[PDF][PDF] Small molecule-mediated TGF-β type II receptor degradation promotes cardiomyogenesis in embryonic stem cells

E Willems, J Cabral-Teixeira, D Schade, W Cai… - Cell stem cell, 2012 - cell.com
E Willems, J Cabral-Teixeira, D Schade, W Cai, P Reeves, PJ Bushway, M Lanier, C Walsh
Cell stem cell, 2012cell.com
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-β receptor (TGFBR2) degradation-1 (ITD-1). ITD analogs enhanced proteasomal
degradation of TGFBR2, effectively clearing the receptor from the cell surface and selectively …
Summary
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-β 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 (IC50 ∼0.4–0.8 μM). ITD-1 was used to evaluate TGF-β 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-β inhibitor and reveals an unexpected role for TGF-β signaling in controlling cardiomyocyte differentiation from multipotent cardiovascular precursors.
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