Senescence impairs successful reprogramming to pluripotent stem cells.

By Ana Banito, S. T. Rashid, J. Acosta, Side Li, C. Pereira, I. Geti, Sandra Pinho, José C. R. Silva, V. Azuara, M. Walsh and 2 more. Genes & Development, 2009

648 citations recorded by the source corpus.

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.

Subfields: Molecular Biology, Physiology

View Paper: https://www.semanticscholar.org/paper/9de012322fb8ebe1d90ec0754dc91c3cf17a5dca

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Citations in the corpus

• Cellular senescence and its effector programs (2014, background): “Collectively, they suggest that senescence can be a barrier to the reprogramming to generate iPS cells from fibroblasts (Banito et al. 2009; Hong et al. 2009; Kawamura et al. 2009; Li et al. 2009; Marión et al. 2009; Utikal et al. 2009).”
• Direct cell reprogramming is a stochastic process amenable to acceleration (2009, background): “23 Banito, A. et al., Senescence impairs successful reprogramming to pluripotent stem cells. Genes Dev 23 (18), 2134-2139 (2009).”
• Induced pluripotency: history, mechanisms, and applications. (2010, background): “…reprogramming is the finding that expression of the reprogramming factors in p53 or ink4a/arf-deficient immortalized fibroblasts leads to dramatic increases in reprogramming efficiency and speed (Banito et al. 2009; Hong et al. 2009; Kawamura et al. 2009; H Li et al. 2009; Utikal et al. 2009b).”
• EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer (2010, background): “…shown that the p16/INK4a tumor suppressor provides a block to efficient induced pluripotent stem cell reprogramming by inducing a senescence response, which may explain its frequent deletion in human cancers, if the CSC model is valid (Banito et al., 2009; Utikal et al., 2009; Li et al., 2009a).”
• mTOR regulates MAPKAPK2 translation to control the senescence-associated secretory phenotype (2015, positive): “These methods have been previously described elsewhere 6,46,47,49 .”
• The essence of senescence. (2010, background): “…and p53 limit the efficiency of iPS cell formation, it has been suggested that cellular senescence counteracts the induced conversion of primary cells into pluripotent stem cells (Banito et al. 2009; Hong et al. 2009; Kawamura et al. 2009; Li et al. 2009; Marión et al. 2009; Utikal et al. 2009).”
• Systematic mapping of occluded genes by cell fusion reveals prevalence and stability of cis-mediated silencing in somatic cells (2014, methodology): “Promoter and gene body were each divided into 20 bins each, and for each bin, the number of reads for which the BWA alignment position falls into the bin was tallied.”
• Cellular Senescence: Aging, Cancer, and Injury. (2019, background): “c-MYC and KLF4 trigger p21 expression via p53, whereas SOX2 expression does it via p53-independent mechanisms (23).”