Reinal Ignacio, Ontoria-Oviedo Imelda, Selva Marta, Casini Marilù, Peiró-Molina Esteban, Fambuena-Santos Carlos, Climent Andreu M, Balaguer Julia, Cañete Adela, Mora Jaume, Raya Ángel, Sepúlveda Pilar
Regenerative Medicine and Heart Transplantation Unit, Health Research Institute Hospital la Fe, 46026 Valencia, Spain.
Hospital Universitari i Politècnic La Fe, 46026 Valencia, Spain.
Antioxidants (Basel). 2023 Jul 3;12(7):1378. doi: 10.3390/antiox12071378.
Anthracyclines are widely used in the treatment of many solid cancers, but their efficacy is limited by cardiotoxicity. As the number of pediatric cancer survivors continues to rise, there has been a concomitant increase in people living with anthracycline-induced cardiotoxicity. Accordingly, there is an ongoing need for new models to better understand the pathophysiological mechanisms of anthracycline-induced cardiac damage. Here we generated induced pluripotent stem cells (iPSCs) from two pediatric oncology patients with acute cardiotoxicity induced by anthracyclines and differentiated them to ventricular cardiomyocytes (hiPSC-CMs). Comparative analysis of these cells (CTX hiPSC-CMs) and control hiPSC-CMs revealed that the former were significantly more sensitive to cell injury and death from the anthracycline doxorubicin (DOX), as measured by viability analysis, cleaved caspase 3 expression, oxidative stress, genomic and mitochondrial damage and sarcomeric disorganization. The expression of several mRNAs involved in structural integrity and inflammatory response were also differentially affected by DOX. Functionally, optical mapping analysis revealed higher arrythmia complexity after DOX treatment in CTX iPSC-CMs. Finally, using a panel of previously identified microRNAs associated with cardioprotection, we identified lower levels of miR-22-3p, miR-30b-5p, miR-90b-3p and miR-4732-3p in CTX iPSC-CMs under basal conditions. Our study provides valuable phenotype information for cellular models of cardiotoxicity and highlights the significance of using patient-derived cardiomyocytes for studying the associated pathogenic mechanisms.
蒽环类药物广泛应用于多种实体癌的治疗，但其疗效受到心脏毒性的限制。随着儿童癌症幸存者数量持续增加，蒽环类药物所致心脏毒性的患者人数也随之上升。因此，持续需要新的模型来更好地理解蒽环类药物所致心脏损伤的病理生理机制。在此，我们从两名因蒽环类药物导致急性心脏毒性的儿科肿瘤患者中生成了诱导多能干细胞（iPSC），并将其分化为心室心肌细胞（hiPSC-CM）。对这些细胞（CTX hiPSC-CM）与对照hiPSC-CM进行比较分析发现，通过活力分析、裂解型半胱天冬酶3表达、氧化应激、基因组和线粒体损伤以及肌节紊乱来衡量，前者对蒽环类药物阿霉素（DOX）所致的细胞损伤和死亡明显更为敏感。几种参与结构完整性和炎症反应的mRNA表达也受到DOX的不同影响。在功能上，光学映射分析显示DOX处理后CTX iPSC-CM的心律失常复杂性更高。最后，通过一组先前鉴定的与心脏保护相关的微小RNA，我们发现在基础条件下CTX iPSC-CM中miR-22-3p、miR-30b-5p、miR-90b-3p和miR-4732-3p的水平较低。我们的研究为心脏毒性细胞模型提供了有价值的表型信息，并突出了使用患者来源的心肌细胞研究相关致病机制的重要性。
