Dissecting the Complexity of Early Heart Progenitor Cells

Abstract

Early heart development depends on the coordinated participation of heterogeneous cell sources. As pioneer work from Adriana C. Gittenberger-de Groot demonstrated, characterizing these distinct cell sources helps us to understand congenital heart defects. Despite decades of research on the segregation of lineages that form the primitive heart tube, we are far from understanding its full complexity. Currently, single-cell approaches are providing an unprecedented level of detail on cellular heterogeneity, offering new opportunities to decipher its functional role. In this review, we will focus on three key aspects of early heart morphogenesis: First, the segregation of myocardial and endocardial lineages, which yields an early lineage diversification in cardiac development; second, the signaling cues driving differentiation in these progenitor cells; and third, the transcriptional heterogeneity of cardiomyocyte progenitors of the primitive heart tube. Finally, we discuss how single-cell transcriptomics and epigenomics, together with live imaging and functional analyses, will likely transform the way we delve into the complexity of cardiac development and its links with congenital defects.

Keywords: cardiac fields; cardiomyocyte; endocardium; heart tube; progenitor specification.

Figure 1

Location of cardiac progenitors in vertebrate models from the onset of gastrulation to the stage preceding primitive heart tube formation. Cardiac progenitors ingress the mesoderm soon after the start of gastrulation, migrating to the opposite side of the embryo to establish the two layers that form the primitive heart tube. The different rows of diagrams show this process in mouse, chicken, zebrafish and a zoom-in for the cellular detail of primitive heart tube progenitors, respectively. Zebrafish diagrams are depicted from dorsal views while those in chick and mouse show ventral views. Morphological staging follows the epiboly rate, Hamburger–Hamilton (HH) and Downs [14] criteria for zebrafish, chicken and mouse, respectively. Approximate time in hours post fertilization (hpf), hours (h) or embryonic day (E) are also provided. CM, cardiomyocytes; EC, endocardium. Dashed arrows depict the migration trajectory of primitive heart tube progenitors during gastrulation.

Figure 2

Progenitor domains contributing to heart tube cell populations in the mouse. Diagrams show whole embryos (A) and midline sections (B). Notice how the First Heart Field (FHF), Second Heart Field (SHF) and the recently characterized Mab21l2/Hand1 population stay in a continuum until differentiation cues recruit the FHF to form the primitive heart tube. In the section diagrams (B), endoderm, epiblast and mesoderm are painted in yellow, cyan and light red, following Figure 1 color code. Diagrams were done based on [18,19].