Lineage and Morphogenetic Analysis of the Cardiac Valves

Abstract

Abstract-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-Creϩ), endocardial (Tie2-Creϩ), and neural crest (Wnt1-Creϩ) 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.

Distinct cardiac malformations caused by absence of connexin 43 in the neural crest and in the non-crest neural tube

“…Both MLC-2v-Cre and ␣-MHC-Cre are expressed in the heart prior to E9 (Chen et al, 1998;de Lange et al, 2004). Despite an 85-95% reduction in cardiac Cx43 expression, cardiac-specific Cx43 CKO mice are grossly and histologically indistinguishable from their non-KO littermates and have normal ventricular function by echocardiography.…”

BMP and FGF regulatory pathways in semilunar valve precursor cells

“…Further, BMP and FGF signaling pathways regulate cell lineage diversification in semilunar and AV valves (Lincoln et al, 2006a). Cell fate analysis in mice demonstrated that these diversified cell lineages arise through differentiation of valve progenitor cells present in the endocardial cushions (de Lange et al, 2004;Lincoln et al, 2004). In this study, our purpose was to examine the effects of BMP and FGF signaling on cell potential, and detailed in vitro analyses of valve progenitor cells derived from avian OFT endocardial cushions demonstrate that BMP treatment or inhibition of FGF signaling increases expression of sox9 and aggrecan associated with increased Smad1/5/8 phosphorylation, while FGF4 treatment or inhibition of BMP signaling promotes expression of scleraxis and tenascin, consistent with activated dpERK1/2.…”

“…Studies to date indicate that although cells from neural crest lineages are present in both semilunar and AV valves (Nakamura et al, 2006), the majority of cells that form the cusps of the semilunar valves and the leaflets and supporting apparatus of the AV valves originate from endothelial-derived cells (de Lange et al, 2004;Lincoln et al, 2004). Endocardial cushions subsequently elongate as a result of cell proliferation, and undergo expansion and remodeling of the extracellular matrix (ECM) to form the mature semilunar and AV valves (Lincoln et al, 2004;Hinton et al, 2006).…”

Expression patterns and immunohistochemical localization of PITX2B transcription factor in the developing mouse heart

“…Interestingly our results show that in the atrioventricular canal compartment PITX2B protein is mainly present in the mural primordium of the mitral valve during heart development, suggesting a role of PITX2B in the maturation of the right portion of the atrioventricular canal. Although Liu et al, (Liu et al, 2002) speculated that Pitx2 daughter cells from myocardium invade the AV cushions and valves, in mice it has been also proposed that the leaflets and tendinous cords of the tricuspid valve are all generated from mesenchyme, derived from the endocardium with no substantial contribution from cells of the myocardial linage (de Lange et al, 2004). In whatever manner this cells arrives to the AV cushions, we cannot determine the source of cells that participate in this process since we have detected the presence of PITX2B in endocardium, myocardium and epicardium.…”