The senescence-associated secretory phenotype induces cellular plasticity and tissue regeneration

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• dc.contributor.author Ritschka, Birgit,1985-
• dc.contributor.author Storer, Mekayla, 1981-
• dc.contributor.author Mas Malavila, Alba
• dc.contributor.author Heinzmann, Florian
• dc.contributor.author Ortells Campos, Mª Carmen, 1984-
• dc.contributor.author Morton, Jennifer P.
• dc.contributor.author Sansom, Owen J.
• dc.contributor.author Zender, Lars
• dc.contributor.author Keyes, William M., 1973-
• dc.date.accessioned 2024-12-03T07:36:05Z
• dc.date.available 2024-12-03T07:36:05Z
• dc.date.issued 2017
• dc.description.abstract Senescence is a form of cell cycle arrest induced by stress such as DNA damage and oncogenes. However, while arrested, senescent cells secrete a variety of proteins collectively known as the senescence-associated secretory phenotype (SASP), which can reinforce the arrest and induce senescence in a paracrine manner. However, the SASP has also been shown to favor embryonic development, wound healing, and even tumor growth, suggesting more complex physiological roles than currently understood. Here we uncover timely new functions of the SASP in promoting a proregenerative response through the induction of cell plasticity and stemness. We show that primary mouse keratinocytes transiently exposed to the SASP exhibit increased expression of stem cell markers and regenerative capacity in vivo. However, prolonged exposure to the SASP causes a subsequent cell-intrinsic senescence arrest to counter the continued regenerative stimuli. Finally, by inducing senescence in single cells in vivo in the liver, we demonstrate that this activates tissue-specific expression of stem cell markers. Together, this work uncovers a primary and beneficial role for the SASP in promoting cell plasticity and tissue regeneration and introduces the concept that transient therapeutic delivery of senescent cells could be harnessed to drive tissue regeneration.
• dc.description.sponsorship We thank Ryan Driskell and Fiona Watt for technical advice, Guillaume Filion and Panagiotis Papasaikas for advice on statistics, Pura Muñoz-Cánoves for β-actin GFP mice, the Centre for Genomic Regulation Bioinformatics unit for assistance, and Pura Muñoz-Cánoves and Juan Valcarcel for critical reading of the manuscript. M.S. and B.R. were supported with fellowships from the “La Caixa” foundation. This work was funded by grants SAF2010-18829 and SAF2013-49082-P (to W.M.K.) from the Spanish Ministry for Economy and Competitiveness, the Agència de Gestió d’Ajuts Universitaris i de Recerca (AGAUR) from the Generalitat de Catalunya, and Centre for Genomic Regulation core funding.
• dc.format.mimetype application/pdf
• dc.identifier.citation Ritschka B, Storer M, Mas A, Heinzmann F, Ortells MC, Morton JP, et al. The senescence-associated secretory phenotype induces cellular plasticity and tissue regeneration. Genes Dev. 2017 Jan 15;31(2):172-83. DOI: 10.1101/gad.290635.116
• dc.identifier.doi http://dx.doi.org/10.1101/gad.290635.116
• dc.identifier.issn 0890-9369
• dc.identifier.uri http://hdl.handle.net/10230/68900
• dc.language.iso eng
• dc.publisher Cold Spring Harbor Laboratory Press (CSHL Press)
• dc.relation.ispartof Genes & Development. 2017 Jan 15;31(2):172-83
• dc.relation.projectID info:eu-repo/grantAgreement/ES/3PN/SAF2010-18829
• dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/SAF2013-49082-P
• dc.rights © 2017 Ritschka et al.; Published by Cold Spring Harbor Laboratory Press. This article, published in Genes & Development, is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by-nc/4.0/
• dc.subject.keyword Senescence
• dc.subject.keyword Plasticity
• dc.subject.keyword Stem cells
• dc.subject.keyword Papilloma
• dc.subject.keyword CD34
• dc.subject.keyword SASP
• dc.title The senescence-associated secretory phenotype induces cellular plasticity and tissue regeneration
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion