Small molecule-mediated TGF-ß type II receptor degradation promotes cardiomyogenesis in embryonic stem cells.
Cell Stem Cell
; 11(2): 242-52, 2012 Aug 03.
Article
in En
| MEDLINE
| ID: mdl-22862949
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-ß 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-ß 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-ß inhibitor and reveals an unexpected role for TGF-ß signaling in controlling cardiomyocyte differentiation from multipotent cardiovascular precursors.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Dihydropyridines
/
Down-Regulation
/
Protein Serine-Threonine Kinases
/
Receptors, Transforming Growth Factor beta
/
Myocytes, Cardiac
/
Embryonic Stem Cells
/
Proteolysis
Type of study:
Prognostic_studies
Limits:
Animals
/
Humans
Language:
En
Journal:
Cell Stem Cell
Year:
2012
Document type:
Article
Affiliation country:
United States