ALPPS surgery induces macroscopic division of labor with metabolic lobe support to accelerate liver regeneration - experimental studies

Abstract

Background: Hepatic surgery rests on the unique, however limited regenerative capacity of the liver. Metabolic duties may be a key factor regulating proliferative abilities of hepatocytes. During regeneration, division of labor leads to spatial separation of proliferation from metabolic tasks, suggesting these opposing activities compete for space. Here, we exploited two-stage-hepatectomy mouse models to explore whether metabolic needs constrain the regenerative capacity of the liver.

Materials and methods: Mice were subjected to sham or ALPPS surgery (a two-stage-hepatectomy renowned for accelerated regeneration), which leaves one fast-regenerating lobe (FLR) plus portally ligated lobes (LLs) that do not grow but have an intact arteriocentral flow. FLR and LLs were analyzed by omics approaches. Functional surgery was applied to create ALPPS variants with differing metabolic capacity.

Results: The FLR and the adjacent LL displayed a similar metabolite profile that however completely diverged during the major FLR growth phase. Combined transcriptomics-metabolomics and histology assigned proliferative activities explicitly to the FLR, while LLs were enriched with metabolic tasks, establishing macroscopic division of labor. In ALPPS variants differing in ligated volume, FLR growth was increased or reduced with gain or loss of metabolic capacity, respectively, revealing control of regeneration through metabolic duties. Notably, FLRs of slow-growing variants had upregulated metabolic activities, reflecting plastic adaptation to the increased metabolic pressure coming with little ligated volume. Transcriptomics disclosed macroscopic division of labor also in human ALPPS regeneration.

Conclusion: LLs act as auxiliary livers after ALPPS, enabling the FLR to focus on growth. Our findings demonstrate the functional requirement for division of labor during regeneration. This transient division roots on plastic behavior of the different lobes during ALPPS regeneration and reveals how metabolic needs define the liver's regenerative capacity.

Keywords: cellular plasticity; functional surgery; liver regeneration; metabolic capacity; posthepatectomy liver failure; two-stage-hepatectomy.