Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai 200032, China.
State Key Laboratory of Genetic Engineering, School of Life Sciences and Human Phenome Institute, Fudan University, Shanghai 200438, China.
Clin Sci (Lond). 2019 Jul 2;133(13):1387-1399. doi: 10.1042/CS20190099. Print 2019 Jul 15.
Recent evidence has shown that cardiomyocytes (CMs) can proliferate at a low level after myocardial infarction (MI), but it is insufficient to reestablish heart function. Several microRNAs (miRNAs) have been proven to sufficiently induce rodent CM proliferation. However, whether miRNAs identified in rodents can promote human CM proliferation is unknown due to the poorly conserved functions of miRNAs among species. In the present study, we demonstrate that i) expression of microRNA-302d (miR-302d) decreased significantly during CM differentiation from human pluripotent stem cells (hPSCs) from day 4 to day 18; ii) miR-302d efficiently promoted proliferation of hPSC-derived CMs; iii) miR-302d promoted CM proliferation by targeting in the Hippo pathway; and iv) RNA-sequencing analysis revealed that overexpression of miR-302d induced changes in gene expression, which mainly converged on the cell cycle. Our study provides further evidence for the therapeutic potential of miR-302d.
最近的证据表明，心肌细胞（CMs）在心肌梗死（MI）后可以低水平增殖，但不足以重建心脏功能。已经证明几种 microRNAs（miRNAs）可以充分诱导啮齿动物 CM 的增殖。然而，由于 miRNA 在物种间的功能保守性较差，尚不清楚在啮齿动物中鉴定的 miRNAs 是否可以促进人 CM 的增殖。在本研究中，我们证明了：i）miR-302d 的表达在人多能干细胞（hPSCs）分化为 CM 的过程中从第 4 天到第 18 天显著降低；ii）miR-302d 有效地促进了 hPSC 衍生的 CM 的增殖；iii）miR-302d 通过靶向 Hippo 通路中的 促进 CM 增殖；iv）RNA 测序分析表明，miR-302d 的过表达诱导了基因表达的变化，这些变化主要集中在细胞周期上。我们的研究为 miR-302d 的治疗潜力提供了进一步的证据。
