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 injury1,2,3, 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 capacity2,5,6,7,8,9, (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.
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Files of Source Data of individual values for all quantitative figures are provided with the paper. Raw images of dot blots are provided as Supplementary Fig. 1. RNA-seq data are available at the NCBI Gene Expression Omnibus under accession number GSE111529. Other data that support the findings of this study are available from the corresponding authors upon reasonable request.
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This work was supported by US National Institutes of Health (NS084030 to M.V.S., F32NS096858 to J.E.B., NS096294 to Z.H., and NS062691 to G.Cop.); Dr. Miriam and Sheldon G. Adelson Medical Foundation (M.V.S., Z.H., T.J.D. and G.Cop.); International Foundation for Research in Paraplegia (146 to M.A.A. and G.Cou.); ALARME Foundation (531066 to M.A.A. and G.Cou.); Association Song Taaba (M.A.A.); Craig H. Neilsen Foundation (381357 to T.M.O. and M.V.S); Consolidator Grant from the European Research Council [ERC-2015-CoG HOW2WALKAGAIN 682999] (G.Cou.); Paralyzed Veterans Foundation of America (3080 to J.E.B. and M.V.S.); Swiss National Science Foundation (323530-164220 to S.L.B and G.Cou.); Microscopy Core Resource of UCLA Broad Stem Cell Research Center; Microscopy Core Resource of the Wyss Center for Bio and Neuroengineering; and Wings for Life (M.V.S., J.E.B. and Z.H.).
Nature thanks J. Fawcett, P. Letourneau and the other anonymous reviewer(s) for their contribution to the peer review of this work.