hepatogenesis

Hepatogenesis is the embryonic development of the liver, beginning with the specification of hepatic endoderm in the ventral foregut and progressing to a full, mature liver containing hepatocytes, biliary tissue, and nonparenchymal cells. In humans and other mammals, hepatic specification occurs in early gestation, with the hepatic diverticulum forming as the foregut endoderm responds to signals from surrounding mesodermal structures.

Key molecular signals and transcriptional regulators guide hepatogenesis. Fibroblast growth factors (FGFs) from the cardiac mesoderm and bone morphogenetic protein (BMP) signals from the septum transversum mesenchyme induce hepatic fate in foregut endoderm, aided by pioneer transcription factors such as FOXA (cooperating FOXA1/FOXA2) and GATA factors that render endoderm competent. Early hepatic specification involves HHEX and other factors, followed by activation of hepatocyte-focused programs driven by HNF4α and C/EBP family members, which coordinate hepatocyte differentiation and metabolic maturation. Notch signaling contributes to biliary lineage specification and ductal plate remodeling to form the intrahepatic bile ducts.

Morphogenesis consists of the growth and branching of the hepatic bud, formation of hepatic cords, and the development of the liver vasculature and sinusoidal network. Hematopoietic activity originates in the fetal liver during mid-gestation, and resident nonparenchymal cells such as hepatic stellate cells and Kupffer cells arise from diverse mesodermal and hematopoietic sources. The biliary system differentiates from the ductal plate through remodeling processes guided by Notch signaling and related pathways, establishing the bile ducts within the liver.

Hepatogenesis is highly conserved across vertebrates and lays the foundation for postnatal liver growth, regeneration, and metabolic function. Disruptions in the signaling networks or transcriptional regulators can lead to congenital liver malformations or impaired hepatic development.