Senescence impairs successful reprogramming to pluripotent stem cells
Open accessAbstract
Somatic cells can be reprogrammed into induced pluripotent stem (iPS) cells by overexpressing combinations of factors such as Oct4, Sox2, Klf4, and c-Myc. Reprogramming is slow and stochastic, suggesting the existence of barriers limiting its efficiency. Here we identify senescence as one such barrier. Expression of the four reprogramming factors triggers senescence by up-regulating p53, p16 INK4a , and p21 CIP1 . Induction of DNA damage response and chromatin remodeling of the INK4a/ARF locus are two of the mechanisms behind senescence induction. Crucially, ablation of different senescence effectors improves the efficiency of reprogramming, suggesting novel strategies for maximizing the generation of iPS cells.
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In vitro, cellular senescence is a potent cell-autonomous barrier to OSKM transcription factor-mediated reprogramming, similar to its tumour suppressor role.
“In vitro studies demonstrated that cellular senescence is a potent cell-autonomous barrier for transcription factor-mediated reprograming using OCT4, SOX2, KLF4 and MYC (commonly referred to as OSKM), in a manner similar to its role in tumour suppression181–183.”
From Cellular senescence in ageing: from mechanisms to therapeutic opportunities (2021) · cites this paper as [182]
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- Authors
- Banito, A., Rashid, S. T., Acosta, J. C., Li, S., Pereira, C. F., Geti, I., Pinho, S., Silva, J. C., Azuara, V., Walsh, M., Vallier, L., & Gil, J.
- Affiliations
- Imperial College London (GB)
- University of Cambridge (GB)
- Icahn School of Medicine at Mount Sinai (US)
- ORCID
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2009-08-20
- Volume
- 23
- Issue
- 18
- Pages
- 2134-2139
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC2751980
- OpenAlex
- W2134328115
- Cited by
- 642
- References
- 29
- Citations by year
- 2026: 15 · 2025: 13 · 2024: 17 · 2023: 22 · 2022: 31 · 2021: 28 · 2020: 31 · 2019: 35 · 2018: 37 · 2017: 30 · 2016: 43 · 2015: 39 · 2014: 47 · 2013: 60 · 2012: 66
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genes & Development (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Research Portal (King's College London) (submittedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- HighWire Press Open Archive (submittedVersion)
- Spiral (Imperial College London) (submittedVersion, cc-by-nc-nd)
- Imperial College Research Computing Service Data Repository
- Funders
- Wellcome Trust
- Cancer Research UK
- National Institute for Health and Care Research
- Medical Research Council
- Fundação para a Ciência e a Tecnologia
- NIHR Cambridge Biomedical Research Centre
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- cellular senescence, induced pluripotent stem cells, reprogramming efficiency, p53, p16INK4a, p21, DNA damage response, chromatin remodeling, INK4a/ARF locus, Oct4, SOX2, KLF4, c-Myc, somatic cell reprogramming
- MeSH terms
- Kruppel-Like Factor 4, Animals, Cell Differentiation, Cell Line, Gene Expression Regulation, Humans, Cellular Senescence, Pluripotent Stem Cells, Cellular Reprogramming
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