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Development. 2015 Sep 15;142(18):3198-209. doi: 10.1242/dev.117010. Epub 2015 Jul 7.

Inhibition of β-catenin signaling respecifies anterior-like endothelium into beating human cardiomyocytes.

Author information

1
Department of Pathology, University of Washington School of Medicine, Seattle, WA 98109, USA Center for Cardiovascular Biology, University of Washington School of Medicine, Seattle, WA 98109, USA Institute for Stem Cell and Regenerative Medicine, University of Washington School of Medicine, Seattle, WA 98109, USA.
2
Center for Cardiovascular Biology, University of Washington School of Medicine, Seattle, WA 98109, USA Institute for Stem Cell and Regenerative Medicine, University of Washington School of Medicine, Seattle, WA 98109, USA Department of Bioengineering, University of Washington School of Medicine, Seattle, WA 98109, USA.
3
Department of Pediatrics, University of Washington School of Medicine, Seattle, WA 98109, USA Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
4
Department of Computer Science and Engineering, University of Washington School of Medicine, Seattle, WA 98109, USA.
5
Institute for Stem Cell and Regenerative Medicine, University of Washington School of Medicine, Seattle, WA 98109, USA Department of Pharmacology, University of Washington School of Medicine, Seattle, WA 98109, USA Howard Hughes Medical Institute, Seattle, WA 98109, USA.
6
Department of Pathology, University of Washington School of Medicine, Seattle, WA 98109, USA Center for Cardiovascular Biology, University of Washington School of Medicine, Seattle, WA 98109, USA Institute for Stem Cell and Regenerative Medicine, University of Washington School of Medicine, Seattle, WA 98109, USA Department of Bioengineering, University of Washington School of Medicine, Seattle, WA 98109, USA Department of Medicine/Cardiology, University of Washington School of Medicine, Seattle, WA 98109, USA murry@uw.edu.

Abstract

During vertebrate development, mesodermal fate choices are regulated by interactions between morphogens such as activin/nodal, BMPs and Wnt/β-catenin that define anterior-posterior patterning and specify downstream derivatives including cardiomyocyte, endothelial and hematopoietic cells. We used human embryonic stem cells to explore how these pathways control mesodermal fate choices in vitro. Varying doses of activin A and BMP4 to mimic cytokine gradient polarization in the anterior-posterior axis of the embryo led to differential activity of Wnt/β-catenin signaling and specified distinct anterior-like (high activin/low BMP) and posterior-like (low activin/high BMP) mesodermal populations. Cardiogenic mesoderm was generated under conditions specifying anterior-like mesoderm, whereas blood-forming endothelium was generated from posterior-like mesoderm, and vessel-forming CD31(+) endothelial cells were generated from all mesoderm origins. Surprisingly, inhibition of β-catenin signaling led to the highly efficient respecification of anterior-like endothelium into beating cardiomyocytes. Cardiac respecification was not observed in posterior-derived endothelial cells. Thus, activin/BMP gradients specify distinct mesodermal subpopulations that generate cell derivatives with unique angiogenic, hemogenic and cardiogenic properties that should be useful for understanding embryogenesis and developing therapeutics.

KEYWORDS:

Cardiac; Differentiation; Endothelium; Hematopoiesis; Human embryonic stem cell

PMID:
26153229
PMCID:
PMC4582173
DOI:
10.1242/dev.117010
[Indexed for MEDLINE]
Free PMC Article

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