title: Wnt/β-catenin signaling directs the regional expansion of first and second heart field-derived ventricular cardiomyocytes.
abstract: In mammals, cardiac development proceeds from the formation of the linear heart tube, through complex looping and septation, all the while increasing in mass to provide the oxygen delivery demands of embryonic growth. The developing heart must orchestrate regional differences in cardiomyocyte proliferation to control cardiac morphogenesis. During ventricular wall formation, the compact myocardium proliferates more vigorously than the trabecular myocardium, but the mechanisms controlling such regional differences among cardiomyocyte populations are not understood. Control of definitive cardiomyocyte proliferation is of great importance for application to regenerative cell-based therapies. We have used murine and human pluripotent stem cell systems to demonstrate that, during in vitro cellular differentiation, early ventricular cardiac myocytes display a robust proliferative response to β-catenin-mediated signaling and conversely accelerate differentiation in response to inhibition of this pathway. Using gain- and loss-of-function murine genetic models, we show that β-catenin controls ventricular myocyte proliferation during development and the perinatal period. We further demonstrate that the differential activation of the Wnt/β-catenin signaling pathway accounts for the observed differences in the proliferation rates of the compact versus the trabecular myocardium during normal cardiac development. Collectively, these results provide a mechanistic explanation for the differences in localized proliferation rates of cardiac myocytes and point to a practical method for the generation of the large numbers of stem cell-derived cardiac myocytes necessary for clinical applications.
authors.affiliation: Cardiovascular Research Center, Massachusetts General Hospital, Charles River Plaza/CPZN 3200, 185 Cambridge Street, Boston, MA 02114-2790, USA.
authors.forename: Jan Willem
authors.initials: JW
authors.lastname: Buikema
authors.forename: Ahmed S
authors.initials: AS
authors.lastname: Mady
authors.forename: Nikhil V
authors.initials: NV
authors.lastname: Mittal
authors.forename: Ayhan
authors.initials: A
authors.lastname: Atmanli
authors.forename: Leslie
authors.initials: L
authors.lastname: Caron
authors.forename: Pieter A
authors.initials: PA
authors.lastname: Doevendans
authors.forename: Joost P G
authors.initials: JP
authors.lastname: Sluijter
authors.forename: Ibrahim J
authors.initials: IJ
authors.lastname: Domian
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D004789:Enzyme Activation; D018507:Gene Expression Regulation, Developmental; D006352:Heart Ventricles / Q000166:cytology* / Q000196:embryology; D006801:Humans; D051379:Mice; D009024:Morphogenesis; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000378:metabolism; D039904:Pluripotent Stem Cells / Q000378:metabolism*; D051153:Wnt Proteins / Q000378:metabolism*; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D051153:Wnt Proteins; D051176:beta Catenin
keywords: Cardiac development; Cardiomyocyte differentiation; Cardiomyocyte proliferation; First heart field; Gsk3 inhibitor; Mouse; Wnt/β-catenin
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