3-Deazaadenosine alleviates senescence to promote cellular fitness and cell therapy efficiency in mice

Guerrero, Ana; Innes, Andrew J.; Roux, Pierre-François; Buisman, Sonja C.; Jung, Johannes; Ortet Cortada, Laura; Moiseeva, Victoria, 1992-; Wagner, Verena; Robinson, Lucas; Ausema, Albertina; Potapova, Anna; Perdiguero, Eusebio, 1968-; Weersing, Ellen; Aarts, Marieke; Martin, Nadine; Wuestefeld, Torsten; Muñoz Cánoves, Pura, 1962-; Haan, Gerald de; Bischof, Oliver; Gil, Jesús

3-Deazaadenosine alleviates senescence to promote cellular fitness and cell therapy efficiency in mice

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dc.contributor.author Guerrero, Ana
dc.contributor.author Innes, Andrew J.
dc.contributor.author Roux, Pierre-François
dc.contributor.author Buisman, Sonja C.
dc.contributor.author Jung, Johannes
dc.contributor.author Ortet Cortada, Laura
dc.contributor.author Moiseeva, Victoria, 1992-
dc.contributor.author Wagner, Verena
dc.contributor.author Robinson, Lucas
dc.contributor.author Ausema, Albertina
dc.contributor.author Potapova, Anna
dc.contributor.author Perdiguero, Eusebio, 1968-
dc.contributor.author Weersing, Ellen
dc.contributor.author Aarts, Marieke
dc.contributor.author Martin, Nadine
dc.contributor.author Wuestefeld, Torsten
dc.contributor.author Muñoz Cánoves, Pura, 1962-
dc.contributor.author Haan, Gerald de
dc.contributor.author Bischof, Oliver
dc.contributor.author Gil, Jesús
dc.date.accessioned 2023-04-28T06:05:45Z
dc.date.available 2023-04-28T06:05:45Z
dc.date.issued 2022
dc.description.abstract Cellular senescence is a stable type of cell cycle arrest triggered by different stresses. As such, senescence drives age-related diseases and curbs cellular replicative potential. Here, we show that 3-deazaadenosine (3DA), an S-adenosyl homocysteinase (AHCY) inhibitor, alleviates replicative and oncogene-induced senescence. 3DA-treated senescent cells showed reduced global Histone H3 Lysine 36 trimethylation (H3K36me3), an epigenetic modification that marks the bodies of actively transcribed genes. By integrating transcriptome and epigenome data, we demonstrate that 3DA treatment affects key factors of the senescence transcriptional program. Remarkably, 3DA treatment alleviated senescence and increased the proliferative and regenerative potential of muscle stem cells from very old mice in vitro and in vivo. Moreover, ex vivo 3DA treatment was sufficient to enhance the engraftment of human umbilical cord blood (UCB) cells in immunocompromised mice. Together, our results identify 3DA as a promising drug enhancing the efficiency of cellular therapies by restraining senescence.
dc.description.sponsorship We thank O.C. Bing (BRC, A*STAR) for the histopathology scoring of liver sections. For the purpose of open access, the author has applied a Creative Commons Attribution license. Core support from MRC (MC_U120085810), a Development Gap Fund grant from LifeArc and Cancer Research UK (C15075/A28647) funded this research in J. Gil’s laboratory. P.M.-C. acknowledges funding from RTI2018-096068-B-I00, ERC-2016-AdG-741966, La Caixa HR17-00040, UPGRADE-H2020-825825, MWRF, Fundació La Marató-TV3, AFM, MDA and DPP-E. This work was supported by grants from the Deutsche Krebshilfe (to J.J.), the Dutch Cancer Society (to G.d.H.) and the Tekke Huizinga Fund (S.B. and G.d.H.). L.R. was supported by the Pasteur - Paris University International PhD Program and by the Fondation pour la Recherche Médicale. O.B was supported by Fondation ARC pour la Recherche sur le Cancer, INSERM-AGEMED and ANR S-ENCODE - 19-CE13-0017-01. O.B. is a Centre National de la Recherche Scientifique Research Director DR2. T.W. was funded by National Medical Research Council, Singapore through NMRC/OFLCG/003b/2018 and A*STAR through the Central Research Fund for Applied/Translational Research.
dc.format.mimetype application/pdf
dc.identifier.citation Guerrero A, Innes AJ, Roux PF, Buisman SC, Jung J, Ortet L, Moiseeva V, Wagner V, Robinson L, Ausema A, Potapova A, Perdiguero E, Weersing E, Aarts M, Martin N, Wuestefeld T, Muñoz-Cánoves P, de Haan G, Bischof O, Gil J. 3-Deazaadenosine alleviates senescence to promote cellular fitness and cell therapy efficiency in mice. Nat Aging. 2022;2(9):851–66. DOI: 10.1038/s43587-022-00279-9
dc.identifier.doi http://dx.doi.org/10.1038/s43587-022-00279-9
dc.identifier.issn 2662-8465
dc.identifier.uri http://hdl.handle.net/10230/56607
dc.language.iso eng
dc.publisher Nature Research
dc.relation.ispartof Nat Aging. 2022;2(9):851–66
dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/741966
dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/RTI2018-096068-B-I00
dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/825825
dc.rights © Springer Nature Publishing AG Guerrero A, Innes AJ, Roux PF, Buisman SC, Jung J, Ortet L et al. 3-Deazaadenosine alleviates senescence to promote cellular fitness and cell therapy efficiency in mice. Nat Aging. 2022;2(9):851–66. DOI: 10.1038/s43587-022-00279-9
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.subject.keyword 3DA
dc.subject.keyword AHCY
dc.subject.keyword Cord blood cells
dc.subject.keyword Muscle stem cells
dc.subject.keyword Senescence
dc.title 3-Deazaadenosine alleviates senescence to promote cellular fitness and cell therapy efficiency in mice
dc.type info:eu-repo/semantics/article
dc.type.version info:eu-repo/semantics/acceptedVersion

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