Fig. 3

Human cardiac development and its regulatory mechanisms. Cardiac development involves five distinct stages. The first stage, mesoderm cardiac induction (15-17 days), begins with cardiac mesoderm progenitors migrating from the primitive streak to the heart-forming region, an anterior lateral area relative to the streak. During migration, these mesodermal cells acquire the ability to differentiate into the cardiac lineage and express markers such as Brachyury and MESP1. The key signaling pathways involved include the Nodal/Activin, BMP, and WNT signaling pathways. In the second stage (17–19 days), the cardiac crescent forms, and MESP1-derived cardiac mesodermal cells differentiate into FHF and SHF progenitors. Molecular signals, including WNT signaling, BMP signaling, and various TFs, are critical. FHF progenitor cells, positioned more anteriorly and laterally in the crescent, readily respond to molecular cues and begin differentiation. SHF progenitors remain proliferative and undifferentiated until they reach later stages when they contribute to the heart tube. The third to fifth stages include heart tube formation (19–22 days), cardiac looping (22–35 days), and the formation of the four-chambered fetal heart (35–60 days). During these stages, the cardiac crescent fuses at the midline and folds into a Y-shaped FHF-derived linear heart tube. SHF cells proliferate rapidly and contribute to the arterial and venous poles of the heart tube. Subsequently, the heart tube undergoes rapid growth and rightward looping, forming distinct chambers by approximately day 32 in humans that are fully septated and connected to the pulmonary trunk and aorta by week 7 of fetal development. Events such as the migration of CNCCs, myocardial trabeculation, and the development of endocardial cushions and the epicardium are crucial during these stages. Signaling pathways, including FGF signaling, Notch signaling, and Shh signaling, are involved in the migration of CNCCs, promoting the development of the aortic arch and outflow tract. FGF signaling, Notch signaling, BMP signaling, and others contribute to myocardial trabeculation. Furthermore, FGF signaling, Notch signaling, TBX5, HAND1/2, and related signals aid in the development of endocardial cushions, facilitating subsequent septum and valve development. Finally, FGF signaling, TBX18, WT1, Notch signaling, and others contribute to epicardial development, promoting coronary artery formation and subsequent proliferation of myocardial cells. BRY brachyury, BMP bone morphogenetic protein, CNCCs cardiac neural crest cells, FGF fibroblast growth factor, FHF first heart field, GATA GATA binding protein, HAND heart and neural crest derivatives expressed, HFR heart-forming region, ISL1 islet 1, MEF myocyte enhancer factor, MESP1 mesoderm posterior 1, NKX2-5 NK2 Homeobox 5, RA retinoic acid, Shh sonic hedgehog, SHF second heart field, TBX T-box transcription factor, TGF transforming growth factor, TFs transcription factors, WT1 Wilms tumor 1. This figure was created using Adobe Illustrator