Ribavirin has been proven to be an antiviral treatment, whereas there are still risks of hemolysis and congenital malformation. Abnormal cardiac development contributes to the occurrence and development of many heart diseases. However, there is so far no evidence that ribavirin induces human cardiac developmental toxicity. Herein, we employed cardiac differentiation model of human induced pluripotent stem cells (hiPSCs) to determine the impact of ribavirin on heart development. Our data showed that ribavirin at clinically high concentrations (5 and 10 μM) significantly inhibited the proliferation and differentiation of hiPSCs from mesoderm to cardiac progenitor cells and cardiac progenitor cells to cardiomyocytes, but not from pluripotent status to mesoderm. Meanwhile, DCFH-DA staining revealed that ribavirin could increase ROS content in the mid-phase of differentiation, but not in the early phase and late phase. In addition, ribavirin treatment (1, 5 and 10 μM) remarkably caused DNA damage which was shown by the increase of γH2AX-positive cells only in the mid-phase and activation of p53 during the differentiation of hiPSCs from mesoderm to cardiomyocytes. Moreover, exposure to ribavirin (5 and 10 μM) markedly upregulated the expression of differentiation blocker lncRNAs Gas5 and HBL1 in the mid-phase and late phase of differentiation. In conclusion, our results suggest that ribavirin is detrimental in cardiac differentiation of hiPSCs, which may be associated with DNA damage and p53 activation. It may provide the evidence for the rational clinical application of ribavirin.

中文翻译：

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利巴韦林抑制人诱导的多能干细胞的心肌分化：对其心脏发育毒性的影响。

利巴韦林已被证明是一种抗病毒药物，但是仍然存在溶血和先天性畸形的风险。心脏发育异常导致许多心脏病的发生和发展。但是，到目前为止，尚无证据表明利巴韦林可诱导人心脏发育毒性。在这里，我们采用了人类诱导的多能干细胞（hiPSCs）的心脏分化模型来确定利巴韦林对心脏发育的影响。我们的数据表明，临床上高浓度（5和10μM）的利巴韦林显着抑制hiPSC从中胚层到心脏祖细胞和心脏祖细胞到心肌细胞的增殖和分化，但不能抑制多能状态到中胚层。与此同时，DCFH-DA染色显示利巴韦林可以在分化中期增加ROS含量，而在早期和晚期则不能。此外，利巴韦林处理（1、5和10μM）显着引起DNA损伤，这仅在hiPSC从中胚层向心肌细胞的分化过程中，γH2AX阳性细胞仅在中期出现增加，而p53激活才显示出来。此外，暴露于利巴韦林（5和10μM）在分化的中期和后期显着上调了分化阻滞剂lncRNA Gas5和HBL1的表达。总之，我们的结果表明，利巴韦林对hiPSC的心脏分化有害，这可能与DNA损伤和p53激活有关。可以为利巴韦林的合理临床应用提供依据。但不在早期和晚期。此外，利巴韦林处理（1、5和10μM）显着引起DNA损伤，这仅在hiPSC从中胚层向心肌细胞的分化过程中，γH2AX阳性细胞仅在中期出现增加，而p53激活才显示出来。此外，暴露于利巴韦林（5和10μM）在分化的中期和后期显着上调了分化阻滞剂lncRNA Gas5和HBL1的表达。总之，我们的结果表明，利巴韦林对hiPSC的心脏分化有害，这可能与DNA损伤和p53激活有关。可以为利巴韦林的合理临床应用提供依据。但不在早期和晚期。此外，利巴韦林处理（1、5和10μM）显着引起DNA损伤，这仅在hiPSC从中胚层向心肌细胞的分化过程中，γH2AX阳性细胞仅在中期出现增加，而p53激活才显示出来。此外，暴露于利巴韦林（5和10μM）在分化的中期和后期显着上调了分化阻滞剂lncRNA Gas5和HBL1的表达。总之，我们的结果表明，利巴韦林对hiPSC的心脏分化有害，这可能与DNA损伤和p53激活有关。可以为利巴韦林的合理临床应用提供依据。5和10μM）显着引起DNA损伤，这仅在hiPSC从中胚层向心肌细胞分化的过程中仅在中间阶段γH2AX阳性细胞的增加和p53的激活所显示。此外，暴露于利巴韦林（5和10μM）在分化的中期和后期显着上调了分化阻滞剂lncRNA Gas5和HBL1的表达。总之，我们的结果表明，利巴韦林对hiPSC的心脏分化有害，这可能与DNA损伤和p53激活有关。它可以为利巴韦林的合理临床应用提供证据。5和10μM）显着引起DNA损伤，这仅在hiPSC从中胚层向心肌细胞分化的过程中仅在中间阶段γH2AX阳性细胞的增加和p53的激活所显示。此外，暴露于利巴韦林（5和10μM）在分化的中期和后期显着上调了分化阻滞剂lncRNA Gas5和HBL1的表达。总之，我们的结果表明，利巴韦林对hiPSC的心脏分化有害，这可能与DNA损伤和p53激活有关。可以为利巴韦林的合理临床应用提供依据。暴露于利巴韦林（5和10μM）显着上调了分化中期和晚期分化阻滞剂lncRNA Gas5和HBL1的表达。总之，我们的结果表明，利巴韦林对hiPSC的心脏分化有害，这可能与DNA损伤和p53激活有关。可以为利巴韦林的合理临床应用提供依据。暴露于利巴韦林（5和10μM）显着上调了分化中期和晚期分化阻滞剂lncRNA Gas5和HBL1的表达。总之，我们的结果表明，利巴韦林对hiPSC的心脏分化有害，这可能与DNA损伤和p53激活有关。它可以为利巴韦林的合理临床应用提供证据。