Ethanol exposure during differentiation of human induced pluripotent stem cells reduces cardiomyocyte generation and alters metabolism

IF 5.1 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Life sciences Pub Date : 2025-03-01 Epub Date: 2025-01-30 DOI:10.1016/j.lfs.2025.123434

Kun Man , Longping Fu , Alicia Lane , Frank Harris , Olivia Reid , Lawrence C. Armand , Parvin Forghani , Ronghu Wu , Victor Faundez , Lou Ann Brown , Chunhui Xu

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Abstract

Prenatal alcohol exposure increases the risk of congenital heart diseases (CHDs) by disrupting fetal development, yet the mechanisms underlying alcohol-induced cellular and molecular changes in human cardiogenesis remain unclear. This study investigates the effects of ethanol exposure on cardiomyocyte differentiation using human induced pluripotent stem cells (hiPSCs) as a model. Cardiomyocyte differentiation was induced using Wnt signaling molecules, and hiPSCs were treated with ethanol at concentrations of 17, 50, and 100 mM from day 0 to day 12. Ethanol treatment impaired cardiac differentiation efficiency in the early stage (days 5–7) and reduced cell proliferation in the late stage (days 12–13) in a dose-dependent manner, resulting in fewer cardiac progenitors and cardiomyocytes. Additionally, ethanol exposure caused mitochondrial defects, characterized by redox imbalance, reduced membrane potential, and decreased mitochondrial content and cellular respiration. Proteomic analysis revealed downregulation of proteins involved in calcium binding and fatty acid oxidation, a key metabolic pathway for cardiac development. These findings shed light on the mechanisms by which alcohol disrupts cardiomyocyte differentiation and may inform strategies to mitigate alcohol-induced CHD risk.

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人诱导多能干细胞分化过程中暴露于乙醇可减少心肌细胞的生成并改变代谢。

产前酒精暴露通过破坏胎儿发育增加先天性心脏病（CHDs）的风险，但酒精诱导的人类心脏发生中细胞和分子变化的机制尚不清楚。本研究以人诱导多能干细胞（hiPSCs）为模型，探讨乙醇暴露对心肌细胞分化的影响。使用Wnt信号分子诱导心肌细胞分化，并在第0天至第12天用浓度为17、50和100 mM的乙醇处理hiPSCs。乙醇处理在早期（5-7天）损害了心脏分化效率，并在后期（12-13天）以剂量依赖的方式降低了细胞增殖，导致心脏祖细胞和心肌细胞减少。此外，乙醇暴露导致线粒体缺陷，其特征是氧化还原失衡、膜电位降低、线粒体含量和细胞呼吸减少。蛋白质组学分析显示，参与钙结合和脂肪酸氧化的蛋白质下调，这是心脏发育的关键代谢途径。这些发现揭示了酒精破坏心肌细胞分化的机制，并可能为减轻酒精诱导的冠心病风险提供策略。

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来源期刊

Life sciences 医学-药学

CiteScore

12.20

自引率

1.60%

发文量

841

审稿时长

6 months

期刊介绍： Life Sciences is an international journal publishing articles that emphasize the molecular, cellular, and functional basis of therapy. The journal emphasizes the understanding of mechanism that is relevant to all aspects of human disease and translation to patients. All articles are rigorously reviewed. The Journal favors publication of full-length papers where modern scientific technologies are used to explain molecular, cellular and physiological mechanisms. Articles that merely report observations are rarely accepted. Recommendations from the Declaration of Helsinki or NIH guidelines for care and use of laboratory animals must be adhered to. Articles should be written at a level accessible to readers who are non-specialists in the topic of the article themselves, but who are interested in the research. The Journal welcomes reviews on topics of wide interest to investigators in the life sciences. We particularly encourage submission of brief, focused reviews containing high-quality artwork and require the use of mechanistic summary diagrams.