Fine-Tuning Mybl2 Is Required for Proper Mesenchymal-to-Epithelial Transition during Somatic Reprogramming

Ward, Carl; Volpe, Giacomo; Cauchy, Pierre; Ptasińska, Anetta; Almaghrabi, Ruba; Blakemore, Daniel; Nafria, Monica; Kestner, Doris; Frampton, Jon; Murphy, George J.; Buganim, Yosef; Kaji, Keisuke; García, Paloma

doi:10.1016/j.celrep.2018.07.026

Cited by 23 publications

(18 citation statements)

References 60 publications

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“…Our study has revealed a spontaneous time-dependent conversion from human skin FBs into a functional KCs phenotype in vitro. Such conversion was significantly different from the previous studies 37. The global morphological change from FBs to KLCs was observed on day 90 in the primary culture.…”

Section: Discussioncontrasting

confidence: 98%

Spontaneous evolution of human skin fibroblasts into wound-healing keratinocyte-like cells

Zhang

Cheng

et al. 2019

Theranostics

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Producing keratinocyte cells (KCs) in large scale is difficult due to their slow proliferation, disabling their use as seed cells for skin regeneration and wound healing. Cell reprogramming is a promising inducer-based approach to KC production but only reaches very low cellular conversion. Here we reported a unique cellular conversion phenomenon, where human skin fibroblasts (FBs) were spontaneously converted into keratinocyte-like cells (KLCs) over the time without using any inducers. Methods : FBs were routinely cultured for more than 120 days in regular culture medium. Characteristics of KLCs were checked at the molecular and cellular level. Then the functionality and safety of the KLCs were verified by wound healing and tumorigenicity assay, respectively. To identify the mechanism of the cell conversion phenomenon, high-throughput RNA sequencing was also performed. Results : The global conversion started on day 90 and reached 90% on day 110. The KLCs were as functional and effective as KCs in wound healing without causing oncogenicity. The conversion was regulated via a PI3K-AKT signaling pathway mediated by a long non-coding RNA, LINC00672. Modulating the pathway could shorten the conversion time to 14 days. Conclusion : The discovered FBs-KLCs conversion in the study might open a new avenue to the scalable production of cell sources needed for regenerating skins and healing large-area wounds.

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Section: Discussioncontrasting

confidence: 98%

Spontaneous evolution of human skin fibroblasts into wound-healing keratinocyte-like cells

Zhang

Cheng

et al. 2019

Theranostics

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“…3c). These factors have all been previously implicated in the EMT, but are not typically considered canonical EMT regulators [29][30][31][32][33][34] . To assess the accuracy of these results, we used ATAC-seq to assess the accessibility of transcription factor motifs throughout the EMT and compared accessibility dynamics to the inferred regulon activity.…”

Section: Resultsmentioning

confidence: 99%

Context specificity of the EMT transcriptional response

2020

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Epithelial-mesenchymal plasticity contributes to many biological processes, including tumor progression. Various epithelial-mesenchymal transition (EMT) responses have been reported and no common, EMT-defining gene expression program has been identified. Here, we have performed a comparative analysis of the EMT response, leveraging highly multiplexed singlecell RNA sequencing (scRNA-seq) to measure expression profiles of 103,999 cells from 960 samples, comprising 12 EMT time course experiments and independent kinase inhibitor screens for each. We demonstrate that the EMT is vastly context specific, with an average of only 22% of response genes being shared between any two conditions, and over half of all response genes were restricted to 1-2 time course experiments. Further, kinase inhibitor screens revealed signaling dependencies and modularity of these responses. These findings suggest that the EMT is not simply a single, linear process, but is highly variable and modular, warranting quantitative frameworks for understanding nuances of the transition.

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“…Loss of HMGN nucleosome‐binding proteins enhances the kinetics of iPSCs formation by accelerating the closing of MEF‐specific open chromatin, while the differentiation potential of iPSCs is unaffected (He et al , 2018), suggesting that HMGNs function to stabilize cell fate rather than determining cell identity. Mybl2 is a somatic cell gatekeeper that inhibits the opening of chromatin to activate MET genes in the early stage of reprogramming (Ward et al , 2018). Mbd3 maintains the somatic cell fate and depletion of Mbd3 strongly promotes MEF reprogramming to iPSCs (Luo et al , 2013; Rais et al , 2013).…”

Section: Introductionmentioning

confidence: 99%