During embryogenesis, various cell types emerge
simultaneously from their common progenitors un-
der the influence of intrinsic signals. Human embry-
onic stem cells can differentiate to diverse cell types
of three embryonic lineages, making them an excel-
lent system for understanding the regulatory mecha-
nism 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 pro-
mote cardiomyocyte differentiation while suppress-
ing epicardial and noncardiac cell fates. LY294002-
induced cardiomyocytes demonstrate characteristic
cardiomyocyte features and provide insights into the
molecular mechanisms underlying cardiac differenti-
ation. We further show that LY294002 induces cardi-
omyocytes 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.