PDF(Pubmed)
Abstract：
Many oncology drugs have been found to induce cardiotoxicity in a subset of patients, which significantly limits their clinical use and impedes the benefit of lifesaving anticancer treatments. Human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) carry donor-specific genetic information and have been proposed for exploring the interindividual difference in oncology drug-induced cardiotoxicity. Herein, we evaluated the inter- and intraindividual variability of iPSC-CM-related assays and presented a proof of concept to prospectively predict doxorubicin (DOX)-induced cardiotoxicity (DIC) using donor-specific iPSC-CMs. Our findings demonstrated that donor-specific iPSC-CMs exhibited greater line-to-line variability than the intraindividual variability in impedance cytotoxicity and transcriptome assays. The variable and dose-dependent cytotoxic responses of iPSC-CMs resembled those observed in clinical practice and largely replicated the reported mechanisms. By categorizing iPSC-CMs into resistant and sensitive cell lines based on their time- and concentration-related phenotypic responses to DOX, we found that the sensitivity of donor-specific iPSC-CMs to DOX may predict in vivo DIC risk. Furthermore, we identified a differentially expressed gene, DND microRNA-mediated repression inhibitor 1 (DND1), between the DOX-resistant and DOX-sensitive iPSC-CMs. Our results support the utilization of donor-specific iPSC-CMs in assessing interindividual differences in DIC. Further studies will encompass a large panel of donor-specific iPSC-CMs to identify potential novel molecular and genetic biomarkers for predicting DOX and other oncology drug-induced cardiotoxicity.
摘要：
已经发现许多肿瘤药物在一部分患者中引起心脏毒性，这极大地限制了它们的临床应用，并阻碍了救生抗癌治疗的益处。人类诱导的多能干细胞衍生的心肌细胞（iPSC-CM）携带供体特异性遗传信息，并已被提出用于探索肿瘤药物诱导的心脏毒性的个体间差异。在这里，我们评估了iPSC-CM相关测定的个体间和个体内变异性，并提出了使用供体特异性iPSC-CM前瞻性预测多柔比星（DOX）诱导的心脏毒性（DIC）的概念证明。我们的发现表明，供体特异性iPSC-CM在细胞毒性和转录测定中表现出比个体内变异性更大的线间变异性。iPSC-CM的可变和剂量依赖性细胞毒性反应与临床实践中观察到的相似，并在很大程度上复制了报告的机制。通过根据iPSC-CM对DOX的时间和浓度相关表型反应将其分为抗性和敏感细胞系，我们发现供体特异性iPSC-CM对DOX的敏感性可以预测体内DIC风险.此外，我们确定了一个差异表达的基因，DNDmicroRNA介导的抑制抑制剂1（DND1），在DOX抗性和DOX敏感性iPSC-CM之间。我们的结果支持利用供体特异性iPSC-CM评估DIC的个体差异。进一步的研究将包括一大群供体特异性iPSC-CM，以鉴定潜在的新型分子和遗传生物标志物，用于预测DOX和其他肿瘤药物诱导的心脏毒性。
