Mechanisms of Trabecular Formation and Specification During Cardiogenesis

Abstract

Trabecular morphogenesis is a key morphologic event during cardiogenesis and contributes to the formation of a competent ventricular wall. Lack of trabeculation results in embryonic lethality. The trabecular morphogenesis is a multistep process that includes, but is not limited to, trabecular initiation, proliferation/growth, specification, and compaction. Although a number of signaling molecules have been implicated in regulating trabeculation, the cellular processes underlying mammalian trabecular formation are not fully understood. Recent works show that the myocardium displays polarity, and oriented cell division (OCD) and directional migration of the cardiomyocytes in the monolayer myocardium are required for trabecular initiation and formation. Furthermore, perpendicular OCD is an extrinsic asymmetric cell division that contributes to trabecular specification, and is a mechanism that causes the trabecular cardiomyocytes to be distinct from the cardiomyocytes in compact zone. Once the coronary vasculature system starts to function in the embryonic heart, the trabeculae will coalesce with the compact zone to thicken the heart wall, and abnormal compaction will lead to left ventricular non-compaction (LVNC) and heart failure. There are many reviews about compaction and LVNC. In this review, we will focus on the roles of myocardial polarity and OCD in trabecular initiation, formation, and specification.

Keywords: Myocardial polarity; Oriented cell division; Trabecular specification; Trabeculation.

Figure 1.. N-Cadherin is required to establish the polarity of the monolayer myocardium.

In the control heart at E9.5, cardiomyocytes migrate inward toward the heart lumen, while some cardiomyocytes in the Nkx2.5^Cre/ERT2; Cdh2^fl/f migrate outward to the pericardial sac indicated by while arrow. Scale bar is 20 μm.

Figure 2.. The monolayer of myocardium displays apical-basal polarity.

Mouse embryonic heart tube at E9.5-E9.0 has a smooth inner surface and contains a monolayer myocardium and a monolayer endocardium. The monolayer myocardium displays transmural polarity with basement membrane inside the heart lumen. ?: The orientation of apical-basal polarity shows some controversy, as a group says the domain that abuts the heart lumen is the apical domain or basal domain by another group.

Figure 3.. Directional migration and OCD contribute to trabecular initiation.

Both directional migration and OCD contribute to trabecular initiation, and N-Cadherin might be essential to establish the apical-basal polarity for directional migration and OCD. This figure is adapted from a published figure.

Figure 4.. The transmural, inner and mixed clones contribute to trabecular formation.

Cells of surface clones localize to the surface of the myocardium. Cells of inner, transmural and mixed clones contribute to the formation of trabeculae and inner compact zone. This figure is adapted from a published figure.

Figure 5.. Perpendicular OCD is an extrinsic asymmetric cell division.

Cell fate determinants are symmetrically distributed to a dividing cell at telophase, but asymmetrically between the two daughter cells that are still linked by midbody, indicating the extrinsic asymmetric cell division. This figure is adapted from a published figure.