FZD5 regulates cellular senescence in human mesenchymal stem/stromal cells,STEM CELLS

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FZD5 regulates cellular senescence in human mesenchymal stem/stromal cells
STEM CELLS ( IF 4.0 ) Pub Date : 2020-12-22 , DOI: 10.1002/stem.3317
Seiko Harada ₁ , Yo Mabuchi _{1,

2,

3} , Jun Kohyama ₁ , Daisuke Shimojo ₁ , Sadafumi Suzuki ₁ , Yoshimi Kawamura _{1,

4} , Daisuke Araki ₁ , Takashi Suyama ₅ , Masunori Kajikawa ₆ , Chihiro Akazawa _{2,

7} , Hideyuki Okano ₁ , Yumi Matsuzaki _{1,

5}

Affiliation

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 non-canonical 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. © AlphaMed Press 2020 SIGNIFICANCE STATEMENT: Mesenchymal stem/stromal cells (MSCs) hold considerable promise for cell therapy. Generally, MSCs are cultured in vitro to increase cell numbers and ensure functionality. However, long-term culture can lead to cellular senescence, wherein cells no longer replicate. Here, we evaluated the clones derived from single MSCs, revealing that the FZD5 regulatory protein is specifically expressed in highly functional MSCs. FZD5 prevents senescence and preserves multipotency in the most immature, rapidly proliferating subtype of MSCs. Controlling FZD5 gene expression may thus allow the suppression of MSC senescence, while maintaining their stem cell properties throughout long-term culture in vitro.

中文翻译：

FZD5调节人间充质干/基质细胞的细胞衰老

人类间充质干/基质细胞 (hMSC) 作为基于细胞的疗法的潜在资源引起了极大的兴趣。然而，调控 hMSCs 衰老的分子机制仍不清楚。为了阐明这些机制，我们进行了基因表达谱分析，以比较表现出多能性的克隆性未成熟 MSC 与效力较低的 MSC。我们发现转录因子 Frizzled 5 (FZD5) 在未成熟的 hMSC 中特异性表达。FZD5 细胞表面抗原也在原代 MSC 部分 (LNGFR+ THY-1+ ) 和培养的 MSC 中高度表达。用 FZD5 配体 WNT5A 处理细胞促进了它们的增殖。在 FZD5 敲低后，hMSCs 表现出显着减弱的增殖和分化能力。观察到的衰老标志物水平的增加表明 FZD5 敲低通过调节非经典 Wnt 途径促进细胞衰老。相反，在 hMSCs 的持续培养过程中，FZD5 过表达延迟了细胞周期停滞。这些结果表明 FZD5 的内在激活在 hMSCs 的负向调节衰老中起着至关重要的作用，并表明控制 FZD5 信号提供了调节 hMSC 质量和提高使用 hMSCs 的细胞替代疗法的功效的潜力。© AlphaMed Press 2020 重要声明：间充质干/基质细胞 (MSC) 对细胞治疗具有相当大的前景。通常，MSC 在体外培养以增加细胞数量并确保功能。然而，长期培养会导致细胞衰老，其中细胞不再复制。在这里，我们评估了源自单个 MSC 的克隆，揭示 FZD5 调节蛋白在高功能性 MSC 中特异性表达。FZD5 在最不成熟、快速增殖的 MSC 亚型中防止衰老并保持多能性。因此，控制 FZD5 基因表达可以抑制 MSC 衰老，同时在体外长期培养中保持其干细胞特性。

更新日期：2020-12-22

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