Somatic stem cells expand massively during tissue regeneration, which might require control of cell fitness, allowing elimination of non-competitive, potentially harmful cells. How or if such cells are removed to restore organ function is not fully understood. Here, we show that a substantial fraction of muscle stem cells (MuSCs) undergo necroptosis because of epigenetic rewiring during chronic skeletal muscle regeneration, which is required for efficient regeneration of dystrophic muscles. Inhibition of necroptosis strongly enhances suppression of MuSC expansion in a non-cell-autonomous manner. Prevention of necroptosis in MuSCs of healthy muscles is mediated by the chromatin remodeler CHD4, which directly represses the necroptotic effector Ripk3, while CHD4-dependent Ripk3 repression is dramatically attenuated in dystrophic muscles. Loss of Ripk3 repression by inactivation of Chd4 causes massive necroptosis of MuSCs, abolishing regeneration. Our study demonstrates how programmed cell death in MuSCs is tightly controlled to achieve optimal tissue regeneration.

Introduction

Skeletal muscle regeneration provides a paradigmatic example for the decisive role of tissue-resident stem cells and the necessity of cellular interactions to achieve organ restoration. Muscle stem cells (MuSCs; also known as satellite cells) are indispensable for muscle regeneration but require assistance and instructions from fibroblasts, endothelial cells, fibroadipogenic progenitor cells (FAPs), and immune cells, among others (Charge´ and Rudnicki, 2004; Tidball, 2011; Relaix and Zammit, 2012). Such cells not only provide critical support for MuSCs, enabling their expansion, but might also promote secondary cell death (Saclier et al., 2013; Latroche et al., 2015; Tidball and Villalta, 2010; Joe et al., 2010; Forbes and Rosenthal, 2014). Secondary cell death is not necessarily harmful but might elicit beneficial effects. For example, programmed cell death in FAPs, induced by TNFreleasing inflammatory macrophages, limits fibrosis in acutely damaged skeletal muscles (Lemos et al., 2015). Moreover, MuSCs might engage in a battle of the ‘‘survival of the fittest’’ to ensure that damaged or less fit stem cells are eliminated (Bowling et al., 2019). It has been proposed that tissue stem cells are routinely lost and replaced in a process called neutral cell competition, but many questions related to such a machinery, including the mechanisms by which unfit cells are removed, have yet to be answered (Klein and Simons, 2011). At present, it is not known whether and to what extent MuSCs succumb to programmed cell death in acutely damaged and continuously regenerating dystrophic muscles.