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Cell Stem Cell. 2012 Aug 3;11(2):242-52. doi: 10.1016/j.stem.2012.04.025.

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

Author information

1
Muscle Development and Regeneration Program, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA. ewillems@sanfordburnham.org

Abstract

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 (IC(50) ~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.

PMID:
22862949
PMCID:
PMC3419596
DOI:
10.1016/j.stem.2012.04.025
[Indexed for MEDLINE]
Free PMC Article

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