Published online before print August 5, 2004, doi: 10.1161/01.RES.0000141429.13560.cb
© 2004 American Heart Association, Inc.
Integrative Physiology |
Lineage and Morphogenetic Analysis of the Cardiac Valves
From the Experimental and Molecular Cardiology Group (F.J.d.L., A.F.M.M., A.T.S., C.d.G.-d.V., M.J.B.v.d.H., V.M.C.), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Cardiac Unit (R.H.A.), Institute of Child Health, University College London, UK; Department of Embryology (J.M.), Center of Anatomy, Georg-August-University Gottingen, Gottingen, Germany; Center for Cardiovascular Development (M.D.S.), Department of Medicine, Molecular and Cellular Biology, and Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Tex; Department of Basic Medical Sciences (S.W.), Anatomy and Developmental Biology, St. George’s Hospital Medical School, Cranmer Terrace, London, UK.
Correspondence to Vincent M. Christoffels, PhD, Department of Anatomy and Embryology, Meibergdreef 15, 1105AZ Amsterdam, The Netherlands. E-mail v.m.christoffels{at}amc.uva.nl
We used a genetic lineage-labeling system to establish the material contributions of the progeny of 3 specific cell types to the cardiac valves. Thus, we labeled irreversibly the myocardial (
MHC-Cre+), endocardial (Tie2-Cre+), and neural crest (Wnt1-Cre+) cells during development and assessed their eventual contribution to the definitive valvar complexes. The leaflets and tendinous cords of the mitral and tricuspid valves, the atrioventricular fibrous continuity, and the leaflets of the outflow tract valves were all found to be generated from mesenchyme derived from the endocardium, with no substantial contribution from cells of the myocardial and neural crest lineages. Analysis of chicken-quail chimeras revealed absence of any substantial contribution from proepicardially derived cells. Molecular and morphogenetic analysis revealed several new aspects of atrioventricular valvar formation. Marked similarities are seen during the formation of the mural leaflets of the mitral and tricuspid valves. These leaflets form by protrusion and growth of a sheet of atrioventricular myocardium into the ventricular lumen, with subsequent formation of valvar mesenchyme on its surface rather than by delamination of lateral cushions from the ventricular myocardial wall. The myocardial layer is subsequently removed by the process of apoptosis. In contrast, the aortic leaflet of the mitral valve, the septal leaflet of the tricuspid valve, and the atrioventricular fibrous continuity between these valves develop from the mesenchyme of the inferior and superior atrioventricular cushions. The tricuspid septal leaflet then delaminates from the muscular ventricular septum late in development.
Key Words: lineage analysis • mitral • tricuspid • atrioventricular valve • tendinous chord • valvular • Cre-lox
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