What came first: Fully functional or metabolically mature liver?

Hepatocytes, which constitute about 70% of the liver cell population, perform complex metabolic functions such as plasma protein synthesis and transport, xenobiotic metabolism, glucose homeostasis, urea synthesis, and ketogenesis. The process of liver development is marked by distinct changes in mitochondrial mass, activity, and function, especially during the transition from the fetal to the adult phenotype. The identification of the biochemical mechanisms implicated in hepatic development in vitro using embryonic stem cells is critical because it can unravel the relationship between metabolic changes and cell-specific functional differentiation. Moreover, embryonic stem cell differentiation into hepatocytes can provide an unlimited source of cells for clinical applications in liver transplantation for cirrhosis and fulminant hepatic failure. The "chicken or the egg" problem of whether functional maturation precedes or follows metabolic maturation remains unanswered, but it might simply be that the two processes develop in a complex integrated mode for metabolic and functional homeostasis. The identification of the regulation of complex developments in liver organogenesis can provide interventions to improve the efficiency of hepatic differentiation and a better understanding of the developmental process. Finally, this reasoning can be extended to various cell specific differentiation systems, including the cardiac, pancreatic, and neuronal lineages.