GDF11 enhances therapeutic efficacy of mesenchymal stem cells for myocardial infarction via YME1L-mediated OPA1 processing.,STEM CELLS Translational Medicine

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GDF11 enhances therapeutic efficacy of mesenchymal stem cells for myocardial infarction via YME1L-mediated OPA1 processing.
STEM CELLS Translational Medicine ( IF 5.4 ) Pub Date : 2020-06-09 , DOI: 10.1002/sctm.20-0005
Yun Zhao _{1,

2} , Jinyun Zhu _{1,

2} , Ning Zhang _{1,

2} , Qi Liu _{1,

2} , Yingchao Wang ₃ , Xinyang Hu _{1,

2} , Jinghai Chen _{1,

2,

4} , Wei Zhu _{1,

2} , Hong Yu _{1,

2}

Affiliation

Growth differentiation factor 11 (GDF11) has been shown to promote stem cell activity, but little is known about the effect of GDF11 on viability and therapeutic efficacy of cardiac mesenchymal stem cells (MSCs) for cardiac injury. To understand the roles of GDF11 in MSCs, mouse heart‐derived MSCs were transduced with lentiviral vector carrying genes for both GDF11 and green fluorescent protein (GFP) (MSCs^LV‐GDF11) or cultured with recombinant GDF11 (MSCs^rGDF11). Either MSCs^rGDF11 or MSCs ^LV‐GDF11 displayed less cell apoptosis and better paracrine function, as well as preserved mitochondrial morphology and function under hypoxic condition as compared with control MSCs. GDF11 enhanced phosphorylation of Smad2/3, which upregulated expression of YME1L, a mitochondria protease that balances OPA1 processing. Inhibitors of TGF‐β receptor (SB431542) or Smad2/3 (SIS3) attenuated the effects of GDF11 on cell viability, mitochondrial function, and expression of YME1L. Transplantation of MSCs^GDF11 into infarct heart resulted in improved cell survival and retention, leading to more angiogenesis, smaller scar size, and better cardiac function in comparison with control MSCs. GDF11 enhanced viability and therapeutic efficiency of MSCs by promoting mitochondrial fusion through TGF‐β receptor/Smad2/3/YME1L‐OPA1 signaling pathway. This novel role of GDF11 may be used for a new approach of stem cell therapy for myocardial infarction.

中文翻译：

GDF11 通过 YME1L 介导的 OPA1 加工增强间充质干细胞对心肌梗塞的治疗效果。

生长分化因子 11 (GDF11) 已被证明可促进干细胞活性，但关于 GDF11 对心脏间充质干细胞 (MSC) 对心脏损伤的活力和治疗功效的影响知之甚少。为了了解 GDF11 在 MSC 中的作用，小鼠心脏来源的 MSC 用携带 GDF11 和绿色荧光蛋白 (GFP) 基因 (MSC ^LV-GDF11 ) 的慢病毒载体转导或与重组 GDF11 (MSC ^rGDF11 )一起培养。MSCs ^rGDF11或 MSCs ^LV-GDF11与对照间充质干细胞相比，细胞凋亡更少，旁分泌功能更好，并且在缺氧条件下保留了线粒体形态和功能。GDF11 增强了 Smad2/3 的磷酸化，从而上调了 YME1L（一种平衡 OPA1 加工的线粒体蛋白酶）的表达。TGF-β 受体 (SB431542) 或 Smad2/3 (SIS3) 抑制剂减弱 GDF11 对细胞活力、线粒体功能和 YME1L 表达的影响。MSCs ^{GDF11 的}移植进入梗塞心脏导致细胞存活和保留改善，与对照 MSC 相比，导致更多的血管生成、更小的疤痕尺寸和更好的心脏功能。GDF11通过TGF-β受体/Smad2/3/YME1L-OPA1信号通路促进线粒体融合，增强MSCs的活力和治疗效率。GDF11 的这种新作用可用于心肌梗塞干细胞治疗的新方法。

更新日期：2020-06-09

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