Cha Seong-Eung, Lee Mi Nam, Kim Eung-Sam
Department of Biological Sciences and Biotechnology, Chonnam National University, Gwangju 61186, Republic of Korea.
Department of Biological Sciences, Chonnam National University, Gwangju 61186, Republic of Korea.
Methods. 2025 Sep;241:114-127. doi: 10.1016/j.ymeth.2025.05.010. Epub 2025 May 29.
Cardiomyocytes are essential models for cardiac disease modeling, drug development, and regenerative therapies. Specifically, human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have emerged as widely used cellular models with high reproducibility. However, cardiomyocytes generated in vitro tend to remain immature and insufficient in replicating the electrophysiological and mechanical functions of adult cardiomyocytes, limiting the clinical and experimental applications of these models. Thus, various biochemical and biophysical strategies have been explored to promote the maturation of cardiomyocytes, to address these limitations, and more accurately mimic the characteristics of mature cardiomyocytes. This review summarizes recent studies on multiple methodologies employed to induce cardiomyocyte maturation, with a particular emphasis on the role of long-chain fatty acids (LCFAs). The evidence summarized in this review is derived from studies utilizing cardiomyocytes from neonatal mice or rats and hiPSC-CMs. Meanwhile, immature cardiomyocytes have been demonstrated to predominantly rely on glycolysis, transitioning to oxidative phosphorylation through maturation, which enhances electrical stability, contractility, and structural organization. LCFAs play a key role in the cardiomyocyte maturation process by serving as key metabolic factors that generate ATP through mitochondrial β-oxidation, thereby improving metabolic efficiency. Additionally, LCFAs are involved in activating cytoskeletal components and signaling pathways integral to cardiomyocyte contractility. Importantly, studies suggest that when multiple biochemical and biophysical stimuli are simultaneously applied, various aspects of cardiomyocyte maturation are synergistically accelerated. Therefore, future studies focusing on the coordinated application of these regulatory factors are expected to enhance the maturation process, ultimately contributing to the generation of mature cardiomyocytes suitable for regenerative medicine and other advanced applications.
心肌细胞是心脏病建模、药物开发和再生疗法的重要模型。具体而言，人诱导多能干细胞衍生的心肌细胞（hiPSC-CMs）已成为广泛使用且具有高重现性的细胞模型。然而，体外生成的心肌细胞往往仍不成熟，在复制成年心肌细胞的电生理和机械功能方面存在不足，限制了这些模型在临床和实验中的应用。因此，人们探索了各种生化和生物物理策略来促进心肌细胞成熟，以解决这些局限性，并更准确地模拟成熟心肌细胞的特征。本综述总结了近期关于多种诱导心肌细胞成熟方法的研究，特别强调了长链脂肪酸（LCFAs）的作用。本综述中总结的证据来自利用新生小鼠或大鼠的心肌细胞以及hiPSC-CMs的研究。同时，已证明未成熟心肌细胞主要依赖糖酵解，通过成熟转变为氧化磷酸化，这增强了电稳定性、收缩性和结构组织。LCFAs通过作为关键代谢因子，通过线粒体β氧化产生ATP，从而提高代谢效率，在心肌细胞成熟过程中发挥关键作用。此外，LCFAs参与激活对心肌细胞收缩性至关重要的细胞骨架成分和信号通路。重要的是，研究表明，当同时应用多种生化和生物物理刺激时，心肌细胞成熟的各个方面会协同加速。因此，未来专注于这些调节因子协同应用的研究有望增强成熟过程，最终有助于生成适用于再生医学和其他先进应用的成熟心肌细胞。
