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Published May 19, 2020 | Version v1
Journal article Open

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

  • 1. Department of Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
  • 2. Department of Pharmacology, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
  • 3. Department of Experimental & Health Sciences, University Pompeu Fabra (UPF), CIBERNED, ICREA, 08003 Barcelona, Spain
  • 4. Department of Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany, CECAD Research Center, Joseph-Stelzmann-Strasse 26, 50931 Cologne, Germany
  • 5. Experimental and Clinical Research Center (ECRC), University Clinic Charité Berlin, Berlin, Germany
  • 6. Department of Pharmacology, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany - German Center for Cardiovascular Research (DZHK)
  • 7. Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28019 Madrid, Spain -Institute of Rare Diseases Research, Instituto de Salud Carlos III, Madrid, Spain
  • 8. Gene Regulation in Cardiovascular Remodelling & Inflammation Laboratory, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), 28029 Madrid, Spain
  • 9. Department of Experimental & Health Sciences, University Pompeu Fabra (UPF), CIBERNED, ICREA, 08003 Barcelona, Spain - Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28019 Madrid, Spain
  • 10. Department of Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany - German Center for Cardiovascular Research (DZHK)
  • 11. Department of Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany - German Center for Cardiovascular Research (DZHK) - German Center for Lung Research (DZL)

Description

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.

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Additional details

Funding

UPGRADE – Unlocking Precision Gene Therapy 825825
European Commission