FZD5 regulates cellular senescence in human mesenchymal stem/stromal cells

• Published in: Stem cells (Dayton, Ohio) Vol. 39; no. 3; pp. 318 - 330
• Main Authors: Harada, Seiko, Mabuchi, Yo, Kohyama, Jun, Shimojo, Daisuke, Suzuki, Sadafumi, Kawamura, Yoshimi, Araki, Daisuke, Suyama, Takashi, Kajikawa, Masunori, Akazawa, Chihiro, Okano, Hideyuki, Matsuzaki, Yumi
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 01.03.2021; Oxford University Press
• Subjects: aging; Antigens; Cell culture; Cell cycle; Cell proliferation; Cell surface; Frizzled protein; FZD5 receptor; Gene expression; human; mesenchymal stem/stromal cells; Mesenchyme; Molecular modelling; Senescence; Stromal cells; Tissue‐specific Stem Cells; Wnt protein; senescence; mesenchymal stem/stromal cells; aging; human; FZD5 receptor
• ISSN: 1066-5099; 1549-4918
• DOI: 10.1002/stem.3317

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. Although mesenchymal stem/stromal cells (MSCs) are promising for cell therapy, long‐term culture leads to MSC senescence with reduced stem cell capacity. We showed that FZD5, which is specifically expressed in immature MSCs, can serve as a stemness indicator. Controlling FZD5 signaling may improve MSC quality and the outcomes of cell therapy.