Phenotypic screen identifies FOXO inhibitor to counteract maturation and promote expansion of human iPS cell-derived cardiomyocytes. (1st July 2022)

• Record Type: Journal Article
• Authors: Schade, Dennis; Drowley, Lauren; Wang, Qing-Dong; Plowright, Alleyn T.; Greber, Boris
• Is Part Of: Bioorganic & medicinal chemistry. Volume 65(2022)
• Publication Date: 2022-07-01
• Subjects: Human induced-pluripotent stem cells (hiPSCs) -- Cardiomyocytes -- Proliferation -- Phenotypic screen -- High-content imaging -- FOXO inhibitor -- FOXO transcription factor; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2022.116782
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: Achieving pharmacological control over cardiomyocyte proliferation represents a prime goal in therapeutic cardiovascular research. Here, we identify a novel chemical tool compound for the expansion of human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes. The forkhead box O (FOXO) inhibitor AS1842856 was identified as a significant hit from an unbiased proliferation screen in early, immature hiPSC- cardiomyocytes (eCMs). The mitogenic effects of AS1842856 turned out to be robust, dose-dependent, sustained, and reversible. eCM numbers increased >30-fold as induced by AS1842856 over three passages. Phenotypically as well as by marker gene expression, the compound interestingly appeared to counteract cellular maturation both in immature hiPSC-CMs as well as in more advanced ones. Thus, FOXO inhibitor AS1842856 presents a novel proliferation inducer for the chemically defined, xeno-free expansion of hiPSC-derived CMs, while its de-differentiation effect might as well bear potential in regenerative medicine.