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

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.

SUBMITTER: Chembazhi UV

PROVIDER: S-EPMC8015853 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:The endogenous ability to dedifferentiate, re-pattern, and re-differentiate adult cells to repair or replace damaged or missing structures is exclusive to only a few tetrapod species. The Mexican axolotl is one example of these species, having the capacity to regenerate multiple adult structures including their limbs by generating a group of progenitor cells, known as the blastema, which acquire pattern and differentiate into the missing tissues. The formation of a limb regenerate is dependent on cells in the connective tissues that retain memory of their original position in the limb, and use this information to generate the pattern of the missing structure. Observations from recent and historic studies suggest that blastema cells vary in their potential to pattern distal structures during the regeneration process; some cells are plastic and can be reprogrammed to obtain new positional information while others are stable. Our previous studies showed that positional information has temporal and spatial components of variation; early bud (EB) and apical late bud (LB) blastema cells are plastic while basal-LB cells are stable. To identify the potential cellular and molecular basis of this variation, we compared these three cell populations using histological and transcriptional approaches. RESULTS:Histologically, the basal-LB sample showed greater tissue organization than the EB and apical-LB samples. We also observed that cell proliferation was more abundant in EB and apical-LB tissue when compared to basal-LB and mature stump tissue. Lastly, we found that genes associated with cellular differentiation were expressed more highly in the basal-LB samples. CONCLUSIONS:Our results characterize histological and transcriptional differences between EB and apical-LB tissue compared to basal-LB tissue. Combined with our results from a previous study, we hypothesize that the stability of positional information is associated with tissue organization, cell proliferation, and pathways of cellular differentiation.

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

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