TPP1 Enhances the Therapeutic Effects of Transplanted Aged Mesenchymal Stem Cells in Infarcted Hearts via the MRE11/AKT Pathway.
TPP1 Enhances the Therapeutic Effects of Transplanted Aged Mesenchymal Stem Cells in Infarcted Hearts via the MRE11/AKT Pathway.
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TPP1 通过 MRE11/AKT 途径增强梗死心脏中移植的老化间充质干细胞的治疗效果。
DOI：
10.3389/fcell.2020.588023
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发表时间：
2020
影响因子：
5.5
通讯作者：
Wang J
中科院分区：
文献类型：
--
作者：
Yu K;Zeng Z;Cheng S;Hu W;Gao C;Liu F;Chen J;Qian Y;Xu D;Zhao J;Liu X;Wang J
移植后细胞存活率低限制了间充质干细胞（MSC）移植到梗死心脏的治疗潜力，特别是在老年人中。TPP 1是参与端粒保护的shelterin复合物的一种成分，在年轻的MSC中高度表达，但在老年人中下降。在这里，我们探讨是否TPP 1过表达在老年小鼠骨髓间充质干细胞提高细胞活力在体内和体外。方法将过表达TPP 1的老龄小鼠MSCs注射到结扎左冠状动脉前降支的小鼠心肌梗死灶周围。同时，为了评估细胞水平的影响，将H2 O2应用于体外MSC以模拟心肌损伤的微环境。结果在体内，与未修饰的老年MSCs相比，移植过表达TPP 1的老年MSCs可提高细胞存活率，增强心功能，减少纤维化。在体外，TPP 1过表达保护老化的MSC免受H2 O2诱导的凋亡和增强的DNA双链断裂（DSB）修复。此外，AKT和关键DSB修复蛋白MRE 11的磷酸化在过表达TPP 1的老年MSC中均显著上调。结论TPP 1可通过AKT/MRE 11途径促进DNA修复，从而提高老年MSC移植的疗效，为老年患者自体移植的临床应用提供了重要的前景。
Background Poor cell survival after transplantation restricts the therapeutic potential of mesenchymal stem cell (MSC) transplantation into infarcted hearts, particularly in older individuals. TPP1, a component of the shelterin complex that is involved in telomere protection, is highly expressed in young MSCs but declines in aged ones. Here, we explore whether TPP1 overexpression in aged mouse MSCs improves cell viability in vivo and in vitro. Methods Aged mouse MSCs overexpressing TPP1 were injected into the peri-infarct area of the mouse heart after left anterior descending coronary artery ligation. In parallel, to evaluate cellular-level effects, H2O2 was applied to MSCs in vitro to mimic the microenvironment of myocardial injury. Results In vivo, the transplantation of aged MSCs overexpressing TPP1 resulted in improved cell survival, enhanced cardiac function, and reduced fibrosis compared to unmodified aged MSCs. In vitro, TPP1 overexpression protected aged MSCs from H2O2-induced apoptosis and enhanced DNA double-strand break (DSB) repair. In addition, the phosphorylation of AKT and the key DSB repair protein MRE11 were both significantly upregulated in aged MSCs that overexpressed TPP1. Conclusions Our results reveal that TPP1 can enhance DNA repair through the AKT/MRE11 pathway, thereby improving the therapeutic effects of aged MSC transplantation and offering significant potential for the clinical application of autologous transplantation in aged patients.
影响因子：
3.7
作者：
Arish N;Cohen PY;Golan-Gerstl R;Fridlender Z;Dayan MR;Zisman P;Breuer R;Wallach-Dayan SB
通讯作者：
Wallach-Dayan SB