Senescence promotes in vivo reprogramming through p16INK4a and IL‐6
Open accessAbstract
Summary: Cellular senescence is a damage response aimed to orchestrate tissue repair. We have recently reported that cellular senescence, through the paracrine release of interleukin‐6 (IL6) and other soluble factors, strongly favors cellular reprogramming by Oct4, Sox2, Klf4, and c‐Myc (OSKM) in nonsenescent cells. Indeed, activation of OSKM in mouse tissues triggers senescence in some cells and reprogramming in other cells, both processes occurring concomitantly and in close proximity. In this system, Ink4a/Arf‐null tissues cannot undergo senescence, fail to produce IL 6, and cannot reprogram efficiently; whereas p53‐null tissues undergo extensive damage and senescence, produce high levels of IL 6, and reprogram efficiently. Here, we have further explored the genetic determinants of in vivo reprogramming. We report that Ink4a, but not Arf, is necessary for OSKM‐induced senescence and, thereby, for the paracrine stimulation of reprogramming. However, in the absence of p53, IL6 production and reprogramming become independent of Ink4a, as revealed by the analysis of Ink4a/Arf/p53 deficient mice. In the case of the cell cycle inhibitor p21, its protein levels are highly elevated upon OSKM activation in a p53‐independent manner, and we show that p21‐null tissues present increased levels of senescence, IL 6, and reprogramming. We also report that Il6‐mutant tissues are impaired in undergoing reprogramming, thus reinforcing the critical role of IL 6 in reprogramming. Finally, young female mice present lower efficiency of in vivo reprogramming compared to male mice, and this gender difference disappears with aging, both observations being consistent with the known anti‐inflammatory effect of estrogens. The current findings regarding the interplay between senescence and reprogramming may conceivably apply to other contexts of tissue damage.
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While senescence is a barrier to reprogramming in vitro, the paracrine activities of senescent cells can promote the expression of stem cell markers and proliferation of neighbouring cells in vivo, and IL6 is a key player in driving this process.
“While senescence is a barrier to reprogramming in vitro, the paracrine activities of senescent cells can promote the expression of stem cell markers and proliferation of neighbouring cells in vivo, 66–68 and IL6 is a key player in driving this process.”
From Paracrine roles of cellular senescence in promoting tumourigenesis (2018) · cites this paper as [68]
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- Authors
- Mosteiro, L., Pantoja, C., de Martino, A., & Serrano, M.
- Affiliations
- Spanish National Cancer Research Centre (ES)
- Tumor Suppression Group Spanish National Cancer Research Centre (CNIO) Madrid Spain
- Institució Catalana de Recerca i Estudis Avançats (ES)
- Corresponding author
- Serrano, Manuel
- Venue
- Aging Cell
- Publisher
- Wiley
- Published
- 2017-12-27
- Volume
- 17
- Issue
- 2
- ISSN
- 1474-9718 (ISSN-L)
- 1474-9726
- PMC
- PMC5847859
- OpenAlex
- W2780749587
- Cited by
- 182
- References
- 46
- Citations by year
- 2026: 11 · 2025: 21 · 2024: 21 · 2023: 14 · 2022: 24 · 2021: 31 · 2020: 28 · 2019: 20 · 2018: 12
- FWCI
- 6.67
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Aging Cell (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, cc-by)
- Funders
- European Regional Development Fund
- H2020 European Research Council
- Banco Santander
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
- Keywords
- cellular senescence, cellular reprogramming, OSKM, p16INK4a, interleukin-6, p53, p21, paracrine signaling, tissue repair, sex differences, aging, estrogen
- MeSH terms
- Kruppel-Like Factor 4, Animals, Female, Humans, Interleukin-6, Cellular Senescence, Cyclin-Dependent Kinase Inhibitor p16, Mice, Cellular Reprogramming
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