title: Inhibition of β-catenin signaling respecifies anterior-like endothelium into beating human cardiomyocytes.
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.
authors.affiliation: 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.
authors.forename: Nathan J
authors.initials: NJ
authors.lastname: Palpant
authors.affiliation: 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.
authors.forename: Lil
authors.initials: L
authors.lastname: Pabon
authors.affiliation: 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.
authors.forename: Meredith
authors.initials: M
authors.lastname: Roberts
authors.affiliation: 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.
authors.forename: Brandon
authors.initials: B
authors.lastname: Hadland
authors.affiliation: Department of Computer Science and Engineering, University of Washington School of Medicine, Seattle, WA 98109, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Jones
authors.affiliation: 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.
authors.forename: Christina
authors.initials: C
authors.lastname: Jones
authors.affiliation: 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.
authors.forename: Randall T
authors.initials: RT
authors.lastname: Moon
authors.affiliation: Department of Computer Science and Engineering, University of Washington School of Medicine, Seattle, WA 98109, USA.
authors.forename: Walter L
authors.initials: WL
authors.lastname: Ruzzo
authors.affiliation: 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.
authors.forename: Irwin
authors.initials: I
authors.lastname: Bernstein
authors.affiliation: 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.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: 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.
authors.forename: Charles E
authors.initials: CE
authors.lastname: Murry
mesh_terms: D028341:Activins / Q000494:pharmacology; D000704:Analysis of Variance; D001483:Base Sequence; D055415:Bone Morphogenetic Protein 4 / Q000494:pharmacology; D018929:Cell Culture Techniques; D054338:Cell Transdifferentiation / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D004727:Endothelium / Q000166:cytology / Q000502:physiology*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D008648:Mesoderm / Q000166:cytology / Q000502:physiology*; D008969:Molecular Sequence Data; D032383:Myocytes, Cardiac / Q000502:physiology*; D040901:Proteomics; D060888:Real-Time Polymerase Chain Reaction; D017423:Sequence Analysis, RNA; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D051176:beta Catenin / Q000037:antagonists & inhibitors*
chemical_list: C525809:BMP4 protein, human; D055415:Bone Morphogenetic Protein 4; C495270:CTNNB1 protein, human; C422405:activin A; D051176:beta Catenin; D028341:Activins
keywords: Cardiac; Differentiation; Endothelium; Hematopoiesis; Human embryonic stem cell