Abstract
Muscular regeneration is a complex biological process that occurs during acute injury and chronic degeneration, implicating several cell types. One of the earliest events of muscle regeneration is the inflammatory response, followed by the activation and differentiation of muscle progenitor cells. However, the process of novel neuromuscular junction formation during muscle regeneration is still largely unexplored. Here, we identify by single-cell RNA sequencing and isolate a subset of vessel-associated cells able to improve myogenic differentiation. We termed them ‘guide’ cells because of their remarkable ability to improve myogenesis without fusing with the newly formed fibers. In vitro, these cells showed a marked mobility and ability to contact the forming myotubes. We found that these cells are characterized by CD44 and CD34 surface markers and the expression of Ng2 and Ncam2. In addition, in a murine model of acute muscle injury and regeneration, injection of guide cells correlated with increased numbers of newly formed neuromuscular junctions. Thus, we propose that guide cells modulate de novo generation of neuromuscular junctions in regenerating myofibers. Further studies are necessary to investigate the origin of those cells and the extent to which they are required for terminal specification of regenerating myofibers.
Highlights
Unraveling the regenerative processes in skeletal and cardiac muscles represents an intriguing and ambitious frontier
We recently described a method to generate bipotent cardiac/skeletal muscle progenitors from murineand human-induced pluripotent stem cells [16]
Clustering resulted in five groups that were annotated as fibroblasts, Schwann cells, activated satellite cells (MuSCs), interstitial stromal cells (ISCs), or the novel guide cells, characterized by a distinct transcriptome profile (Figure 1B,C)
Summary
Unraveling the regenerative processes in skeletal and cardiac muscles represents an intriguing and ambitious frontier. Skeletal muscle progenitors are less prone to differentiate into different lineages, probably due to their strong differentiation commitment and the existence of cardiac progenitor cells is still debated [8,9,10,11]. Lately, it is still unclear whether a fate switch between skeletal and cardiac adult myogenesis is possible [12,13]. It has been recently demonstrated that some neck muscles (trapezius and sternocleidomastoid) derive from progenitors of the pharyngeal mesoderm
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