BMPs functionally replace Klf4 and support efficient reprogramming of mouse fibroblasts by Oct4 alone

Chen, Jiekai; Liu, Jing; Yang, Jiaqi; Chen, You; Chen, Jing; Ni, Su; Sui, Hong; Zeng, Lingwen; Ding, Ke; Pei, Duanqing

doi:10.1038/cr.2010.172

Cited by 127 publications

(113 citation statements)

References 26 publications

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“…This is especially crucial because adult fibroblasts do not express Sox2. This study, together with others is an important step forward in defining the critical determinants for the generation of iPS cells from differentiated fibroblasts [25][26][27]. Future studies will determine if we can combine our direct reprogramming procedure with small molecule compounds to activate endogenous expression of Oct4, knock down Oct4-specific suppressor(s), or achieve reprogramming with Oct4 recombinant protein alone.…”

Section: Discussionmentioning

confidence: 99%

Reprogramming fibroblasts into induced pluripotent stem cells with Bmi1

et al. 2011

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Section: Discussionmentioning

confidence: 99%

Reprogramming fibroblasts into induced pluripotent stem cells with Bmi1

et al. 2011

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“…[6][7][8][9][10] For mechanistic studies of reprogramming, mouse embryo fibroblasts (MEFs) are the most commonly used source of somatic cells. [10][11][12][13][14][15] These studies showed that reprogramming is largely a stochastic process that relies on multiple independent epigenetic events. 12,16,17 Thus, individual cells convert into iPSCs with different latencies described by a Gaussian distribution.…”

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confidence: 99%

“…10 Nonetheless, several studies also provided evidence for some deterministic steps, such as accelerated cell division and decreased cell size in all MEFs that become reprogrammed, 13 and mesenchymal-epithelial transition (MET). 11,14,15 Interestingly, both the stochastic process and MET are amenable to regulation, and one common factor capable of doing so is p53.…”

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ΔNp63 regulates select routes of reprogramming via multiple mechanisms

Petrenko

Nemajerová

et al. 2013

Cell Death Differ

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Somatic cells can be converted into induced pluripotent stem cells (iPSCs) by forced expression of various combinations of transcription factors, but the molecular mechanisms of reprogramming are poorly understood. Specifically, evidence that the reprogramming process can take many distinct routes only begins to emerge. It is definitively established that p53 deficiency greatly enhances reprogramming, revealing p53's barrier function for induced pluripotency, but the role of its homologs p63 and p73 are unknown. Here we report that in stark contrast to p53, p73 has no role in reprogramming. However, p63 is an enabling (rather than a barrier) factor for Oct4, Sox2 and Klf4 (OSK) and Oct4 and Sox2 (OS), but not for Oct4 and Klf4 (OK) reprogramming of mouse embryonic fibroblasts. Specifically, p63 is essential during reprogramming for maximum efficiency, albeit not for the ability to reprogram per se, and is dispensable for maintaining stability and pluripotency of established iPSC colonies. DNp63, but not TAp63, is the principal isoform involved. Loss of p63 can affect reprogramming via several mechanisms such as reduced expression of mesenchymal-epithelial transition and pluripotency genes, hypoproliferation and loss of the most reprogrammable cell populations. During OSK and OS reprogramming, different mechanisms seem to be critical, such as regulation of epithelial and pluripotency genes in OSK reprogramming versus regulation of proliferation in OS reprogramming. Finally, our data reveal three different routes of reprogramming by OSK, OS or OK, based on their differential p63 requirements for iPSC efficiency and pluripotency marker expression. This supports the concept that many distinct routes of reprogramming exist.

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“…Bone morphogenetic protein (BMP) signalling also plays an important role in the initiation stage of mouse iPS cell reprogramming by promoting MET via upregulation of epithelial genes such as E-cadherin, Occludin and Epithelial cell adhesion molecule [36] . Chen et al [54] have shown that BMPs can replace Klf4 in the reprogramming cocktail, allowing mouse embryonic fibroblasts (MEFs) to be reprogrammed using Oct4 alone. However, constitutive BMP activation prevents human somatic cell reprogramming.…”

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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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BMPs functionally replace Klf4 and support efficient reprogramming of mouse fibroblasts by Oct4 alone

Cited by 127 publications

References 26 publications

Reprogramming fibroblasts into induced pluripotent stem cells with Bmi1

Reprogramming fibroblasts into induced pluripotent stem cells with Bmi1

ΔNp63 regulates select routes of reprogramming via multiple mechanisms

Cell signalling pathways underlying induced pluripotent stem cell reprogramming

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