Woo Laura A, Wintruba Kaitlyn L, Wissmann Bethany, Tkachenko Svyatoslav, Kubicka Ewa, Farber Emily, Engkvist Ola, Barrett Ian, Granberg Kenneth L, Plowright Alleyn T, Wolf Matthew J, Brautigan David L, Bekiranov Stefan, Wang Qing-Dong, Saucerman Jeffrey J
Department of Biomedical Engineering and Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA 22903, USA.
Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44196, USA.
iScience. 2024 Jul 11;27(8):110485. doi: 10.1016/j.isci.2024.110485. eCollection 2024 Aug 16.
Mammalian hearts lose their regenerative potential shortly after birth. Stimulating the proliferation of preexisting cardiomyocytes is a potential therapeutic strategy for cardiac damage. In a previous study, we identified 30 compounds that induced the bona-fide proliferation of human iPSC-derived cardiomyocytes (hiPSC-CM). Here, we selected five active compounds with diverse targets, including ALK5 and CB1R, and performed multi-omic analyses to identify common mechanisms mediating the cell cycle progression of hiPSC-CM. Transcriptome profiling revealed the top enriched pathways for all compounds including cell cycle, DNA repair, and kinesin pathways. Functional proteomic arrays found that the compounds collectively activated multiple receptor tyrosine kinases including ErbB2, IGF1R, and VEGFR2. Network analysis integrating common transcriptomic and proteomic signatures predicted that MAPK/PI3K pathways mediated compound responses. Furthermore, VEGFR2 negatively regulated endoreplication, enabling the completion of cell division. Thus, in this study, we applied high-content imaging and molecular profiling to establish mechanisms linking pro-proliferative agents to mechanisms of cardiomyocyte cell cycling.
哺乳动物的心脏在出生后不久就会失去其再生潜力。刺激已有的心肌细胞增殖是一种治疗心脏损伤的潜在策略。在先前的一项研究中，我们鉴定出30种可诱导人诱导多能干细胞来源的心肌细胞（hiPSC-CM）真正增殖的化合物。在此，我们选择了5种具有不同靶点（包括ALK5和CB1R）的活性化合物，并进行了多组学分析，以确定介导hiPSC-CM细胞周期进程的共同机制。转录组分析揭示了所有化合物中富集程度最高的通路，包括细胞周期、DNA修复和驱动蛋白通路。功能蛋白质组阵列发现这些化合物共同激活了多种受体酪氨酸激酶，包括ErbB2、IGF1R和VEGFR2。整合共同转录组和蛋白质组特征的网络分析预测，MAPK/PI3K通路介导了化合物反应。此外，VEGFR2负向调节核内复制，从而使细胞分裂得以完成。因此，在本研究中，我们应用高内涵成像和分子分析来建立将促增殖剂与心肌细胞细胞周期机制联系起来的机制。
