Formation of the Building Plan of the Human Heart

Abstract

T he intricate process of formation of the heart relies on the spatiotemporal regulation of differentiation and growth of its different parts. Errors in these processes can result in hypoplasia of the chambers and incorrect alignment of the atria and great arteries with the ventricles, with such abnormalities producing the worst forms of congenital heart disease. 1 Although recent advances in molecular embryology have greatly improved our understanding of normal cardiac development, our insights into the pathogenesis of human cardiac malformations remain limited. 2 With the current lack of data on gene expression in humans, inferences concerning morphogenesis rely on classic studies of human cardiac development or on extrapolation of experimental data from animal studies. Most textbooks on human embryology describe the embryonic heart tube as already possessing a linear array of the definitive components, despite this so-called segmental concept being disproved some time ago by fatemapping experiments in chickens, 3,4 which are now endorsed by recent molecular lineage analyses in mice. 5 Proliferation studies in chickens revealed that the primary heart tube proliferates minimally and that its growth occurs through addition of differentiating cells from visceral mesoderm at the venous and arterial poles. 6 These findings underscore previous lineage studies performed in mice, which have shown that transcription factors Islet1 and Tbx1 play a crucial role in the intricate balance between the cardiac precursor state and differentiation. 7,8 Subsequent to its formation, the heart tube elongates and loops, producing its inner and outer curvatures and providing the general building plan for formation of the chambers and conduction system. 9 The chambers themselves form by local proliferation and differentiation at the outer curvature. 10,11 At the same time, the differentiating chamber myocardium remains flanked by primary myocardium, which is prevented from further differentiation by the transcriptional repressors T-box factors 2 and 3 (TBX2 and TBX3), thus providing the precursors of the cardiac conduction system. 9 Because it is impossible to perform experiments in the developing human heart and because of the scarcity of gene expression data, the descriptions of its development remained controversial. In this study, we report patterns of proliferation and gene expression in tubular and chamber-forming stages of the human heart, supplementing our account with 3-dimensional (3D) analyses presented in interactive fashion. Our findings show the comparability of the mechanisms governing cardiac development in humans, mice, and chickens. Methods Human EmbryosWe used human embryos ranging from Carnegie stages 9 to 16 derived from 2 different collections. Acquisition and preparation of the first group of embryos were performed at the Gynecology Department of Tartu University Hospital, Tartu, Estonia. To extend the number of embryos in this study, we have included a series of previously performed stainings of ser...

Molecular Analysis of Patterning of Conduction Tissues in the Developing Human Heart

“…Our previous studies showed that the expression patterns of some key cardiac genes in the developing human heart are similar to those reported for the developing mouse and chicken heart, but small differences in morphology were observed. 13,14 Also, our current study on the molecular analysis of the patterning of the conduction tissues confirms the similarities in gene expression patterns between human and mouse.…”

“…13,14 Serial sections of the embryos collected at Leiden University Medical Center were processed by indirect immunohistochemistry. Detailed description of the protocols, antibodies, and riboprobe are given in the online-only Data Supplement.…”

Association analysis identifies new risk loci for congenital heart disease in Chinese populations

“…These genes often act in a combinatorial manner and exhibit an exquisite dose sensitivity when controlling heart developmental processes 19,20 . In the human heart, TBX3 is expressed in the atrial floor and atrioventricular canal myocardium 21 . Various cardiac defects, such as VSD, double outlet right ventricle and TGA, have been observed in Tbx3-deficient model animals [22][23][24] .…”

Building and re-building the heart by cardiomyocyte proliferation

“…Furthermore, regional variations in proliferation rates suggest that positional cues play a role in chamber morphogenesis, both in experimental models and in humans (Christoffels et al, 2000;Sizarov et al, 2011;Soufan et al, 2006). For instance, a transcriptional program including Anf (Nppa -Mouse Genome Informatics), Mlc2v (Myl2 -Mouse Genome Informatics), Irx4 and other genes is activated in the relatively hyperproliferative outer curvature of the looped heart, leading to 'ballooning' of the cardiac chambers (Christoffels et al, 2000).…”