Division-of-labor model for liver regeneration. Following surgical resection (PHx), the remnant liver tissue regenerates quickly and restores its original size and function. Hepatocyte proliferation initiates in the midlobular region before proceeding toward the periportal and pericentral areas. We propose that a subset of residual hepatocytes in the midlobular area reversibly activate an early-postnatal-like gene program to enter a proliferative state. Simultaneously, a distinct population near the portal and central vein proximal regions up-regulates their metabolic gene program to offset any regeneration-induced deficits in liver function. These reversible cell state transitions are guided by distinct ligand-receptor-mediated signaling events between hepatocytes and nonparenchymal cells. Thus, the division of labor maximizes the benefit-cost ratio of regeneration for an organism, ensuring quick and robust replenishment of the hepatic parenchyma while sustaining adequate metabolic and detoxification activities. (NPCs) PA: portal artery; PV: portal vein; CV: central vein.
