FZD5 regulates cellular senescence in human mesenchymal stem/stromal cells

Seiko Harada, Yo Mabuchi, Jun Kohyama, Daisuke Shimojo, Sadafumi Suzuki, Yoshimi Kawamura, Daisuke Araki, Takashi Suyama, Masunori Kajikawa, Chihiro Akazawa, Hideyuki Okano, Yumi Matsuzaki

Research output: Contribution to journalArticlepeer-review

Abstract

Human mesenchymal stem/stromal cells (hMSCs) have garnered enormous interest as a potential resource for cell-based therapies. However, the molecular mechanisms regulating senescence in hMSCs remain unclear. To elucidate these mechanisms, we performed gene expression profiling to compare clonal immature MSCs exhibiting multipotency with less potent MSCs. We found that the transcription factor Frizzled 5 (FZD5) is expressed specifically in immature hMSCs. The FZD5 cell surface antigen was also highly expressed in the primary MSC fraction (LNGFR+THY-1+) and cultured MSCs. Treatment of cells with the FZD5 ligand WNT5A promoted their proliferation. Upon FZD5 knockdown, hMSCs exhibited markedly attenuated proliferation and differentiation ability. The observed increase in the levels of senescence markers suggested that FZD5 knockdown promotes cellular senescence by regulating the noncanonical Wnt pathway. Conversely, FZD5 overexpression delayed cell cycle arrest during the continued culture of hMSCs. These results indicated that the intrinsic activation of FZD5 plays an essential role in negatively regulating senescence in hMSCs and suggested that controlling FZD5 signaling offers the potential to regulate hMSC quality and improve the efficacy of cell-replacement therapies using hMSCs.

Original languageEnglish
Pages (from-to)318-330
Number of pages13
JournalStem Cells
Volume39
Issue number3
DOIs
Publication statusPublished - 2021 Mar

Keywords

  • FZD5 receptor
  • aging
  • human
  • mesenchymal stem/stromal cells
  • senescence

ASJC Scopus subject areas

  • Molecular Medicine
  • Developmental Biology
  • Cell Biology

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