Endogenous IGF Signaling Directs Heterogeneous Mesoderm Differentiation in Human Embryonic Stem Cells

Abstract

Summary: During embryogenesis, various cell types emerge simultaneously from their common progenitors under the influence of intrinsic signals. Human embryonic stem cells can differentiate to diverse cell types of three embryonic lineages, making them an excellent system for understanding the regulatory mechanism that maintains the balance of different cell types in embryogenesis. In this report, we demonstrate that insulin-like growth factor (IGF) proteins are endogenously expressed during differentiation, and their temporal expression contributes to the cell fate diversity in mesoderm differentiation. Small molecule LY294002 inhibits the IGF pathway to promote cardiomyocyte differentiation while suppressing epicardial and noncardiac cell fates. LY294002-induced cardiomyocytes demonstrate characteristic cardiomyocyte features and provide insights into the molecular mechanisms underlying cardiac differentiation. We further show that LY294002 induces cardiomyocytes through CK2 pathway inhibition. This study elucidates the crucial roles of endogenous IGF in mesoderm differentiation and shows that the inhibition of the IGF pathway is an effective approach for generating cardiomyocytes. : Yang et al. demonstrate that temporal regulation by insulin/IGF is essential for cell-type heterogeneity during human embryonic stem cell (hESC) differentiation. Inhibition of the endogenous IGF pathway promotes cardiomyocyte differentiation from mesoderm progenitors. Keywords: human embryonic stem cells, insulin, IGF, temporal regulation, heterogeneity, mesoderm, cardiomyocyte, PI3K, casein kinase II, WNT