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

doi:10.1016/j.stem.2012.04.025

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 journal › Article › peer-review

113 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 language	English (US)
Pages (from-to)	242-252
Number of pages	11
Journal	Cell Stem Cell
Volume	11
Issue number	2
DOIs	https://doi.org/10.1016/j.stem.2012.04.025
State	Published - Aug 3 2012
Externally published	Yes

ASJC Scopus subject areas

Molecular Medicine
Genetics
Cell Biology

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10.1016/j.stem.2012.04.025

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@article{7463430e741a45db82fd964824f17361,

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

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.",

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

note = "Funding Information: The authors would like to thank Fabio Cerignoli and Karl Willert for running calcium transient assays and Wnt TOPflash assays, respectively. This work was supported by CIRM T2-00004 and AHA fellowship to E.W., German Research Foundation Grant SCHA 1663/1-1 to D.S., NIH HL088293 and MINECO to J.C.I.B., CIRM Seed RS-00169-1 and T Foundation to J.C., CIRM RC1-000132 and NIH HL059502 to M.M., and NIH STTR R41-HL108714 to ChemRegen Inc. E.W., M.M., and J.C. are cofounders of ChemRegen, Inc. ",

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AU - Willems, Erik

AU - Cabral-Teixeira, Joaquim

AU - Schade, Dennis

AU - Cai, Wenqing

AU - Reeves, Patrick

AU - Bushway, Paul J.

AU - Lanier, Marion

AU - Walsh, Christopher

AU - Kirchhausen, Tomas

AU - Izpisua Belmonte, Juan Carlos

AU - Cashman, John

AU - Mercola, Mark

N1 - Funding Information: The authors would like to thank Fabio Cerignoli and Karl Willert for running calcium transient assays and Wnt TOPflash assays, respectively. This work was supported by CIRM T2-00004 and AHA fellowship to E.W., German Research Foundation Grant SCHA 1663/1-1 to D.S., NIH HL088293 and MINECO to J.C.I.B., CIRM Seed RS-00169-1 and T Foundation to J.C., CIRM RC1-000132 and NIH HL059502 to M.M., and NIH STTR R41-HL108714 to ChemRegen Inc. E.W., M.M., and J.C. are cofounders of ChemRegen, Inc.

PY - 2012/8/3

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N2 - 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.

AB - 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.

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

Abstract

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