Liver logic: Spatio-temporal ploidy modelling unravels hepatocyte regenerative strategies

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Introduction. Postnatal liver growth and regeneration involve unique hepatocyte proliferation modes, including nuclear division without cytokinesis, leading to diverse ploidy classes. Understanding hepatocyte nuclearity and ploidy dynamics is essential for characterizing regeneration and developing predictive models. Aim and Methods. We analyzed these dynamics using high-resolution 3D imaging of 100 µm-thick vibratome liver slices from mice undergoing 2/3 partial hepatectomy (PHx) across time points from 0.5 to 90 days post-surgery, compared to sham controls. Liver sections were stained to label the sinusoidal network, pericentral hepatocytes, S-phase (BrdU), and DNA. Nuclearity (mono-/binucleation) and ploidy (nuclear DNA content) were quantified using TiQuant² software. Results. In healthy adult mouse livers, approximately 75% of hepatocytes are binucleated, with polyploid cells comprising over 85% of the population. Remarkably, within 24 hours post-PHx, nearly 50% of binucleated hepatocytes are lost, indicating a rapid shift in cellular composition. This shift results in hepatocytes with fewer nuclei but increased DNA content per nucleus, highlighting a transient dominance of mononucleated polyploid cells during regeneration. BrdU incorporation studies demonstrated that DNA synthesis occurs equally in mono- and binucleated hepatocytes, suggesting that both contribute to the regenerative process. To model these transitions, we developed a heuristic yet statistically rigorous state transition model that simulates hepatocyte proliferation states, incorporating cytokinesis, nuclear fusion, and polyploidy dynamics. Model simulations indicate that cytokinesis and nuclear fusion are key regulators of transitions between mono- and binucleated states. Corroborative 2D imaging of human liver tissues obtained during in situ split procedures revealed a positive correlation between the percentage of binucleated hepatocytes and the remnant liver volume, suggesting translational relevance. These findings establish binucleation as a quantitative marker of regenerative potential. Conclusion. Our combined experimental and computational approach provides novel insights into the cellular mechanisms underpinning liver regeneration. We demonstrate that hepatocyte nuclearity and ploidy can serve as measurable, predictive indicators of regenerative capacity in both mice and humans, offering potential biomarkers and modeling tools for clinical and translational applications. Informationen zum Einsatz von KI : 1Hammad S, Arch Toxicol. 2014;88(5): 1161-83. 2Friebel A, et al. Bioinformatics. 2015;1;31(19):3234-6 Publication History Article published online: 04 September 2025 © 2025. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany

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