Physiology of Cardiac Development: From Genetics to Signaling to Therapeutic Strategies

Abstract

The heart is one of the first organs to form and function during embryonic development. It is comprised of multiple cell lineages, each integral for proper cardiac development, and include cardiomyocytes, endothelial cells, epicardial cells and neural crest cells. The molecular mechanisms regulating cardiac development and morphogenesis are dependent on signaling crosstalk between multiple lineages through paracrine interactions, cell-ECM interactions, and cell-cell interactions, which together, help facilitate survival, growth, proliferation, differentiation and migration of cardiac tissue. Aberrant regulation of any of these processes can induce developmental disorders and pathological phenotypes. Here, we will discuss each of these processes, the genetic factors that contribute to each step of cardiac development, as well as the current and future therapeutic targets and mechanisms of heart development and disease. Understanding the complex interactions that regulate cardiac development, proliferation and differentiation is not only vital to understanding the causes of congenital heart defects, but to also finding new therapeutics that can treat both pediatric and adult cardiac disease in the near future.

Keywords: congenital; development; disease; genetics; heart; signaling.

Figure 1. Schematic representation of the physiology, major vessels, and circulation of the heart

The heart structures, major blood vessels, and directions of blood flow are implicated. The oxygenated (red) and deoxygenated (blue) blood exchanges occur through systemic and pulmonary circulations. LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle.

Figure 2. Schematic representation of murine heart development

At E7.5, the cardiac mesodermal cells form the crescent like structure comprised of the first heart field (FHF) and the second heart field (SHF). The FHF cells fuse at the midline, forming the primitive heart tube that mostly contributes to left ventricle (LV) by E8.0. The lumen of this tubule structure is covered by a layer of endocardial cells which is required for the development of atrioventricular (AV) canal and outflow tract (OFT), the precursor cells that give rise to valvular structures. Meanwhile, the SHF cells migrate and integrate into the heart, giving rise to right ventricle (RV), parts of the left and right atrium (LA and RA), and the outflow tract (OFT). After the initiation of heart looping at E8.5, the epicardium expands from the venous pole and covers the entire embryonic heart by E11.5. The epicardial derivatives give rise to multiple cardiac cell lineages including fibroblasts and coronary vascular smooth muscle cells. In addition, cardiac neural crest cells (NCCs) migrate from the neural tube (NT), invade the OFT, mediating the development of endocardium derived cushion tissue and the septation of the myocardial wall. By E15.5, septation is completed, enclosing the ventricular chambers and generating the fully functional four-chambered heart.

Figure 3. Differentiation of the myocardial cell lineage during development

Schematic representation shows the genetic regulation in stagewise commitment of cardiac mesodermal cells. The inhibition of WNT/β-catenin is required for the MESP1 positive cardiac mesoderm to undergo further specification. While the FHF and SHF cells share the expression of some of the same core transcription factors, the two lineages have differences in signaling effects and give rise to distinct myocardial cell types. AV, atrioventricular; SA, sinoatrial.

Figure 4. Schematic representation of cardiac valve development and the crosstalk between cardiac cell lineages

In response to myocardial signals, the endocardial cells undergo epithelial–mesenchymal transition (EMT), delaminating from the endocardial surface and differentiating into mesenchymal cells, which proliferate and invade the cardiac jelly to form the endocardial cushion in the atrioventricular (AV) canal and outflow tract (OFT). Signaling from endocardium thus regulates myocardial proliferation and specification, as well as pathological events that include hypertrophic cardiomyopathy (HCM). In later stages of valvular maturation, signaling from endocardium directs remodeling events that include apoptosis and differentiation of mesenchymal cells.

Figure 5. Schematic representation of signaling pathways regulating the differentiation of epicardium during cardiogenesis

TGFβ and FGF are the predominant signaling pathways required to promote epithelial–mesenchymal transition (EMT). Mediated by TGFβ, PDGF, and WNT/β-catenin, epicardial derived cells (EDCs) undergo specification and differentiate into cardiac fibroblasts and vascular smooth muscle cells.

Figure 6. Distinct roles of cardiac fibroblasts between embryonic and adult stages

Embryonic cardiac fibroblasts promote cardiomyocyte proliferation through expression and activation of transcriptional regulators FN1 and COL3a1, growth factors HB-EGF and β1 integrin, as well as upregulation of ERK and PI3K/AKT signaling pathways. Activation of cardiac fibroblasts in adult myocardium typically occurs in response to stress, including hypertrophic cardiomyopathy (HCM) and/or other adult-onset cardiac diseases.