Yao Su, Zhu Yalin, He Fenglian, Yuan Min, Jiang Rui, Zhang Hongjie, Fu Yanbin, Wei Ke
Institute for Regenerative Medicine, State Key Laboratory of Cardiology and Medical Innovation Center, Shanghai East Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
Shanghai Cancer Institute, Department of Biliary-Pancreatic Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Eur J Cell Biol. 2024 Dec;103(4):151452. doi: 10.1016/j.ejcb.2024.151452. Epub 2024 Aug 23.
Cardiac development requires precise gene expression programs at each developmental stage guided by multiple signaling pathways and transcription factors (TFs). MESP1 is transiently expressed in mesoderm, and is essential for subsequent cardiac development, while the precise mechanism regulating its own transcription and mesoderm cell fate is not fully understood. Therefore, we developed a high content screen assay to identify regulators of MESP1 expression in mesodermal cells differentiated from human pluripotent stem cells (hPSCs). The screen identified CYT387, a JAK1/JAK2 kinase inhibitor, as a potent activator of MESP1 expression, which was also found to promote cardiomyocyte differentiation in vitro. Mechanistic studies found that JAK inhibition promotes MESP1 expression by reducing cytoplasmic calcium concentration and subsequently activating canonical WNT signaling. Our study identified a role of JAK signaling in early mesodermal cells, and sheds light on the connection between the JAK-STAT pathway and transcriptional regulation of MESP1, which expands our understanding of mesoderm and cardiac development.
心脏发育需要在多个信号通路和转录因子（TFs）的引导下，在每个发育阶段进行精确的基因表达程序。MESP1在中胚层中短暂表达，对随后的心脏发育至关重要，但其自身转录和中胚层细胞命运的精确调控机制尚未完全了解。因此，我们开发了一种高内涵筛选分析方法，以鉴定从人多能干细胞（hPSCs）分化而来的中胚层细胞中MESP1表达的调节因子。该筛选鉴定出CYT387，一种JAK1/JAK2激酶抑制剂，作为MESP1表达的有效激活剂，还发现其能促进体外心肌细胞分化。机制研究发现，JAK抑制通过降低细胞质钙浓度并随后激活经典WNT信号来促进MESP1表达。我们的研究确定了JAK信号在早期中胚层细胞中的作用，并揭示了JAK-STAT通路与MESP1转录调控之间的联系，这扩展了我们对中胚层和心脏发育的理解。
