Required growth facilitators propel axon regeneration across complete spinal cord injury

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 injury, but efficient reversal of this regrowth failure remains elusive. 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 capacity, (ii) growth-supportive substrate and (iii) chemoattraction-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 SCI; induced growth-supportive substrates with fibroblast growth factor 2 and epidermal growth factor; and chemoattracted propriospinal axons with glial-derived neurotrophic factor delivered via spatially and temporally controlled release from biomaterial depots, 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.

Foreign body responses in central nervous system mimic natural wound responses and alter biomaterial functions

“…Brain sections were stored transiently in TBS buffer at 4°C or in antifreeze solution of 50% glycerol/30% Sucrose in PBS at -20°C for long term storage. Brain sections were processed for immunofluorescence as described previously [4,5]. The primary antibodies used in this study were: rabbit anti-GFAP (1:1000; Dako, Santa Clara, CA); rat anti-GFAP (1:1000, Thermofisher, Grand Island, NY); rabbit anti NeuN (1:1000, Abcam, Cambridge, MA); guinea pig anti-NeuN (1:1000, Synaptic Systems, Goettingen, Germany); goat anti-CD13 (1:200, R&Dsystems, Minneapolis, MN); rabbit anti-Laminin 1 (1:100, Sigma, St.Louis, MO); rabbit anti-Fibronectin (1:500, Millipore, Burlington, MA); rabbit anti-Collagen 1a1 (1:300, Novus Biologicals, Littleton, CO); rabbit anti-RFP (1:1000, Rockland, Limerick, PA); goat anti-Albumin (1:300, Novus Biologicals, Littleton, CO); rat anti-PECAM-1…”

“…Biomaterials with specialized properties have been incorporated in implantable neuroprostheses that are used clinically for recording neuronal activity and stimulating neural circuits in the CNS [2,3]. In addition, injectable biomaterial hydrogels are used extensively as experimental tools to provide local delivery of growth factors for example to attract injured and regenerating axons to grow across CNS lesions [4,5] as well as to afford molecular and physical support to co-suspended neural progenitor cells (NPC) to improve survival and modulate differentiation upon grafting into the CNS [6][7][8].…”

IGFBP2 Plays an Essential Role in Cognitive Development during Early Life

“…2019, 6,1901152 The correlation between excitatory and inhibitory inputs onto pyramidal neurons was interrupted in igfbp2 −/− mice and rescued after IGFBP2 treatment for 20 min ( Figure S7A,B, Supporting Information). Sci.…”

“…[4] IGF-1 receptors regulate transmission via mitochondrial mediation in the hippocampus. [6,7] IGF-II enhances memory and prevents forgetting via IGF-II receptors. [6,7] IGF-II enhances memory and prevents forgetting via IGF-II receptors.…”

“…2019,6, 1901152 By contrast, in cells with higher spontaneous activity [≥2±0.5 Hz; termed "H-cells"];Figure 4D-F andFigure S5C, Supporting Information), IGFBP2 reduced both the eEPSCs and the eIPSCs (Figure 4G,H).…”