Cellular plasticity balances the metabolic and proliferation dynamics of a regenerating liver

The liver is a multifunctional organ critical for carrying out numerous biosynthetic, metabolic, and detoxification functions. Owing to its detoxification roles, the liver is frequently exposed to many hepatotoxins, resulting in tissue damage and cell death. Accordingly, it has evolved a unique ability to regenerate in response to a wide range of physical and toxic injuries (Diehl and Chute 2013), and mammalian livers can replenish up to 70% of The adult liver has an exceptional ability to regenerate, but how it maintains its specialized functions during regeneration is unclear. Here, we used partial hepatectomy (PHx) in tandem with single-cell transcriptomics to track cellular transitions and heterogeneities of ?22,000 liver cells through the initiation, progression, and termination phases of mouse liver regeneration. Our results uncovered that, following PHx, a subset of hepatocytes transiently reactivates an early-postnatal-like gene expression program to proliferate, while a distinct population of metabolically hyperactive cells appears to compensate for any temporary deficits in liver function. Cumulative EdU labeling and immunostaining of metabolic, portal, and central vein?specific markers revealed that hepatocyte proliferation after PHx initiates in the midlobular region before proceeding toward the periportal and pericentral areas. We further demonstrate that portal and central vein proximal hepatocytes retain their metabolically active state to preserve essential liver functions while midlobular cells proliferate nearby. Through combined analysis of gene regulatory networks and cell?cell interaction maps, we found that regenerating hepatocytes redeploy key developmental regulons, which are guided by extensive ligand-receptor-mediated signaling events between hepatocytes and nonparenchymal cells. Altogether, our study offers a detailed blueprint of the intercellular crosstalk and cellular reprogramming that balances the metabolic and proliferative requirements of a regenerating liver.

Automated summary

The liver has a unique ability to regenerate in response to injuries, with a subset of hepatocytes reactivating early-postnatal-like gene expression program to proliferate and another population of metabolically active cells compensating for temporary deficits in liver function. The study also reveals the spatial and metabolic dynamics of hepatocyte proliferation after partial hepatectomy, with midlobular cells proliferating nearby while portal and central vein proximal hepatocytes remain metabolically active to preserve liver functions. Intercellular crosstalk and cellular reprogramming play a crucial role in balancing metabolic and proliferative requirements during liver regeneration.