title: The senescence-associated secretory phenotype induces cellular plasticity and tissue regeneration.
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.
authors.affiliation: Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona 08003, Spain.|Universitat Pompeu Fabra (UPF), Barcelona 08003, Spain.
authors.forename: Birgit
authors.initials: B
authors.lastname: Ritschka
authors.affiliation: Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona 08003, Spain.|Universitat Pompeu Fabra (UPF), Barcelona 08003, Spain.
authors.forename: Mekayla
authors.initials: M
authors.lastname: Storer
authors.affiliation: Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona 08003, Spain.|Universitat Pompeu Fabra (UPF), Barcelona 08003, Spain.
authors.forename: Alba
authors.initials: A
authors.lastname: Mas
authors.affiliation: Department of Internal Medicine VIII, University Hospital Tübingen, 72076 Tübingen, Germany.|Department of Physiology I, Institute of Physiology, Eberhard Karls University Tübingen, 72076 Tübingen, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Heinzmann
authors.affiliation: Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona 08003, Spain.|Universitat Pompeu Fabra (UPF), Barcelona 08003, Spain.
authors.forename: Mari Carmen
authors.initials: MC
authors.lastname: Ortells
authors.affiliation: Cancer Research UK Beatson Institute, Glasgow G61 1BD, United Kingdom.|Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1BD, United Kingdom.
authors.forename: Jennifer P
authors.initials: JP
authors.lastname: Morton
authors.affiliation: Cancer Research UK Beatson Institute, Glasgow G61 1BD, United Kingdom.|Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1BD, United Kingdom.
authors.forename: Owen J
authors.initials: OJ
authors.lastname: Sansom
authors.affiliation: Department of Internal Medicine VIII, University Hospital Tübingen, 72076 Tübingen, Germany.|Department of Physiology I, Institute of Physiology, Eberhard Karls University Tübingen, 72076 Tübingen, Germany.|Translational Gastrointestinal Oncology Group, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.
authors.forename: Lars
authors.initials: L
authors.lastname: Zender
authors.affiliation: Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona 08003, Spain.|Universitat Pompeu Fabra (UPF), Barcelona 08003, Spain.|Institut de Génétique et de Biologie Moléculaire et Cellulaire, UMR7104, Centre National de la Recherche Scientifique, U964, Institut National de la Santé et de la Recherche Médicale, Université de Strasbourg, Illkirch 67404, France.
authors.forename: William M
authors.initials: WM
authors.lastname: Keyes
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D000066670:Cell Plasticity / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000235:genetics / Q000502:physiology*; D004847:Epithelial Cells / Q000166:cytology / Q000502:physiology; D005260:Female; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D015603:Keratinocytes / Q000166:cytology / Q000502:physiology; D008099:Liver / Q000166:cytology / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000235:genetics; D010641:Phenotype; D012038:Regeneration / Q000235:genetics / Q000502:physiology*; D055571:Secretory Pathway / Q000235:genetics / Q000502:physiology*; D013234:Stem Cells / Q000378:metabolism
chemical_list: D015415:Biomarkers; D016328:NF-kappa B
keywords: CD34; SASP; papilloma; plasticity; senescence; stem cells