Transcriptional characterization of major cellular compartments within muscle tissue at homeostasis and after acute injury in mice. Transcriptional characterization of major cellular compartments within muscle tissue at homeostasis and after acute injury in mice

A distinct population of Foxp3+CD4+ regulatory T (Treg) cells promotes repair of acutely or chronically injured skeletal muscle. The accumulation of these cells depends critically on interleukin (IL)-33 produced by local mesenchymal stromal cells (mSCs). An intriguing physical association between muscle nerves, IL-33+ mSCs and Tregs has been reported, and begs a deeper exploration of this cell triumvirate. Here we evidence a striking proximity between IL-33+ muscle mSCs and both large-fiber nerve bundles and small-fiber sensory neurons; report that muscle mSCs transcribe an array of genes encoding neuropeptides, neuropeptide receptors and other nerve-related proteins; define muscle mSC subtypes that express both IL-33 and the receptor for the calcitonin-gene-related peptide (CGRP); and demonstrate that up- or down- tuning of CGRP signals augments or diminishes, respectively, IL-33 production by muscle mSCs and later accumulation of muscle Tregs. Indeed, a single injection of CGRP induced much of the genetic program elicited in mSCs early after acute skeletal muscle injury. These findings highlight neural/stromal/immune-cell cross-talk in tissue repair, suggesting future therapeutic approaches. Overall design: Gene expression profiles of hematopoietic cells (CD45+), endothelial cells (CD31+), mesenchymal stromal cells (CD45-CD31-Sca1+PDGFRa+, MSCs), and satellite cells (CD45-CD31-Sca1-Vcam1+, MuSCs) from uninjured hindlimb muscle and from cardiotoxin-injured hindlimb muscle (day 1 post-injury). 3 biological replicates were obtained per experimental group.