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Hypoxia Regulates the Self-Renewal of Endometrial Mesenchymal Stromal/Stem-like Cells via Notch Signaling.

Sisi ZhangRachel W S ChanErnest Hung Yu NgWilliam S B Yeung
Published in: International journal of molecular sciences (2022)
Human endometrium is an incredibly dynamic tissue undergoing cyclic regeneration and shedding during a woman's reproductive life. Endometrial mesenchymal stromal/stem-like cells (eMSC) contribute to this process. A hypoxic niche with low oxygen levels has been reported in multiple somatic stem cell types. However, the knowledge of hypoxia on eMSC remains limited. In mice, stromal stem/progenitor cells can be identified by the label-retaining technique. We examined the relationship between the label-retaining stromal cells (LRSC) and hypoxia during tissue breakdown in a mouse model of simulated menses. Our results demonstrated that LRSC resided in a hypoxic microenvironment during endometrial breakdown and early repair. Immunofluorescence staining revealed that the hypoxic-located LRSC underwent proliferation and was highly colocalized with Notch1. In vitro studies illustrated that hypoxia activated Notch signaling in eMSC, leading to enhanced self-renewal, clonogenicity and proliferation of cells. More importantly, HIF-1α played an essential role in the hypoxia-mediated maintenance of eMSC through the activation of Notch signaling. In conclusion, our findings show that some endometrial stem/progenitor cells reside in a hypoxic niche during menstruation, and hypoxia can regulate the self-renewal activity of eMSC via Notch signaling.
Keyphrases
  • endothelial cells
  • stem cells
  • bone marrow
  • mouse model
  • endometrial cancer
  • signaling pathway
  • healthcare
  • induced apoptosis
  • cell proliferation
  • type diabetes
  • single cell
  • endoplasmic reticulum stress
  • cell therapy