Epigenetic integration of signaling from the regenerative environment

Skeletal muscle has an extraordinary capacity to regenerate itself after injury due to the presence of tissue-resident muscle stem cells. While these muscle stem cells are the primary contributor to the regenerated myofibers, the process occurs in a regenerative microenvironment where multiple different cell types act in a coordinated manner to clear the damaged myofibers and restore tissue homeostasis. In this regenerative environment, immune cells play a well-characterized role in initiating repair by establishing an inflammatory state that permits the removal of dead cells and necrotic muscle tissue at the injury site. More recently, it has come to be appreciated that the immune cells also play a crucial role in communicating with the stem cells within the regenerative environment to help coordinate the timing of repair events through the secretion of cytokines, chemokines, and growth factors. Evidence also suggests that stem cells can help modulate the extent of the inflammatory response by signaling to the immune cells, demonstrating a cross-talk between the different cells in the regenerative environment. Here, we review the current knowledge on the innate immune response to sterile muscle injury and provide insight into the epigenetic mechanisms used by the cells in the regenerative niche to integrate the cellular cross-talk required for efficient muscle repair.