Small Molecule-mediated TGF-β Type II Receptor Degradation Promotes Cardiomyogenesis in Embryonic Stem Cells

Overview

Journal Cell Stem Cell

Publisher Cell Press

Specialty Cell Biology

Date 2012 Aug 7

PMID 22862949

Citations 67

Authors

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

Affiliations

Soon will be listed here.

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.

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