Biomedical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea.
Molecular Medicine & Biopharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea.
Mol Ther. 2018 Mar 7;26(3):845-859. doi: 10.1016/j.ymthe.2017.12.015. Epub 2017 Dec 19.
Human embryonic stem cell-derived mesenchymal stem cells (hE-MSCs) have greater proliferative capacity than other human mesenchymal stem cells (hMSCs), suggesting that they may have wider applications in regenerative cellular therapy. In this study, to uncover the anti-senescence mechanism in hE-MSCs, we compared hE-MSCs with adult bone marrow (hBM-MSCs) and found that hepatocyte growth factor (HGF) was more abundantly expressed in hE-MSCs than in hBM-MSCs and that it induced the transcription of RAD51 and facilitated its SUMOylation at K70. RAD51 induction/modification by HGF not only increased telomere length but also increased mtDNA replication, leading to increased ATP generation. Moreover, HGF-treated hBM-MSCs showed significantly better therapeutic efficacy than naive hBM-MSCs. Together, the data suggest that the RAD51-mediated effects of HGF prevent hMSC senescence by promoting telomere lengthening and inducing mtDNA replication and function, which opens the prospect of developing novel therapies for liver disease.
人胚胎干细胞来源的间充质干细胞（hE-MSCs）比其他人类间充质干细胞（hMSCs）具有更强的增殖能力，这表明它们在再生细胞治疗中有更广泛的应用。在这项研究中，为了揭示 hE-MSCs 的抗衰老机制，我们将 hE-MSCs 与成人骨髓（hBM-MSCs）进行了比较，发现肝细胞生长因子（HGF）在 hE-MSCs 中的表达量明显高于 hBM-MSCs，并且它能诱导 RAD51 的转录，并促进其在 K70 位的 SUMO 化。HGF 诱导/修饰 RAD51 不仅能增加端粒长度，还能增加 mtDNA 复制，从而产生更多的 ATP。此外，经 HGF 处理的 hBM-MSCs 表现出明显优于原始 hBM-MSCs 的治疗效果。综上所述，这些数据表明，HGF 通过促进端粒延长和诱导 mtDNA 复制和功能来介导 RAD51 的作用，从而防止 hMSC 衰老，这为开发治疗肝脏疾病的新疗法开辟了前景。
