Decoding muscle-resident Schwann cell dynamics during neuromuscular junction remodeling

Abstract

23 24 This investigation single-cell RNA sequencing (scRNA-Seq) to delineate the contributions of 25 muscle-resident Schwann cells to neuromuscular junction (NMJ) remodeling by comparing a 26 model of stable innervation with models of reinnervation following partial or complete 27 denervation. The study discovered multiple distinct Schwann cell subtypes, including a terminal 28 Schwann cell (tSC) subtype integral to the denervation-reinnervation cycle, identified by a 29 transcriptomic signature indicative of cell migration and polarization. The data also characterizes 30 three myelin Schwann cell subtypes, which are distinguished based on enrichment of genes 31 associated with myelin production, mesenchymal differentiation or collagen synthesis. 32 Importantly, SPP1 signaling emerges as a pivotal regulator of NMJ dynamics, promoting Schwann 33 cell proliferation and muscle reinnervation across nerve injury models. These findings advance 34 our understanding of NMJ maintenance and regeneration and underscore the therapeutic potential 35 of targeting specific molecular pathways to treat neuromuscular and neurodegenerative disorders. 36 37 38 39 40 41 42 43 44 2 45 46 47 48 Graphical Abstract 49 50 Severity of denervation tunes both the magnitude and cellular sources of SPP1 in the NMJ niche, 51 thereby scaling the repair response. After nerve crush injury, SPP1 rises early and strongly, with 52 contributions from myelin Schwann cells and Spp1 + phagocytic cells, engaging terminal 53 Schwann cells, mesenchymal-like Schwann cells, and macrophages, coordinating matrix 54 remodeling, cell migration, and synaptic rebuilding to achieve full reinnervation. In non-55 injurious denervation modeled by young Sod1-/-muscle, fewer cell types are engaged and overall 56 SPP1 induction is lower, yet NMJs still regenerate. 57 58 3