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Updated: May 19, 2026
Suppression of Pro-fibrotic Signaling Potentiates Factor-mediated Reprogramming of Mouse Embryonic Fibroblasts into Induced Cardiomyocytes
Published on: June 3, 2018
Small molecule-mediated TGF-β type II receptor degradation promotes cardiomyogenesis in embryonic stem cells
Erik Willems1, Joaquim Cabral-Teixeira, Dennis Schade
1Muscle 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.
Insights
A novel compound, ITD-1, selectively inhibits transforming growth factor-beta receptor type II (TGFBR2) degradation. This reveals TGF-β signaling
Area of Science:
- Developmental Biology
- Stem Cell Biology
- Molecular Pharmacology
Background:
- Cellular signals governing mesoderm differentiation into cardiomyocytes, vascular smooth muscle, and endothelial cells remain largely unknown.
- Understanding these pathways is crucial for regenerative medicine and developmental studies.
Purpose of the Study:
- To identify novel small molecules regulating cardiovascular cell differentiation from embryonic stem cells (ESCs).
- To elucidate the role of transforming growth factor-beta (TGF-β) signaling in mesoderm and cardiomyocyte development.
Main Methods:
- Screening of a small molecule library using a mouse ESC-based differentiation assay.
- Identification and characterization of ITD-1, a 1,4-dihydropyridine derivative targeting TGFBR2.
- Assessment of ITD-1's effects on mesoderm formation and differentiation into various cardiovascular cell types.
Main Results:
- ITD-1 selectively induces proteasomal degradation of TGFBR2, inhibiting its cell surface expression and intracellular signaling (IC50 ~0.4-0.8 μM).
- ITD-1 treatment significantly enhanced the differentiation of ESC-derived mesoderm into cardiomyocytes.
- ITD-1 did not promote differentiation into vascular smooth muscle or endothelial cells, indicating selectivity.
Conclusions:
- ITD-1 is a potent and selective inhibitor of TGF-β signaling through TGFBR2 degradation.
- TGF-β signaling plays a critical and previously unrecognized role in promoting cardiomyocyte differentiation from cardiovascular precursors.
- This study provides a valuable chemical tool for dissecting TGF-β's function in cardiovascular development.
