Reprogramming to pluripotency: stepwise resetting of the epigenetic landscape

Papp, Bernadett; Plath, Kathrin

doi:10.1038/cr.2011.28

Cited by 163 publications

(122 citation statements)

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“…Nuclear reprogramming induced by trans cription factors resets the epigenetic landmarks, which leads to the global reversion of the somatic epigenomes to an ESC like state (Maherali et al, 2007;Papp and Plath, 2011). However, the mechanisms involved, particu larly the posttranslational interactions and modifications, remain undetermined.…”

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confidence: 99%

Poly(ADP-ribose) polymerase 1 regulates nuclear reprogramming and promotes iPSC generation without c-Myc

Chiou¹,

Jiang²,

Yu³

et al. 2013

J Cell Biol

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85Somatic cell reprogramming is a promising strat egy for stem cell biology and regenerative medicine. Accumulated data have shown that nuclear reprogramming can be experimentally induced by three methods: nuclear transfer, cell fusion, or forced expression of transcription factors (Yamanaka and Blau, 2010). It is con ceivable that mature oocytes and embryonic stem cells (ESCs) contain reprogramming fac tors (proteins, RNAs, lipids, and small mole cules) that enable these somatic cells to undergo efficient nuclear reprogramming, a process of converting somatic cells to pluripotent states (Jullien et al., 2010;Wang et al., 2010). Recent evidence has emphasized the pivotal roles of nuclear proteins in the regulation of chromatin remodeling and epigenetic modifications during the reprogramming process . However, the precise molecular mechanisms of the regulation of nuclear factors during cellular reprogramming remain uncertain.Induced pluripotent stem cells (iPSCs) are a recently developed technology that holds promise for stem cell biology and regenerative medicine (Takahashi et al., 2007;Nakagawa et al., 2008). Nuclear reprogramming induced by trans cription factors resets the epigenetic landmarks, which leads to the global reversion of the somatic

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mentioning

confidence: 99%

Poly(ADP-ribose) polymerase 1 regulates nuclear reprogramming and promotes iPSC generation without c-Myc

Chiou¹,

Jiang²,

Yu³

et al. 2013

J Cell Biol

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“…Mechanistically, this group have shown that FGF2 promotes the early stages of reprogramming through accelerating cell proliferation, facilitating MET and eliminating extracellular collagens. In addition to an increased proliferation rate, the minority of cells that undergo successful reprogramming also exhibit resistance to apoptosis and senescence, by transgene expression [56] . Recent studies have shown that miR-302 expression allows cells to overcome reprogramminginduced senescence [62] and that silencing of the INK4/ ARF locus is also likely to be involved, since INK4/ARF blockade improves reprogramming efficiency [63,64] .…”

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confidence: 99%

Cell signalling pathways underlying induced pluripotent stem cell reprogramming

Hawkins

Joy

McKay

2014

WJSC

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Induced pluripotent stem (iPS) cells, somatic cells reprogrammed to the pluripotent state by forced expression of defined factors, represent a uniquely valuable resource for research and regenerative medicine. However, this methodology remains inefficient due to incomplete mechanistic understanding of the reprogramming process. In recent years, various groups have endeavoured to interrogate the cell signalling that governs the reprogramming process, including LIF/STAT3, BMP, PI3K, FGF2, Wnt, TGFβ and MAPK pathways, with the aim of increasing our understanding and identifying new mechanisms of improving safety, reproducibility and efficiency. This has led to a unified model of reprogramming that consists of 3 stages: initiation, maturation and stabilisation. Initiation of reprogramming occurs in almost all cells that receive the reprogramming transgenes; most commonly Oct4, Sox2, Klf4 and cMyc , and involves a phenotypic mesenchymal-to-epithelial transition. The initiation stage is also characterised by increased proliferation and a metabolic switch from oxidative phosphorylation to glycolysis. The maturation stage is considered the major bottleneck within the process, resulting in very few "stabilisation competent" cells progressing to the final stabilisation phase. To reach this stage in both mouse and human cells, pre-iPS cells must activate endogenous expression of the core circuitry of pluripotency, comprising Oct4, Sox2, and Nanog , and thus reach a state of transgene independence. By the stabilisation stage, iPS cells generally use the same signalling networks that govern pluripotency in embryonic stem cells. These pathways differ between mouse and human cells although recent work has demonstrated that this is context dependent. As iPS cell generation technologies move forward, tools are being developed to interrogate the process in more detail, thus allowing a greater understanding of this intriguing biological phenomenon.© 2014 Baishideng Publishing Group Inc. All rights reserved.Key words: Pluripotency; Reprogramming; Induced pluripotent stem; Cell signalling; Embryonic stem Core tip: Induced pluripotent stem (iPS) cells present great promise, both to research and to medicine. However, we know very little regarding the mechanisms that occur throughout the iPS cell reprogramming process and thus the process remains inefficient. In this review, we discuss the 3 stages of reprogramming, initiation, maturation and stabilisation, and clarify the signalling pathways underlying each phase. We draw together the current knowledge to propose a model for the interactions between the key pathways in iPS cell reprogramming with the aim of illuminating this complex yet fascinating process.Hawkins K, Joy S, McKay T. Cell signalling pathways underlying induced pluripotent stem cell reprogramming. World J Stem Cells

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“…The reprogramming process demonstrates the profound flexibility of the mammalian epigenome, indicating modulators of epigenome are critically involved in iPSC generation [55] . Accordingly, small molecules that directly modulate the epigenetic enzymes or mechanisms, which in turn change DNA or histone modifications, have been demonstrated to affect reprogramming.…”

Section: Epigenetic Modifiersmentioning

confidence: 99%

iPSCs and small molecules: a reciprocal effort towards better approaches for drug discovery

Zhang

Xie

2013

Acta Pharmacol Sin

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The revolutionary induced pluripotent stem cell (iPSC) technology provides a new path for cell replacement therapies and drug screening. Patient-specific iPSCs and subsequent differentiated cells manifesting disease phenotypes will finally position human disease pathology at the core of drug discovery. Cells used to test the toxic effects of drugs can also be generated from normal iPSCs and provide a much more accurate and cost-effective system than many animal models. Here, we highlight the recent progress in iPSC-based cell therapy, disease modeling and drug evaluations. In addition, we discuss the use of small molecule drugs to improve the generation of iPSCs and understand the reprogramming mechanism. It is foreseeable that the interplay between iPSC technology and small molecule compounds will push forward the applications of iPSC-based therapy and screening systems in the real world and eventually revolutionize the methods used to treat diseases.

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Reprogramming to pluripotency: stepwise resetting of the epigenetic landscape

Cited by 163 publications

References 133 publications

Poly(ADP-ribose) polymerase 1 regulates nuclear reprogramming and promotes iPSC generation without c-Myc

Poly(ADP-ribose) polymerase 1 regulates nuclear reprogramming and promotes iPSC generation without c-Myc

Cell signalling pathways underlying induced pluripotent stem cell reprogramming

iPSCs and small molecules: a reciprocal effort towards better approaches for drug discovery

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