Attenuated epigenetic suppression of muscle stem cell necroptosis is required for efficient regeneration of dystrophic muscles

Sreenivasan, Krishnamoorthy; Ianni, Alessandro; Künne, Carsten; Strilic, Boris; Günther, Stefan; Perdiguero, Eusebio, 1968-; Krüger, Marcus; Spuler, Simone; Offermanns, Stefan; Gómez del Arco, Pablo; Redondo, Juan Miguel; Muñoz Cánoves, Pura, 1962-; Kim, Johnny; Braun, Thomas

Attenuated epigenetic suppression of muscle stem cell necroptosis is required for efficient regeneration of dystrophic muscles

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dc.contributor.author Sreenivasan, Krishnamoorthy
dc.contributor.author Ianni, Alessandro
dc.contributor.author Künne, Carsten
dc.contributor.author Strilic, Boris
dc.contributor.author Günther, Stefan
dc.contributor.author Perdiguero, Eusebio, 1968-
dc.contributor.author Krüger, Marcus
dc.contributor.author Spuler, Simone
dc.contributor.author Offermanns, Stefan
dc.contributor.author Gómez del Arco, Pablo
dc.contributor.author Redondo, Juan Miguel
dc.contributor.author Muñoz Cánoves, Pura, 1962-
dc.contributor.author Kim, Johnny
dc.contributor.author Braun, Thomas
dc.date.accessioned 2020-06-03T06:16:20Z
dc.date.available 2020-06-03T06:16:20Z
dc.date.issued 2020
dc.description.abstract 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.
dc.description.sponsorship This work was supported by the DFG (Cardiopulmonary Institute [CPI], SFB TRR81 TP A02 and SFB 1213, TP A02 and B02); the LOEWE Center for Cell and Gene Therapy; the German Center for Cardiovascular Research; the European Research Area Network on Cardiovascular Diseases (grant CLARIFY); and Foundation Leducq. P.G.A. is supported by MICINN (SAF2016-77816-P). P.M.-C. acknowledges funding from grants RTI2018-096068-B-I00, MDM-2014-0370, SEV-2015-0505, ERC-2016-AdG-741966, La Caixa-HEALTH-HR17-00040, MDA, UPGRADE-H2020-825825, AFM, and DPP-E. T.B. is a member of the German Center for Cardiovascular Research (DZHK) and of the German Center for Lung Research (DZL).
dc.format.mimetype application/pdf
dc.identifier.citation Sreenivasan K, Ianni A, Künne C, Strilic B, Günther S, Perdiguero E, Krüger M, Spuler S, Offermanns S, Gómez-Del Arco P, Redondo JM, Munoz-Canoves P, Kim J, Braun T. Attenuated epigenetic suppression of muscle stem cell necroptosis is required for efficient regeneration of dystrophic muscles. Cell Rep. 2020; 31(7):107652. DOI: 10.1016/j.celrep.2020.107652
dc.identifier.doi http://dx.doi.org/10.1016/j.celrep.2020.107652
dc.identifier.issn 2211-1247
dc.identifier.uri http://hdl.handle.net/10230/44880
dc.language.iso eng
dc.publisher Elsevier
dc.relation.ispartof Cell Rep. 2020; 31(7):107652
dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/741966
dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/SAF2016-77816-P
dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/825825
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.rights.uri http://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subject.keyword Chd4/NuRD
dc.subject.keyword Ripk3
dc.subject.keyword Muscle dystrophy
dc.subject.keyword Muscle stem cells
dc.subject.keyword Necroptosis
dc.subject.keyword Regeneration
dc.title Attenuated epigenetic suppression of muscle stem cell necroptosis is required for efficient regeneration of dystrophic muscles
dc.type info:eu-repo/semantics/article
dc.type.version info:eu-repo/semantics/publishedVersion

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