Inhibition of cardiomyocyte differentiation of human induced pluripotent stem cells by Ribavirin: Implication for its cardiac developmental toxicity

被引：23

作者：

Ye, Danyu ^{[1
,2
]}

Bao, Zhengyi ^{[1
,2
]}

Yu, Yang ^{[1
,2
]}

Han, Zhenbo ^{[1
,2
]}

Yu, Ying ^{[1
,2
]}

Xu, Zihang ^{[1
,2
]}

Ma, Wenya ^{[1
,2
]}

Yuan, Ye ^{[1
,2
]}

Zhang, Lai ^{[1
,2
]}

Xu, Yan ^{[1
,2
]}

Ma, Tianshuai ^{[1
,2
]}

Liu, Shenzhen ^{[1
,2
]}

Gao, Xinlu ^{[1
,2
]}

Yan, Gege ^{[1
,2
]}

Huang, Qi ^{[1
,2
]}

Wang, Xiuxiu ^{[1
,2
]}

Hua, Bingjie ^{[1
,2
]}

Yang, Fan ^{[1
,2
]}

Li, Yuan ^{[1
,2
]}

Cai, Benzhi ^{[1
,2
,3
]}

机构：

[1] Harbin Med Univ, Dept Pharm, Affiliated Hosp 2, Harbin 150086, Peoples R China

[2] Harbin Med Univ, Dept Pharmacol, Key Lab Cardiovasc Res, Coll Pharm,Minist Educ, Harbin 150086, Peoples R China

[3] Heilongjiang Acad Med Sci, Translat Med Res & Cooperat Ctr Northern China, Harbin 150081, Peoples R China

来源：

TOXICOLOGY | 2020年 / 435卷

关键词：

Ribavirin; hiPSCs; Cardiomyocyte differentiation; Proliferation; DNA damage; Cardiac developmental toxicity; CHRONIC HEPATITIS-C; LONG NONCODING RNAS; INTERFERON-ALPHA; PROGENITOR CELLS; DRUG; PROLIFERATION; EXPRESSION; THERAPY; ISL-1;

D O I：

10.1016/j.tox.2020.152422

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

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 the 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 mu M) 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. In addition, ribavirin treatment (1, 5 and 10 mu M) remarkably caused DNA damage which was shown by the increase of gamma H2AX-positive cells and upregulation of the p53 during the differentiation of hiPSCs from mesoderm to cardiac progenitor cells. Moreover, exposuring to ribavirin (5 and 10 mu M) markedly upregulated the expression of lncRNAs Gas5 in both mid-phase and late phase of differentiation and HBL1 in the mid-phase. In conclusion, our results suggest that ribavirin is detrimental in cardiac differentiation of hiPSCs, which may be associated with DNA damage, upregulated p53 and increased Gas5. It may provide the evidence for the rational clinical application of ribavirin.

引用

页数：11

共 51 条

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