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

TLDR

The adult liver can regenerate, yet how it preserves its specialized functions during this process remains unclear. We performed partial hepatectomy in mice and applied single‑cell RNA sequencing to follow ~22,000 liver cells through initiation, progression, and termination of regeneration. We found that after PHx a transient hepatocyte subset re‑engages an early‑postnatal gene program to proliferate while a separate metabolically hyperactive population maintains liver function, proliferation begins in the midlobular zone and spreads to periportal and pericentral areas, with portal and central‑vein hepatocytes remaining metabolically active, and these dynamics are orchestrated by redeployed developmental regulons and extensive ligand‑receptor signaling that together balance metabolic and proliferative demands.

Abstract

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.