A Muscle Stem Cell Support Group: Coordinated Cellular Responses in Muscle Regeneration

Abstract

Skeletal muscle has an extraordinary regenerative capacity due to the activity of tissue-specific muscle stem cells. Consequently, these cells have received the most attention in studies investigating the cellular processes of skeletal muscle regeneration. However, efficient capacity to rebuild this tissue also depends on additional cells in the local milieu, as disrupting their normal contributions often leads to incomplete regeneration. Here, we review these additional cells that contribute to the regenerative process. Understanding the complex interactions between and among these cell populations has the potential to lead to therapies that will help promote normal skeletal muscle regeneration under conditions in which this process is suboptimal.

Keywords: aging; fatty and fibrotic degeneration; fibroadipogenic progenitors; injury; muscle mesenchymal stem cells; muscle stem cells; muscular dystrophy; regenerative milieu; satellite cells; skeletal muscle regeneration.

Figure 1. Cellular dynamics during the regenerative response of skeletal muscle

Following injury, there is a cascade of cellular expansion followed by reduction that occurs during the first 14 days of the regenerative response. For many of these populations in the regenerative milieu, the maximum expansion varies with the type of injury and estimates vary depending on the assay used to assess cell numbers or percentages. Thus, the relative abundance of each population of cells is normalized to 1 on the y-axis. M1 and M2 – macrophages; FAPs – fibroadipogenic progenitors; MuSCs – muscle stem cells; Tregs – regulatory T cells; ECs – endothelial cells.

Figure 2. Paracrine signaling between MuSCs and the cells of the regenerative milieu

The regenerative milieu is a dynamic singling environment with at least one goal being the nurturing of MuSCs to expand, differentiate to myoblasts, and finally fuse to repair damaged myofibers and create nascent myofibers. The cells of the regenerative milieu have a coordinated response to secrete a multitude of cytokines that target MuSCs and one another to accomplish this regenerative endeavor and rebuild functional skeletal muscle. M1 and M2 – macrophages; FAPs – fibroadipogenic progenitors; MuSCs – muscle stem cells; Tregs – regulatory T cells; ECs – endothelial cells; Apln – Apelin; Postn – Periostin, Osm – Oncostatin M.