Attenuated Epigenetic Suppression of Muscle Stem Cell Necroptosis Is Required for Efficient Regeneration of Dystrophic Muscles

• Main Authors: Krishnamoorthy Sreenivasan, Alessandro Ianni, Carsten Künne, Boris Strilic, Stefan Günther, Eusebio Perdiguero, Marcus Krüger, Simone Spuler, Stefan Offermanns, Pablo Gómez-del Arco, Juan Miguel Redondo, Pura Munoz-Canoves, Johnny Kim, Thomas Braun
• Format: Article
• Language: English
• Published: Elsevier 2020-05-01
• Series: Cell Reports
• Subjects: muscle stem cells; regeneration; necroptosis; muscle dystrophy; Chd4/NuRD; Ripk3
• Online Access: http://www.sciencedirect.com/science/article/pii/S2211124720306057

Summary: 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.