TY - JOUR
T1 - Small molecule-mediated TGF-β type II receptor degradation promotes cardiomyogenesis in embryonic stem cells
AU - Willems, Erik
AU - Cabral-Teixeira, Joaquim
AU - Schade, Dennis
AU - Cai, Wenqing
AU - Reeves, Patrick
AU - Bushway, Paul J.
AU - Lanier, Marion
AU - Walsh, Christopher
AU - Kirchhausen, Tomas
AU - Izpisua Belmonte, Juan Carlos
AU - Cashman, John
AU - Mercola, Mark
PY - 2012/8/3
Y1 - 2012/8/3
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84864610045&partnerID=8YFLogxK
U2 - 10.1016/j.stem.2012.04.025
DO - 10.1016/j.stem.2012.04.025
M3 - Article
C2 - 22862949
AN - SCOPUS:84864610045
SN - 1934-5909
VL - 11
SP - 242
EP - 252
JO - Cell Stem Cell
JF - Cell Stem Cell
IS - 2
ER -