Primitive mammalian heart transforms from a single heart tube to a four-chambered muscular organ during a short developmental window. The adult mammalian heart has limited potential for regeneration and repair. Understanding the mechanism of early mammalian heart development and early cardiovascular progenitor cell fate decision could provide potential therapeutic value for heart regeneration and cardiovascular disease.
In this new published paper, researchers found that knocking out global microRNA by deleting Dgcr8 microprocessor in Mesp1 cardiovascular progenitor cells lead to the formation of extremely dilated and enlarged heart. Single cell RNA sequencing study uncovered the defect was due to the increase of angiogenesis genes in Dgcr8 cKO cardiomyocytes. They also performed global microRNA profiling of E9.5 heart for the first time, and identified that miR-541 was transiently highly expressed in E9.5 hearts. Interestingly, introducing miR-541 back into microRNA-free cardiomyocytes partially rescued their defects, downregulated angiogenesis genes, and significantly upregulated cardiac genes. Moreover, miR-541 can directly suppress angiogenesis related gene Ctgf, inhibit endothelial function, and promote cardiomyocyte differentiation from mESCs.
This study provided rich information about global miRNA expression and function during early mammalian heart development and cardiovascular progenitor cell fate decision. Their results discovered the unexpected role of miRNA-541 during this time window to suppress endothelial genes and function, which may be exploited to treat blood vessel hyperplasia or promote cardiac regeneration.
Dr. Jie Na from School of Medicine, Tsinghua University, is the corresponding author of this work. Ph.D. candidate, Ms. Xi Chen is the first author. Collaborators include Dr. Jianbin Wang from School of life science, Tsinghua University, and Dr. Yangming Wang, from Institute of Molecular Medicine, Peking University. This work also received miRNA-Seq analysis assistance and cell lines provided by Dr. Michael Zhang, Dr. Zhi Lu, and Dr. Yongzhang Luo from Tsinghua University. This work was supported by funding from the National Key R&D Program of China, the National Natural Science Foundation of China (NSFC), the National Basic Research Program of China, and the funding from Tsinghua-Peking Center for Life Sciences and core facilities of Tsinghua-Peking Center for Life Sciences.