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.

尽管人们普遍认为人类诱导多能干细胞衍生的心肌细胞 (hiPSC-CM) 易于获得、可重复性强且生理上适合心血管领域的临床应用和研究，但体外培养的 hiPSC-CM保留了限制其应用的未成熟代谢表型，并且在人类诱导多能干细胞 (hiPSCs) 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。在这项研究中，我们发现过氧化物酶体增殖物激活受体 γ 共激活因子-1α (PGC-1α) 在 hiPSC 的心脏分化过程中在诱导线粒体生物发生和建立氧化磷酸化 (OXPHOS) 方面发挥着重要作用。siRNA 敲低 PGC-1α 会损害线粒体呼吸，而 ZLN005 上调 PGC-1α 通过调节参与 hiPSC-CM 中线粒体动力学和氧化代谢的下游基因的表达来促进线粒体生物合成和功能。此外，我们发现在 hiPSC-CM 中诱导 PGC-1α 刺激作用需要雌激素相关受体 α（ERRα）。这些发现为心脏分化过程中线粒体代谢的分子控制提供了关键见解，并可用于产生更多代谢成熟的心肌细胞以供应用。