Early cardiac development: a view from stem cells to embryos

Abstract

From the 1920s, early cardiac development has been studied in chick and, later, in mouse embryos in order to understand the first cell fate decisions that drive specification and determination of the endocardium, myocardium, and epicardium. More recently, mouse and human embryonic stem cells (ESCs) have demonstrated faithful recapitulation of early cardiogenesis and have contributed significantly to this research over the past few decades. Derived almost 15 years ago, human ESCs have provided a unique developmental model for understanding the genetic and epigenetic regulation of early human cardiogenesis. Here, we review the biological concepts underlying cell fate decisions during early cardiogenesis in model organisms and ESCs. We draw upon both pioneering and recent studies and highlight the continued role for in vitro stem cells in cardiac developmental biology.

Figure 1

Comparison of cardiac ES cell differentiation and early embryonic heart development. (A) Time course and embryonic stages of cardiogenesis in mouse embryo. (B) Time course and embryonic stages recapitulated by ESC to differentiate towards a cardiac fate. (C) Time course and pattern of expression of MesP1 in early mouse embryo monitored by in situ hybridization (left panel). MesP1 Cell lineage tracing in embryos obtained from breeding MesP1-Cre with Rosa26lacZ (R26R) mice (right panel). MesP1+ cells give rise to the whole heart, as well as head and tail muscles. ExE, extraembryonic ectoderm; VE, visceral endoderm; DE, definitive endoderm.

Figure 2

Early segregation of the cardiogenic and haemogenic roads. A likely existing bipotent early progenitor in the epiblast gives rise to both a Flk1+ /Brachyury+ and a Flk1-/Brachyury+ cell population, under the action of BMP4 secreted by the extraembryonic ectoderm (ExE) and BMP2 in the visceral endoderm (VE), respectively. This early event already segregates the future haemogenic and cardiogenic (i.e. myocardial) cell populations. A parallel route used by a Flk1+ lineage re-emerging from a Flk1- cell population, and also possibly part from the hemangioblast lineage leads to the endocardial cell population.

Figure 3

Cardiac fields and lineages. The cartoon depicts the cardiogenic tree with specific fields and lineages as described in the last decade literature.

Figure 4

Genetic and epigenetic regulation of the cardiogenic transcriptional network. Both the NURF and the SWI/SNF complexes participate in the modulation of expression of genes required for cardiogenesis. The figure briefly summarizes the key stages through which the embryo develops to generate its heart and the major genes participating within networks in cardiogenesis. The enzymes written in red have specifically been reported to regulate expression of genes important for normal cardiogenesis.