Arsenic trioxide blocked proliferation and cardiomyocyte differentiation of human induced pluripotent stem cells: Implication in cardiac developmental toxicity
Arsenic trioxide blocked proliferation and cardiomyocyte differentiation of human induced pluripotent stem cells: Implication in cardiac developmental toxicity
复制标题
三氧化二砷阻断人诱导多能干细胞的增殖和心肌细胞分化：对心脏发育毒性的影响
DOI：
10.1016/j.toxlet.2019.03.008
复制
发表时间：
2019-07-01
影响因子：
3.5
通讯作者：
Cai, Benzhi
中科院分区：
文献类型：
--
作者：
Bao, Zhengyi;Han, Zhenbo;Cai, Benzhi
三氧化二砷（ATO）由于具有显著的抗癌作用，已被推荐作为治疗急性早幼粒细胞白血病（APL）的一线药物。大量的临床报告表明，ATO是一种可导致人类出生缺陷的发育毒性物质。但三氧化二砷是否会导致人类心脏发育毒性仍不得而知。因此，本研究旨在通过建立人诱导多能干细胞（hiPSCs）体外心脏分化模型，探讨ATO对人心脏发育的影响及其机制。本研究发现，在临床上可达到的浓度（0.1、0.5和1 μ M）下，ATO在hipsc心脏分化的整个过程中都能显著抑制增殖。同时，TUNEL实验显示ATO在心脏分化过程中以浓度依赖性的方式引起细胞凋亡。我们一致发现，ATO降低了分化的hipsc中中胚层标记物Brachyury和EOMES、心脏祖细胞标记物GATA-4、msp -1和TBX-5以及心脏特异性标记物α -肌动素的表达。此外，ATO处理导致DNA损伤，表现在DNA双链断裂的敏感标志物γ H2AX上调。综上所述，ATO在hipsc心脏分化过程中阻断心肌细胞分化，诱导细胞凋亡和细胞生长停止，这可能与DNA损伤有关。
Arsenic trioxide (ATO) has been recommended as the first-line agent for the treatment of acute promyelocytic leukaemia (APL), due to its substantial anticancer effect. Numerous clinical reports have indicated that ATO is a developmental toxicant which can result in birth defects of human beings. But whether arsenic trioxide can lead to human cardiac developmental toxicity remains largely unknown. So the present study aims to explore the influence and mechanisms of ATO on human cardiac development by using a vitro cardiac differentiation model of human induced pluripotent stem cells (hiPSCs). Here we found that clinically achievable concentrations (0.1, 0.5 and 1 mu M) of ATO resulted in a significant inhibition of proliferation during the whole process of cardiac differentiation of hiPSCs. Meanwhile, TUNEL assay revealed that ATO could cause cell apoptosis during cardiac differentiation in a concentration-dependent manner. Consistently, we found that ATO reduced the expressions of mesoderm markers Brachyury and EOMES, cardiac progenitor cell markers GATA-4, MESP-1 and TBX-5, and cardiac specific marker alpha-actinin in differentiated hiPSCs. Furthermore, ATO treatment had caused DNA damage which was shown in the upregulation of gamma H2AX, a sensitive marker for DNA double-strand breaks. Taken together, ATO blocked cardiomyocyte differentiation, induced apoptosis and cell growth arrest during cardiac differentiation of hiPSCs, which might be associated with DNA damage.