repair strategy for complete SCI lesions that could be suitable to use with rehabilitation models designed to augment the functional recovery of remodelling circuits.

Suggested Citation

  • Mark A. Anderson & Timothy M. O’Shea & Joshua E. Burda & Yan Ao & Sabry L. Barlatey & Alexander M. Bernstein & Jae H. Kim & Nicholas D. James & Alexandra Rogers & Brian Kato & Alexander L. Wollenberg , 2018. "Required growth facilitators propel axon regeneration across complete spinal cord injury," Nature, Nature, vol. 561(7723), pages 396-400, September.
    • Handle: RePEc:nat:nature:v:561:y:2018:i:7723:d:10.1038_s41586-018-0467-6
    DOI: 10.1038/s41586-018-0467-6
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    Citations

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    Cited by:

    1. Yongheng Fan & Xianming Wu & Sufang Han & Qi Zhang & Zheng Sun & Bing Chen & Xiaoyu Xue & Haipeng Zhang & Zhenni Chen & Man Yin & Zhifeng Xiao & Yannan Zhao & Jianwu Dai, 2023. "Single-cell analysis reveals region-heterogeneous responses in rhesus monkey spinal cord with complete injury," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    2. 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.
    3. Faith H. Brennan & Yang Li & Cankun Wang & Anjun Ma & Qi Guo & Yi Li & Nicole Pukos & Warren A. Campbell & Kristina G. Witcher & Zhen Guan & Kristina A. Kigerl & Jodie C. E. Hall & Jonathan P. Godbout, 2022. "Microglia coordinate cellular interactions during spinal cord repair in mice," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
    4. 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.
    5. Vishnu Muraleedharan Saraswathy & Lili Zhou & Mayssa H. Mokalled, 2024. "Single-cell analysis of innate spinal cord regeneration identifies intersecting modes of neuronal repair," Nature Communications, Nature, vol. 15(1), pages 1-21, December.
    6. Chun-Xiao Huang & Yacong Zhao & Jie Mao & Zhen Wang & Lulu Xu & Jianwei Cheng & Na N. Guan & Jianren Song, 2021. "An injury-induced serotonergic neuron subpopulation contributes to axon regrowth and function restoration after spinal cord injury in zebrafish," Nature Communications, Nature, vol. 12(1), pages 1-13, December.

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