1. PLK inhibitors identified by high content phenotypic screening promote maturation of human PSC-derived cardiomyocytes.
- Author
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Feng, Mengying, Tang, Yansong, Yao, Su, Zhang, Hongjie, Xu, Dachun, and Wei, Ke
- Subjects
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PLURIPOTENT stem cells , *NUCLEAR membranes , *CELL cycle , *CELLULAR signal transduction , *PHENOTYPES , *CELLULAR therapy - Abstract
Human pluripotent stem cells-derived cardiomyocytes (hPSC-CMs) provide an unlimited source of human cardiomyocytes for disease modeling, cell therapies, and other biomedical applications. However, hPSC-CMs remain developmentally immature which limits their suitability in translational applications. High Content Screening (HCS) is a powerful tool for identifying novel molecules and pathways regulating complex biological processes, but no HCS assay for hPSC-CM maturation has yet been reported. PCM1, a centriole satellite protein, is specifically restricted on nuclear envelope in mature cardiomyocytes. We developed a High Content Screen (HCS) based on PCM1 subcellular localization in hPSC-CMs to identify novel molecules promoting cardiomyocyte maturation, which identified 93 from 1693 compounds that enhance maturation of hPSC-CMs, including multiple PLK inhibitors. Volasertib and Centrinone, two PLK inhibitors, can enhance binucleation, and promote metabolic and electrophysiological maturation in hPSC-CMs. Furthermore, PI3K-AKT signaling pathway was found to be suppressed by PLK inhibitors, and VO-Ohpic, a PTEN inhibitor that activates AKT pathway, blunted the effect of PLK inhibitors on hPSC-CM maturation. In summary, our HCS assay found that PLK inhibitors can promote maturation of hPSC-CMs through suppressing AKT signaling pathway. [Display omitted] • Pericentriolar Material 1 (PCM1) specifically localizes on nuclear envelope in mature cardiomyocytes. • High content screen based on PCM1 localization identifies cell cycle inhibitors promoting hPSC-CM maturation. • PLK inhibitors promote hPSC-CM maturation via downregulating PI3K-AKT signaling pathway. [ABSTRACT FROM AUTHOR] more...
- Published
- 2022
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