Fig. 2. The different states of hepatocyte organoids and modulation of metabolic gene expression in vitro based on the principles of liver zonation.

a Hepatocyte organoids can adopt a proliferative state in the presence of growth factors or a metabolic state in the presence of maturation factors. b Liver zonation is governed by multiple factors, including morphogen gradients. For instance, RAS signaling is high in periportal hepatocytes, while WNT signaling is high in pericentral hepatocytes in vivo. The metabolic gene expression of hepatocyte organoids can be modulated to some extent by either inducing EGF signaling for periportal-like or WNT signaling for pericentral-like gene expression in vitro.