PGC-1α promotes mitochondrial respiration and biogenesis during the differentiation of hiPSCs into cardiomyocytes.
PGC-1α promotes mitochondrial respiration and biogenesis during the differentiation of hiPSCs into cardiomyocytes.
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DOI：
10.1016/j.gendis.2020.12.006
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发表时间：
2021-11
期刊：
影响因子：
6.8
通讯作者：
Zhu J
中科院分区：
文献类型：
--
作者：
Zhou Q;Xu H;Yan L;Ye L;Zhang X;Tan B;Yi Q;Tian J;Zhu J
虽然人们普遍认为，人诱导多能干细胞衍生的心肌细胞尽管hiPSC-CM（hiPSC-CM）是容易获得的、稳健可再现的、并且在生理学上适合于心血管领域中的临床应用和研究的人细胞，但体外培养的hiPSC-CM保留了限制其应用的不成熟代谢表型，而在人诱导多能干细胞（hiPSC）分化为心肌细胞期间控制线粒体代谢成熟的潜在分子机制知之甚少。在本研究中，我们发现过氧化物酶体增殖物激活受体γ共激活因子-1 α（PGC-1α）在诱导hiPSCs心肌分化过程中的线粒体生物合成和氧化磷酸化（OXPHOS）的建立中发挥重要作用。通过siRNA敲低PGC-1α可损伤线粒体呼吸，而ZLN 005上调PGC-1α可通过调节参与线粒体动力学和氧化代谢的下游基因的表达，促进hiPSC-CM中线粒体生物合成和功能。此外，我们发现雌激素相关受体α（ERRα）是诱导hiPSC-CM中PGC-1α刺激效应所必需的。这些发现为心肌分化过程中线粒体代谢的分子控制提供了关键的见解，并可用于产生代谢更成熟的心肌细胞以供应用。
Although it is widely accepted that human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are readily available, robustly reproducible, and physiologically appropriate human cells for clinical applications and research in the cardiovascular field, hiPSC-CMs cultured in vitro retain an immature metabolic phenotype that limits their application, and little is known about the underlying molecular mechanism controlling mitochondrial metabolic maturation during human induced pluripotent stem cells (hiPSCs ) differentiation into cardiomyocytes. In this study, we found that peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) played an important role in inducing mitochondrial biogenesis and establishing oxidative phosphorylation (OXPHOS) during the cardiac differentiation of hiPSCs. Knocking down PGC-1α by siRNA impaired mitochondrial respiration, while upregulating PGC-1α by ZLN005 promoted mitochondrial biosynthesis and function by regulating the expression of downstream genes involved in mitochondrial dynamics and oxidative metabolism in hiPSC-CMs. Furthermore, we found that estrogen-related receptor α (ERRα) was required for the induction of PGC-1α stimulatory effects in hiPSC-CMs. These findings provide key insights into the molecular control of mitochondrial metabolism during cardiac differentiation and may be used to generate more metabolically mature cardiomyocytes for application.
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影响因子：
7
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
通讯作者：
Lim SY
影响因子：
20.1
作者：
Hu D;Linders A;Yamak A;Correia C;Kijlstra JD;Garakani A;Xiao L;Milan DJ;van der Meer P;Serra M;Alves PM;Domian IJ
通讯作者：
Domian IJ
影响因子：
29
作者：
Chen H;Chan DC
通讯作者：
Chan DC
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.
DOI：
10.1073/pnas.1016354108
发表时间：
2011-04-19
影响因子：
11.1
作者：
D'Errico, Ilenia;Salvatore, Lorena;Moschetta, Antonio
通讯作者：
Moschetta, Antonio