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

Birgit Ritschka (1, 2) , Mekayla Storer (1, 2) , Alba Mas (1, 2) , Florian Heinzmann (3, 4) , Mari Carmen Ortells (1, 2) , Jennifer Morton (5, 6) , Owen Sansom (5, 6) , Lars Zender (3, 4, 7) , William M Keyes (8, 1, 2)

1 BIST - Barcelona Institute of Science and Technology
2 UPF - Universitat Pompeu Fabra [Barcelona]
3 Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen
4 Universitätsklinikum Tübingen - University Hospital of Tübingen
5 Cancer Research UK Beatson Institute [Glasgow]
6 University of Glasgow
7 DKFZ - German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg]
8 IGBMC - Institut de Génétique et de Biologie Moléculaire et Cellulaire

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.

Mots clés: Liver/cytology/physiology; Mice; Inbred C57BL; NF-kappa B/genetics; Phenotype; Regeneration/genetics/*physiology; Secretory Pathway/genetics/*physiology; Stem Cells/metabolism; Cd34; Sasp; CD34; SASP; papilloma; plasticity; senescence; stem cells; Animals; Biomarkers/metabolism; Cell Aging/genetics/*physiology; Cell Plasticity/genetics/*physiology; Cells; Cultured; Epithelial Cells/cytology/physiology; Female; Gene Deletion; Gene Expression Regulation; Developmental/genetics; Keratinocytes/cytology/physiology

Domaines: Sciences du Vivant [q-bio]; Génétique

Birgit Ritschka, Mekayla Storer, Alba Mas, Florian Heinzmann, Mari Carmen Ortells, et al.. The senescence-associated secretory phenotype induces cellular plasticity and tissue regeneration. Genes and Development, 2017, 31 (2), pp.172-183. ⟨10.1101/gad.290635.116⟩. ⟨hal-03715520⟩