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Downregulation of odd-skipped related 2, a novel regulator of epithelial-mesenchymal transition, enables efficient somatic cell reprogramming

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Item Type:Article
Title:Downregulation of odd-skipped related 2, a novel regulator of epithelial-mesenchymal transition, enables efficient somatic cell reprogramming
Creators Name:Anh, L.P.H. and Nishimura, K. and Kuno, A. and Nguyen, T.L. and Kato, T. and Ohtaka, M. and Nakanishi, M. and Sugihara, E. and Sato, T.A. and Hayashi, Y. and Fukuda, A. and Hisatake, K.
Abstract:Somatic cell reprogramming proceeds through a series of events to generate induced pluripotent stem cells (iPSCs). The early stage of reprogramming of mouse embryonic fibroblasts (MEFs) is characterized by rapid cell proliferation and morphological changes, which are accompanied by downregulation of mesenchyme-associated genes. However, the functional relevance of their downregulation to reprogramming remains poorly defined. In this study, we have screened transcriptional regulators that are downregulated immediately upon reprogramming, presumably through direct targeting by reprogramming factors. To test if these transcriptional regulators impact reprogramming when expressed continuously, we generated an expression vector that harbors human cytomegalovirus upstream open reading frame 2 (uORF2), which reduces translation to minimize the detrimental effect of an expressed protein. Screening of transcriptional regulators with this expression vector revealed that downregulation of odd-skipped related 2 (Osr2) is crucial for efficient reprogramming. Using a cell-based model for epithelial-mesenchymal transition (EMT), we show that Osr2 is a novel EMT regulator that acts through induction of TGF-(β) signaling. During reprogramming, Osr2 downregulation not only diminishes TGF-(β) signaling but also allows activation of Wnt signaling, thus promoting mesenchymal-epithelial transition (MET) toward acquisition of pluripotency. Our results illuminate the functional significance of Osr2 downregulation in erasing the mesenchymal phenotype at an early stage of somatic cell reprogramming.
Keywords:Osr2, Reprogramming, Epithelial-Mesenchymal Transition, TGF-(ß), Wnt, Animals, Mice
Source:Stem Cells
Publisher:Oxford University Press
Page Range:397-410
Date:29 April 2022
Additional Information:Copyright © The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.
Official Publication:https://doi.org/10.1093/stmcls/sxac012
PubMed:View item in PubMed

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