Downregulation of Odd-Skipped Related 2, a Novel Regulator of Epithelial-Mesenchymal Transition, Enables Efficient Somatic Cell Reprogramming

Le Phuong Hoang Anh, Ken Nishimura, Akihiro Kuno, Nguyen Thuy Linh, Tetsuo Kato, Manami Ohtaka, Mahito Nakanishi, Eiji Sugihara, Taka Aki Sato, Yohei Hayashi, Aya Fukuda, Koji Hisatake

Research output: Contribution to journalArticlepeer-review

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 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 transforming growth factor-β (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.

Original languageEnglish
Pages (from-to)397-410
Number of pages14
JournalInternational Journal of Cell Cloning
Volume40
Issue number4
DOIs
Publication statusPublished - 29-04-2022

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Developmental Biology
  • Cell Biology

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