Required growth facilitators propel axon regeneration across complete spinal cord injury

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, Riki Kawaguchi, Giovanni Coppola, Chen Wang, Timothy J. Deming, Zhigang He, Gregoire Courtine () and Michael V. Sofroniew ()
Additional contact information
Mark A. Anderson: David Geffen School of Medicine, University of California, Los Angeles
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

Nature, 2018, vol. 561, issue 7723, 396-400

Abstract: 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.

Keywords: Propriospinal Axons; Propriospinal Neurons; Lesion Core; Scar Border; High Pressure Tube (search for similar items in EconPapers)
Date: 2018
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Citations: View citations in EconPapers (6)

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DOI: 10.1038/s41586-018-0467-6

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