Leptin increases mitochondrial OPA1 via GSK3-mediated OMA1 ubiquitination to enhance therapeutic effects of mesenchymal stem cell transplantation.
Leptin increases mitochondrial OPA1 via GSK3-mediated OMA1 ubiquitination to enhance therapeutic effects of mesenchymal stem cell transplantation.
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瘦素通过GSK3介导的OMA1泛素化增加线粒体OPA1以增强间充质干细胞移植的治疗效果
DOI：
10.1038/s41419-018-0579-9
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发表时间：
2018-05-01
影响因子：
9
通讯作者：
Wang J
中科院分区：
文献类型：
--
作者：
Yang F;Wu R;Jiang Z;Chen J;Nan J;Su S;Zhang N;Wang C;Zhao J;Ni C;Wang Y;Hu W;Zeng Z;Zhu K;Liu X;Hu X;Zhu W;Yu H;Huang J;Wang J
越来越多的证据表明，间充质干细胞（MSCs）对心肌梗死（MI）具有心脏保护作用。然而，移植细胞的存活率和植入率较低，限制了它们在心脏治疗中的疗效。与缺氧预处理相关的瘦素生成增加有助于提高间充质干细胞的存活率。线粒体完整性决定细胞命运。因此，我们旨在研究瘦素是否能增强人源间充质干细胞（hMSCs）的线粒体完整性，以抵御各种应激。在体内实验中，将过表达瘦素的人源间充质干细胞移植到梗死心脏中，可提高细胞活力，进而增强血管生成和心脏功能。在体外实验中，用重组瘦素预处理人源间充质干细胞（hMSCs-Leppre），可提高细胞在严重缺血条件（缺氧下葡萄糖和血清剥夺）下的存活率，这与线粒体融合增加有关。随后，视神经萎缩蛋白1（OPA1），一种调节线粒体融合和嵴结构的线粒体内膜蛋白，在hMSCs-Leppre组中显著升高，而用选择性小干扰RNA靶向OPA1可消除瘦素的保护作用。此外，OMA1，一种切割OPA1的线粒体蛋白酶，以瘦素依赖的方式减少。用蛋白酶体抑制剂（MG132）预处理细胞，可阻止瘦素诱导的OMA1降解，这表明泛素化/蛋白酶体系统是瘦素保护途径的一部分。此外，糖原合成酶激酶3（GSK3）抑制剂（SB216763）也参与了OMA1的降解。总之，在心肌梗死导致的恶劣微环境中，（a）瘦素可维持人源间充质干细胞的线粒体完整性并延长其存活时间；（b）瘦素介导的线粒体完整性需要GSK3磷酸化，这是OMA1泛素化依赖性降解和长链OPA1切割减弱的先决条件。因此，靶向GSK3/OMA1/OPA1信号通路的瘦素可优化人源间充质干细胞对心肌梗死等心血管疾病的治疗。
Accumulating evidence revealed that mesenchymal stem cells (MSCs) confer cardioprotection against myocardial infarction (MI). However, the poor survival and engraftment rate of the transplanted cells limited their therapeutic efficacy in the heart. The enhanced leptin production associated with hypoxia preconditioning contributed to the improved MSCs survival. Mitochondrial integrity determines the cellular fate. Thus, we aimed to investigate whether leptin can enhance mitochondrial integrity of human MSCs (hMSCs) to protect against various stress. In vivo, transplantation of leptin-overexpressing hMSCs into the infarcted heart resulted in improved cell viability, leading to enhanced angiogenesis and cardiac function. In vitro, pretreatment of hMSCs with recombinant leptin (hMSCs-Leppre) displayed improved cell survival against severe ischemic condition (glucose and serum deprivation under hypoxia), which was associated with increased mitochondrial fusion. Subsequently, Optic atrophy 1 (OPA1), a mitochondrial inner membrane protein that regulates fusion and cristae structure, was significantly elevated in the hMSCs-Leppregroup, and the protection of leptin was abrogated by targeting OPA1 with a selective siRNA. Furthermore, OMA1, a mitochondrial protease that cleaves OPA1, decreased in a leptin-dependent manner. Pretreatment of cells with an inhibitor of the proteasome (MG132), prevented leptin-induced OMA1 degradation, implicating the ubiquitination/proteasome system as a part of the protective leptin pathway. In addition, GSK3 inhibitor (SB216763) was also involved in the degradation of OMA1. In conclusion, in the hostile microenvironment caused by MI, (a) leptin can maintain the mitochondrial integrity and prolong the survival of hMSCs; (b) leptin-mediated mitochondrial integrity requires phosphorylation of GSK3 as a prerequisite for ubiquitination-depended degradation of OMA1 and attenuation of long-OPA1 cleavage. Thus, leptin targeting the GSK3/OMA1/OPA1 signaling pathway can optimize hMSCs therapy for cardiovascular diseases such as MI.
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影响因子：
21.3
作者：
通讯作者：
--
影响因子：
11.2
作者：
Fava G;Alpini G;Rychlicki C;Saccomanno S;DeMorrow S;Trozzi L;Candelaresi C;Venter J;Di Sario A;Marzioni M;Bearzi I;Glaser S;Alvaro D;Marucci L;Francis H;Svegliati-Baroni G;Benedetti A
通讯作者：
Benedetti A
合成间充质干细胞的制备用于治疗小鼠急性心肌梗死
影响因子：
20.1
作者：
Luo L;Tang J;Nishi K;Yan C;Dinh PU;Cores J;Kudo T;Zhang J;Li TS;Cheng K
通讯作者：
Cheng K
影响因子：
4.4
作者：
Buravkova, L. B.;Andreeva, E. R.;Zhivotovsky, B.
通讯作者：
Zhivotovsky, B.
影响因子：
4.8
作者：
Käser, M;Kambacheld, M;Langer, T
通讯作者：
Langer, T