Immortalization eliminates a roadblock during cellular reprogramming into iPS cells

By J. Utikal, J. Polo, M. Stadtfeld, Nimet Maherali, Warakorn Kulalert, R. Walsh, A. Khalil, J. Rheinwald, K. Hochedlinger. 2009

877 citations recorded by the source corpus.

The overexpression of defined transcription factors in somatic cells results in their reprogramming into induced pluripotent stem (iPS) cells. The extremely low efficiency and slow kinetics of in vitro reprogramming suggest that further rare events are required to generate iPS cells. The nature and identity of these events, however, remain elusive. We noticed that the reprogramming potential of primary murine fibroblasts into iPS cells decreases after serial passaging and the concomitant onset of senescence. Consistent with the notion that loss of replicative potential provides a barrier for reprogramming, here we show that cells with low endogenous p19Arf (encoded by the Ink4a/Arf locus, also known as Cdkn2a locus) protein levels and immortal fibroblasts deficient in components of the Arf–Trp53 pathway yield iPS cell colonies with up to threefold faster kinetics and at a significantly higher efficiency than wild-type cells, endowing almost every somatic cell with the potential to form iPS cells. Notably, the acute genetic ablation of Trp53 (also known as p53) in cellular subpopulations that normally fail to reprogram rescues their ability to produce iPS cells. Our results show that the acquisition of immortality is a crucial and rate-limiting step towards the establishment of a pluripotent state in somatic cells and underscore the similarities between induced pluripotency and tumorigenesis.

Subfields: Molecular Biology

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Citations in the corpus

Cellular Senescence: Aging, Cancer, and Injury. (2019, background): “Mouse and human fibroblasts silenced for p21 or p53 generate a greater number of induced pluripotent stem (iPS) cell colonies with an accelerated rate, indicating that reprogramming is more efficient when senescence is ablated (23, 162, 180, 219, 322).”
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).”
Copy number variation and selection during reprogramming to pluripotency (2011, background): “d, Genomic representation demonstrating the sharp decline in the number of CNVs from early passage (passage 5) to intermediate passage (8) and intermediate–late passage (12) of the human iPS cell line FiPS7-5 relative to the CNVs in the parental fibroblast (F).”
Senescence impairs successful reprogramming to pluripotent stem cells. (2009, background): “…time that the work present here was published, several groups showed that knocking down p53 or its transcriptional target CDKN1a in human or mouse cells can significantly increase the efficiency of reprogramming (Hong et al., 2009; Kawamura et al., 2009; Marion et al., 2009a; Utikal et al., 2009).”
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).”
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).”
Induced pluripotency: history, mechanisms, and applications. (2010, background): “The absence of common integration sites in iPSCs produced with retroviruses (Varas et al. 2009) or lentiviruses (Winkler et al. 2010) corroborated this conclusion, and showed that insertional mutagenesis at best plays a supportive role during iPSC formation.”
Direct cell reprogramming is a stochastic process amenable to acceleration (2009, background): “16 Utikal, J. et al., Immortalization eliminates a roadblock during cellular reprogramming into iPS cells. Nature 460, 1145-1148 (2009).”
Vitamin C enhances the generation of mouse and human induced pluripotent stem cells. (2010, result): “While our work was in progress, six independent laboratories identified cell senescence as a roadblock for reprogramming (Hong et al., 2009; Kawamura et al., 2009; Li et al., 2009; Marión et al., 2009; Utikal et al., 2009; Zhao et al., 2008), creating significant interest in finding compounds that a”
Highly efficient reprogramming to pluripotency and directed differentiation of human cells using synthetic modified mRNA (2010, methodology): “Lowoxygen (5% O2) culture conditions and a KMOS stoichiometry of 1:1:3:1 were employed, because these have been reported to promote efficient iPSC conversion (Kawamura et al., 2009; Papapetrou et al., 2009; Utikal et al., 2009; Yoshida et al., 2009).”