The heart is the first organ to develop and function. In humans, heart development begins during the third week of gestation, at approximately day 17 of gestation. In mice, this process begins around embryonic day (E) 7.5 when mesodermal progenitor cells migrate from the anterior portion of the primitive streak to the splanchnic (ventral) mesoderm to form the cardiac crescent. The cardiac crescent is composed of two layers; the first heart field (FHF), which contributes to the left ventricle as well as to some of the right ventricle, both atria and the atrioventricular (AV) canal, and the second heart field (SHF) which contributes to the cardiac outflow tract (OFT) and the remainder of the right ventricle and atria. The contributions of these two cell populations overlap within most of the heart’s structures with the exception of the left ventricle, in which cells are exclusively provided by the FHF, and within the right atrium, where cell contributions appear to be complimentary.
Cells that make up the heart
Cardiac cells originate in the epiblast located within the anterior portion of the primitive streak. Cardiogenic, mesodermal progenitor cells, ingress through the primitive streak and, as previously mentioned, migrate to the splanchic (ventral) mesoderm. These cells contribute to the cardiogenic fields that comprise the cardiac crescent and will contribute to both the myocardium and the endocardium.
The myocardium and the endocardium arise from common multipotent Flk+, Isl1 + progenitor cells. Initiation of transcriptional regulators specifies these progenitor cells for either the myocardial or endocardial lineage.
Following the divergence of the myocardium and endocardium from a common progenitor these distinct cell types contribute differently to the development of the heart and its structures beginning in the linear heart tube. The myocardium comprises the outer layer of the heart tube while the endocardium comprises the inner layer. The myocardial walls begin to form during the linear heart tube stage along with the specification of the heart chambers. Unique to the developing myocardial walls of the atria is the contribution of cells from the great veins as well as cells surrounding the venous poles. Initially, the myocardial wall is a thin, avascular layer of cells located just beneath the epicardium. During these early stages in development, the myocardium receives nutrients via diffusion through the endocardium; but as the myocardial wall thickens, simple diffusion is no longer sufficient and the coronary vasculature begins to form within this layer. The thickening of the myocardial walls occurs via proliferation of myocardial cells. This begins between E9.5 and E10.5, with the most rapid proliferation occurring between E11.5 and E14.5.
There are two zones within the myocardial wall, the compact zone and the trabecular zone. The trabecular zone is closest to the endocardium and these cells proliferate at a lower rate than those cells adjacent to the epicardium within the compact zone. The high rate of proliferation of the compact zone myocardium is maintained by the epicardium, as loss of the epicardium results in defects of both the myocardial wall and the septa. In addition to its contribution to the muscular walls of the heart, the myocardium also contributes to the septa. This provides one example of how the interactions between cell layers within the heart contribute to its development.
The inner lining of the heart, the endocardium, contributes to a number of different structures but its role in valvulogenesis is probably the most well-known. Signaling from the myocardium as well as signaling from factors located within the cardiac jelly, the space within the endocardial cushions between the endocardium and myocardium induces the EMT. These endocardial cushions will later remodel to become the mature heart valves and the membranous portion of the interventricular septum as well as a portion of the septum of the OFT. The role of the endocardium in valvulogenesis and septation will be discussed in greater detail in subsequent sections.
The third cell population of the heart, the epicardium, begins to form around E9.0 and envelops the myocardium of the looping heart. The majority of the epicardium originates in the proepicardium, an extracardiac population of cells, with the epicardium covering the arterial poles originating from splanchic mesoderm located near the outflow pole. The atrioventricular groove and the groove marking the junction of the future right ventricle and the conal myocardium are the first portions of the heart to be covered by the epicardium while the atria and the OFT are covered last. A subepicardial matrix forms between the epicardium and myocardium containing growth factors such as Vegf and fibroblast growth factor (Fgf) that play roles in initiating the migration of cells that contribute to the blood-island like structures that will give rise to the capillaries of the coronary plexus located within this subepicardial layer in avians, but not in mice.
Epicardial cells have been shown to generate the smooth muscle cells of the coronary vasculature and to contribute to coronary endothelial cells, however the extent by which they contribute to the latter has been controversial. While epicardial cells have been shown to contribute to some of the coronary endothelial cells in avian species, our lab has shown through fate-mapping studies in mice that endocardial cells are the major contributor to the endothelial cells of the coronary arteries, arterioles and capillaries.