GDF11 enhances therapeutic efficacy of mesenchymal stem cells for myocardial infarction via YME1L-mediated OPA1 processing.
GDF11 enhances therapeutic efficacy of mesenchymal stem cells for myocardial infarction via YME1L-mediated OPA1 processing.
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GDF11通过YME1L介导的OPA1处理增强间充质干细胞对心肌梗死的治疗功效
DOI：
10.1002/sctm.20-0005
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发表时间：
2020-10
影响因子：
6
通讯作者：
Yu H
中科院分区：
文献类型：
--
作者：
Zhao Y;Zhu J;Zhang N;Liu Q;Wang Y;Hu X;Chen J;Zhu W;Yu H
生长分化因子11（GDF11）已被证实能促进干细胞活性，但关于GDF11对心脏间充质干细胞（MSCs）活力以及其治疗心脏损伤疗效的影响，目前知之甚少。为了解GDF11在间充质干细胞中的作用，研究人员用携带GDF11基因和绿色荧光蛋白（GFP）的慢病毒载体转导小鼠心脏来源的间充质干细胞（MSCsLV - GDF11），或用重组GDF11培养间充质干细胞（MSCsrGDF11）。与对照间充质干细胞相比，无论是MSCsrGDF11还是MSCsLV - GDF11，在缺氧条件下，细胞凋亡更少，旁分泌功能更佳，线粒体形态和功能也得以维持。GDF11增强了Smad2/3的磷酸化，从而上调了YME1L的表达，YME1L是一种线粒体蛋白酶，可平衡视神经萎缩蛋白1（OPA1）的加工过程。转化生长因子-β（TGF-β）受体抑制剂（SB431542）或Smad2/3抑制剂（SIS3）会减弱GDF11对细胞活力、线粒体功能以及YME1L表达的影响。与对照间充质干细胞相比，将MSCsGDF11移植到梗死心脏中，可提高细胞存活率和留存率，促进更多血管生成，缩小瘢痕面积，并改善心脏功能。GDF11通过TGF-β受体/Smad2/3/YME1L - OPA1信号通路促进线粒体融合，从而增强间充质干细胞的活力和治疗效果。GDF11的这一新作用，或可用于心肌梗死干细胞治疗的新方法。
生长分化因子11（GDF11）通过激活素受体样激酶4/5（ALK4/5）-磷酸化Smad2/3（p - Smad2/3）通路，诱导缺氧间充质干细胞（MSCs）中的线粒体网络融合。YME1L的增加重新平衡了OPA1的加工过程，并抑制了缺氧应激条件下间充质干细胞中的线粒体碎片化。本研究表明，GDF11诱导的YME1L增加，可作为一种潜在的方法，在缺氧条件下保护间充质干细胞，并提高其对心肌梗死的治疗效果。
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) (MSCsLV‐GDF11) or cultured with recombinant GDF11 (MSCsrGDF11). Either MSCsrGDF11 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 MSCsGDF11 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. Growth differentiation factor 11 (GDF11) induces fusion of mitochondrial networks in hypoxic mesenchymal stem cells (MSCs) through ALK4/5‐p‐Smad2/3 pathway. Increased YME1L rebalances OPA1 processing and inhibits mitochondrial fragmentation in the MSCs under hypoxia stress condition. This study suggests that YME1L promotion induced by GDF11 can serve as a potential approach to protect MSCs under hypoxia condition, and improve their therapeutic effect for myocardial infarction
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影响因子：
29
作者：
Egerman MA;Cadena SM;Gilbert JA;Meyer A;Nelson HN;Swalley SE;Mallozzi C;Jacobi C;Jennings LL;Clay I;Laurent G;Ma S;Brachat S;Lach-Trifilieff E;Shavlakadze T;Trendelenburg AU;Brack AS;Glass DJ
通讯作者：
Glass DJ
影响因子：
4.8
作者：
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通讯作者：
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影响因子：
7.7
作者：
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通讯作者：
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影响因子：
20.1
作者：
Luger, Dror;Lipinski, Michael J.;Epstein, Stephen E.
通讯作者：
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影响因子：
7.7
作者：
Rosselin M;Santo-Domingo J;Bermont F;Giacomello M;Demaurex N
通讯作者：
Demaurex N