Mitochondrial fission protein Drp1 inhibition promotes cardiac mesodermal differentiation of human pluripotent stem cells.
Mitochondrial fission protein Drp1 inhibition promotes cardiac mesodermal differentiation of human pluripotent stem cells.
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DOI：
10.1038/s41420-018-0042-9
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发表时间：
2018-12
影响因子：
7
通讯作者：
Lim SY
中科院分区：
文献类型：
--
作者：
Hoque A;Sivakumaran P;Bond ST;Ling NXY;Kong AM;Scott JW;Bandara N;Hernández D;Liu GS;Wong RCB;Ryan MT;Hausenloy DJ;Kemp BE;Oakhill JS;Drew BG;Pébay A;Lim SY
人诱导多能干细胞（iPSC）是体外研究心脏发育过程的有价值的工具，并且来自iPSC的心肌细胞是用于个性化医学的假定细胞来源。线粒体形态的变化已被证明发生在细胞重编程和多能干细胞分化过程中。然而，线粒体动力学和iPSC的心脏中胚层定型之间的关系仍然不清楚。在这里，我们证明了从多能干细胞的小颗粒碎片表型到分化的心肌细胞的丝状网状细长网络的线粒体形态变化是心脏中胚层分化所需的。通过小干扰RNA或Mdivi-1分别对线粒体分裂蛋白Drp 1进行遗传和药理学抑制，增加了iPSCs中心脏中胚层基因的表达。在胚状体形成过程中用Mdivi-1处理iPSC显著增加了跳动胚状体的百分比和心脏特异性基因的表达。此外，Drp 1基因沉默伴随着线粒体呼吸增加和有氧糖酵解减少。我们的研究结果表明，通过抑制Drp 1将线粒体形态的平衡向融合转移，促进了人iPSCs的心脏分化，代谢从糖酵解向氧化磷酸化转移。这些研究结果表明，Drp 1可能代表了未来发展策略的新分子靶点，以促进人类iPSCs分化为患者特异性心脏再生医学的心脏谱系。
Human induced pluripotent stem cells (iPSCs) are a valuable tool for studying the cardiac developmental process in vitro, and cardiomyocytes derived from iPSCs are a putative cell source for personalized medicine. Changes in mitochondrial morphology have been shown to occur during cellular reprogramming and pluripotent stem cell differentiation. However, the relationships between mitochondrial dynamics and cardiac mesoderm commitment of iPSCs remain unclear. Here we demonstrate that changes in mitochondrial morphology from a small granular fragmented phenotype in pluripotent stem cells to a filamentous reticular elongated network in differentiated cardiomyocytes are required for cardiac mesodermal differentiation. Genetic and pharmacological inhibition of the mitochondrial fission protein, Drp1, by either small interfering RNA or Mdivi-1, respectively, increased cardiac mesoderm gene expression in iPSCs. Treatment of iPSCs with Mdivi-1 during embryoid body formation significantly increased the percentage of beating embryoid bodies and expression of cardiac-specific genes. Furthermore, Drp1 gene silencing was accompanied by increased mitochondrial respiration and decreased aerobic glycolysis. Our findings demonstrate that shifting the balance of mitochondrial morphology toward fusion by inhibition of Drp1 promoted cardiac differentiation of human iPSCs with a metabolic shift from glycolysis towards oxidative phosphorylation. These findings suggest that Drp1 may represent a new molecular target for future development of strategies to promote the differentiation of human iPSCs into cardiac lineages for patient-specific cardiac regenerative medicine.
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影响因子：
11.1
作者：
Dorn GW 2nd
通讯作者：
Dorn GW 2nd
影响因子：
4.3
作者：
Hernández D;Millard R;Sivakumaran P;Wong RC;Crombie DE;Hewitt AW;Liang H;Hung SS;Pébay A;Shepherd RK;Dusting GJ;Lim SY
通讯作者：
Lim SY
影响因子：
3
作者：
Knowlton AA;Chen L;Malik ZA
通讯作者：
Malik ZA
影响因子：
29
作者：
Folmes CD;Nelson TJ;Martinez-Fernandez A;Arrell DK;Lindor JZ;Dzeja PP;Ikeda Y;Perez-Terzic C;Terzic A
通讯作者：
Terzic A
影响因子：
23.9
作者：
Gu, Wen;Gaeta, Xavier;Sahakyan, Anna;Chan, Alanna B.;Hong, Candice S.;Kim, Rachel;Braas, Daniel;Plath, Kathrin;Lowry, William E.;Christofk, Heather R.
通讯作者：
Christofk, Heather R.