Small Molecule-Mediated TGF-beta Type II Receptor Degradation Promotes Cardiomyogenesis in Embryonic Stem Cells.
Cell Stem Cell
The cellular signals controlling the formation of cardiomyocytes, vascular smooth muscle, and endothelial cells from stem cell-derived mesoderm are poorly understood. We didscovered ITD-1 as a highly selective TGF-beta inhibitor that induces cardiomyocyte differentiation from multipotent cardiovascular precursors.
The cellular signals controlling the formation of cardiomyocytes, vascular smooth muscle, and endothelial cells from stem cell-derived mesoderm are poorly understood. To identify these signals, a mouse embryonic stem cell (ESC)-based differentiation assay was screened against a small molecule library resulting in a 1,4-dihydropyridine inducer of type II TGF-beta receptor (TGFBR2) degradation-1 (ITD-1). ITD analogs enhanced proteasomal degradation of TGFBR2, effectively clearing the receptor from the cell surface and selectively inhibiting intracellular signaling (IC(50) approximately 0.4-0.8 muM). ITD-1 was used to evaluate TGF-beta involvement in mesoderm formation and cardiopoietic differentiation, which occur sequentially during early development, revealing an essential role in both processes in ESC cultures. ITD-1 selectively enhanced the differentiation of uncommitted mesoderm to cardiomyocytes, but not to vascular smooth muscle and endothelial cells. ITD-1 is a highly selective TGF-beta inhibitor and reveals an unexpected role for TGF-beta signaling in controlling cardiomyocyte differentiation from multipotent cardiovascular precursors.