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

Erik Willems*, Joaquim Cabral-Teixeira, Dennis Schade, Wenqing Cai, Patrick Reeves, Paul J. Bushway, Marion Lanier, Christopher Walsh, Tomas Kirchhausen, Juan Carlos Izpisua Belmonte, John Cashman, Mark Mercola

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

91 Scopus citations

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 (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.

Original languageEnglish (US)
Pages (from-to)242-252
Number of pages11
JournalCell Stem Cell
Volume11
Issue number2
DOIs
StatePublished - Aug 3 2012

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Cell Biology

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