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Review
. 2022 Apr 19;9(5):122.
doi: 10.3390/jcdd9050122.

Endocardial Regulation of Cardiac Development

Lara Feulner  1   2 , Patrick Piet van Vliet  1   3   4 , Michel Puceat  3   4   5 , Gregor Andelfinger  1   6   7   8
Affiliations
Review

Endocardial Regulation of Cardiac Development

Lara Feulner et al. J Cardiovasc Dev Dis. .

Abstract

The endocardium is a specialized form of endothelium that lines the inner side of the heart chambers and plays a crucial role in cardiac development. While comparatively less studied than other cardiac cell types, much progress has been made in understanding the regulation of and by the endocardium over the past two decades. In this review, we will summarize what is currently known regarding endocardial origin and development, the relationship between endocardium and other cardiac cell types, and the various lineages that endocardial cells derive from and contribute to. These processes are driven by key molecular mechanisms such as Notch and BMP signaling. These pathways in particular have been well studied, but other signaling pathways and mechanical cues also play important roles. Finally, we will touch on the contribution of stem cell modeling in combination with single cell sequencing and its potential translational impact for congenital heart defects such as bicuspid aortic valves and hypoplastic left heart syndrome. The detailed understanding of cellular and molecular processes in the endocardium will be vital to further develop representative stem cell-derived models for disease modeling and regenerative medicine in the future.

Keywords: BMP; Notch; endocardium; heart development; heart disease.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Schematic representation (not drawn to scale) of endocardial development. Unipotent cardiac progenitor cells (CPCs) committed to become either endocardial (Etv2+, Nfatc1+) or myocardial (Nkx2-5+, Myl7+) cells migrate from the primitive streak (PS) at an early stage to form the FHF, which contributes to the left ventricle (LV). Unipotent and bipotent (capable of becoming either endocardial or myocardial cells) CPCs migrate to form the Isl+ SHF, which contributes to right ventricle (RV) and outflow tract (OFT) at mid-late PS stages, respectively. The contribution of Isl+ SHF cells to endocardium is however small, as the majority of endocardium is derived from a population of Isl1− vascular endothelial progenitor cells located lateral to the cardiac crescent. The endocardium also receives a contribution from a population of Tal1+ cells that migrate from the yolk sac at E7.5. Molecular mechanisms are illustrated on right side via red arrows in contrast to migration (black arrows). Endocardial Etv2 is activated by NKX2-5 and Tie2 is a downstream target of ETV2.
Figure 2
Figure 2
Known endocardial cell lineages, adapted from Zhang et al. [31]. Endocardial cells can develop into valve cushion mesenchymal cells (VICs), coronary endothelial cells, blood cells, liver vasculature cells, fat cells, and mural cells (potentially via “intermediate” cushion mesenchyme).
Figure 3
Figure 3
The same signaling pathway (Notch) can produce different effects based on location during early development (E9–E14 in mouse). In the AVC, myocardial cells have high BMP2/TBX2 levels. This represses expression of chamber markers (Nppa/Cx40) and leads to high activation of the Notch pathway in endocardial cells, resulting in EndoMT, ECM cardiac jelly deposition, and cushion formation. By contrast, Bmp2/Tbx2 is lowly expressed in ventricular chamber myocardium and Notch activation in endocardial cells is lower; thus, EndoMT does not occur. Instead, Notch activates Nrg1 via EphrinB2 and Hand2 to induce trabeculation and expression of Bmp10 in myocardium. A correct balance between Nrg1-regulated ECM synthesis and Notch1-regulated ECM degradation is necessary for normal trabeculation to occur. Vcan: Versican, Postn: Periostin, VECad: VE cadherin, Mfng: Manic fringe, Nrg1: Neuregulin.
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