Stem Cell Reports
Volume 8, Issue 2, 14 February 2017, Pages 446-459
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Article
Mesenchymal to Epithelial Transition Mediated by CDH1 Promotes Spontaneous Reprogramming of Male Germline Stem Cells to Pluripotency

https://doi.org/10.1016/j.stemcr.2016.12.006Get rights and content
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Highlights

  • OCT4 and TGF-β signaling regulate GSC reprogramming by influencing MET

  • ZEB1 regulates CDH1 expression and MET by binding to E boxes in the Cdh1 promoter

  • MET controlled by CDH1 is a barrier in GSC reprogramming

  • GSCs and SSCs with higher CDH1 expression exhibit enhanced reprogramming potential

Summary

Cultured spermatogonial stem cells (GSCs) can spontaneously form pluripotent cells in certain culture conditions. However, GSC reprogramming is a rare event that is largely unexplained. We show GSCs have high expression of mesenchymal to epithelial transition (MET) suppressors resulting in a developmental barrier inhibiting GSC reprogramming. Either increasing OCT4 or repressing transforming growth factor β (TGF-β) signaling promotes GSC reprogramming by upregulating CDH1 and boosting MET. Reducing ZEB1 also enhances GSC reprogramming through its direct effect on CDH1. RNA sequencing shows that rare GSCs, identified as CDH1+ after trypsin digestion, are epithelial-like cells. CDH1+ GSCs exhibit enhanced reprogramming and become more prevalent during the course of reprogramming. Our results provide a mechanistic explanation for the spontaneous emergence of pluripotent cells from GSC cultures; namely, rare GSCs upregulate CDH1 and initiate MET, processes normally kept in check by ZEB1 and TGF-β signaling, thereby ensuring germ cells are protected from aberrant acquisition of pluripotency.

Keywords

male germline stem cell
reprogramming
Mesenchymal to epithelial transition
CDH1
ZEB1
TGFb signalling

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