title: Tissue damage and senescence provide critical signals for cellular reprogramming in vivo.
abstract: Reprogramming of differentiated cells into pluripotent cells can occur in vivo, but the mechanisms involved remain to be elucidated. Senescence is a cellular response to damage, characterized by abundant production of cytokines and other secreted factors that, together with the recruitment of inflammatory cells, result in tissue remodeling. Here, we show that in vivo expression of the reprogramming factors OCT4, SOX2, KLF4, and cMYC (OSKM) in mice leads to senescence and reprogramming, both coexisting in close proximity. Genetic and pharmacological analyses indicate that OSKM-induced senescence requires the Ink4a/Arf locus and, through the production of the cytokine interleukin-6, creates a permissive tissue environment for in vivo reprogramming. Biological conditions linked to senescence, such as tissue injury or aging, favor in vivo reprogramming by OSKM. These observations may be relevant for tissue repair.
authors.affiliation: Tumor Suppression Group, Spanish National Cancer Research Centre (CNIO), Madrid E28029, Spain.
authors.forename: Lluc
authors.initials: L
authors.lastname: Mosteiro
authors.affiliation: Tumor Suppression Group, Spanish National Cancer Research Centre (CNIO), Madrid E28029, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Pantoja
authors.affiliation: Tumor Suppression Group, Spanish National Cancer Research Centre (CNIO), Madrid E28029, Spain.
authors.forename: Noelia
authors.initials: N
authors.lastname: Alcazar
authors.affiliation: Telomeres and Telomerase Group, CNIO, Madrid E28029, Spain.
authors.forename: Rosa M
authors.initials: RM
authors.lastname: Marión
authors.affiliation: Tumor Suppression Group, Spanish National Cancer Research Centre (CNIO), Madrid E28029, Spain.
authors.forename: Dafni
authors.initials: D
authors.lastname: Chondronasiou
authors.affiliation: Tumor Suppression Group, Spanish National Cancer Research Centre (CNIO), Madrid E28029, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Rovira
authors.affiliation: Tumor Suppression Group, Spanish National Cancer Research Centre (CNIO), Madrid E28029, Spain.|Laboratory of Bioactive Products and Metabolic Syndrome, Madrid Institute for Advanced Studies (IMDEA) in Food, CEI UAM+CSIC, Madrid E28049, Spain.
authors.forename: Pablo J
authors.initials: PJ
authors.lastname: Fernandez-Marcos
authors.affiliation: Tumor Suppression Group, Spanish National Cancer Research Centre (CNIO), Madrid E28029, Spain.
authors.forename: Maribel
authors.initials: M
authors.lastname: Muñoz-Martin
authors.affiliation: Experimental Therapeutics Programme, CNIO, Madrid E28029, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Blanco-Aparicio
authors.affiliation: Experimental Therapeutics Programme, CNIO, Madrid E28029, Spain.
authors.forename: Joaquin
authors.initials: J
authors.lastname: Pastor
authors.affiliation: Bioinformatics Unit, CNIO, Madrid E28029, Spain.
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Gómez-López
authors.affiliation: Histopathology Unit, CNIO, Madrid E28029, Spain.
authors.forename: Alba
authors.initials: A
authors.lastname: De Martino
authors.affiliation: Telomeres and Telomerase Group, CNIO, Madrid E28029, Spain.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Blasco
authors.affiliation: Tumor Suppression Group, Spanish National Cancer Research Centre (CNIO), Madrid E28029, Spain.|Cell Plasticity and Cancer Group, Vall d'Hebron Institute of Oncology (VHIO), Barcelona E08035, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Abad
authors.affiliation: Tumor Suppression Group, Spanish National Cancer Research Centre (CNIO), Madrid E28029, Spain. mserrano@cnio.es.
authors.forename: Manuel
authors.initials: M
authors.lastname: Serrano
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D065150:Cellular Reprogramming / Q000235:genetics*; D016922:Cellular Senescence / Q000235:genetics*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D056426:Genetic Loci; D057026:Induced Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D013724:Teratoma / Q000235:genetics / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D015850:Interleukin-6; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; C489428:Myc protein, mouse; D050814:Octamer Transcription Factor-3; C494174:Pou5f1 protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D055748:SOXB1 Transcription Factors; C527783:Sox2 protein, mouse; D013449:Sulfonamides; D014157:Transcription Factors; C528561:navitoclax