Sequential introduction of reprogramming factors reveals a time-sensitive requirement for individual factors and a sequential EMT–MET mechanism for optimal reprogramming

Liu, Xiaopeng; Sun, Hao; Qi, Jing; Wang, Linli; He, Songbing; Liu, Jing; Feng, Chengqian; Chen, Chunlan; Li, Wen; Guo, Yunqian; Qin, Dajiang; Pan, Guangjin; Chen, Jiekai; Pei, Duanqing; Zheng, Hui

doi:10.1038/ncb2765

Cited by 209 publications

(215 citation statements)

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“…135 It was recently shown that optimal reprogramming to stem cells was obtained by step-wise introduction of the factors listed above and involved a sequential EMT-MET process. 133 Data from other research groups also confirm the reprogramming to iPSCs as a multistep process, where pluripotency during the early EMT phase is promoted by TGFb. In the later MET phase, BMP signaling plays a key role by upregulating miR-200 family members that enforce the epithelial phenotype.…”

Section: Emt and Breast Cancer Stem Cellsmentioning

confidence: 53%

Reprogramming during epithelial to mesenchymal transition under the control of TGFβ

Tan¹,

Olsson

Moustakas

2014

Cell Adhesion & Migration

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Epithelial-mesenchymal transition (EMT) refers to plastic changes in epithelial tissue architecture. Breast cancer stromal cells provide secreted molecules, such as transforming growth factor b (TGFb), that promote EMT on tumor cells to facilitate breast cancer cell invasion, stemness and metastasis. TGFb signaling is considered to be abnormal in the context of cancer development; however, TGFb acting on breast cancer EMT resembles physiological signaling during embryonic development, when EMT generates or patterns new tissues. Interestingly, while EMT promotes metastatic fate, successful metastatic colonization seems to require the inverse process of mesenchymal-epithelial transition (MET). EMT and MET are interconnected in a timedependent and tissue context-dependent manner and are coordinated by TGFb, other extracellular proteins, intracellular signaling cascades, non-coding RNAs and chromatin-based molecular alterations. Research on breast cancer EMT/MET aims at delivering biomolecules that can be used diagnostically in cancer pathology and possibly provide ideas for how to improve breast cancer therapy.

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Section: Emt and Breast Cancer Stem Cellsmentioning

confidence: 53%

Reprogramming during epithelial to mesenchymal transition under the control of TGFβ

Tan¹,

Olsson

Moustakas

2014

Cell Adhesion & Migration

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“…Mechanistically, Sox2 suppresses expression of Snail, an EMT inducer [48] , and Klf4 induces E-cadherin expression, thus promoting MET [41] . In addition, Maekawa et al [49] have shown that the Glis family zinc finger 1 protein Glis1 can substitute cMyc in the reprogramming cocktail by inducing MET, thus initiating iPS cell reprogramming.…”

Section: Initiationmentioning

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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“…To practically group cells into the M-and E-Grand divisions, we could take advantage of the ratio of E-cadherin (epithelial) to N-cadherin (mesenchymal) as it was successfully utilized to predict reprogramming potentials of various cells [2]. To extend this logic further, we have performed a metaanalysis on the gene expression profiles of 745 human primary cell samples from BioGPS (http://biogps.org, dataset Primary Cell Atlas) and found that ~25% of all cell types are high in N-cadherin (mesenchymal) and ~55% of cell types are high in E-cadherin (epithelial).…”

mentioning

confidence: 99%