Mesenchymal to Epithelial Transition Mediated by CDH1 Promotes Spontaneous Reprogramming of Male Germline Stem Cells to Pluripotency

Stem Cell Reports. 2017 Feb 14;8(2):446-459. doi: 10.1016/j.stemcr.2016.12.006. Epub 2017 Jan 5.

Abstract

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

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cellular Reprogramming / genetics*
  • Cellular Reprogramming Techniques
  • Gene Expression
  • Gene Expression Regulation, Developmental
  • Germ Cells / cytology*
  • Germ Cells / metabolism*
  • Induced Pluripotent Stem Cells / cytology*
  • Induced Pluripotent Stem Cells / metabolism*
  • Male
  • Mice
  • Octamer Transcription Factor-3 / genetics
  • Signal Transduction
  • Transforming Growth Factor beta / metabolism
  • Zinc Finger E-box-Binding Homeobox 1 / genetics
  • Zinc Finger E-box-Binding Homeobox 1 / metabolism

Substances

  • Octamer Transcription Factor-3
  • Transforming Growth Factor beta
  • ZEB1 protein, mouse
  • Zinc Finger E-box-Binding Homeobox 1