A digital liver twin demonstrating the interplay between biomechanics and cell kinetics can explain fibrotic scar formation
Year: 2023
Type: preprint
Abstract: How homeostasis is maintained in the liver remains the subject of debate, often driven by observations of replenishment after liver injury.Some authors report self-replication of hepatocytes, 1 others a contribution of biliary cells, especially in late-stage disease. 2 However, the homeostatic situation may differ from the organ response after liver injury.Early studies utilized 3 H thymidine to track hepatocytes in rat livers over time, 3 showing hepatocyte migration along the portal tract (PT)-central vein (CV) axis, a phenomenon called 'the streaming liver'.4 Subsequent studies proposed neohepatocyte generation from all three zones in the hepatic lobule of the mouse liver: periportal, 5 mid zonal 6 and pericentral.7 Further still, there is evidence that homeostatic turnover results from zone-agnostic, broadly distributed hepatocytes.8,9 Besides rodent models, there is evidence supporting the existence of a periportal progenitor niche in the human liver; however, this is in the context of end-stage liver disease when the majority of hepatocytes have been lost, or in the context of organoids generated from adult bile duct-derived bipotent progenitor cells.In this issue, Passman et al. 10 have elegantly addressed the question of homeostatic liver cell renewal in the human liver using a systems medicine approach, integrating experiments and computational modeling in a simplified digital twin.They applied a rich combination of experimental techniques to "healthy" liver tissue samples, mainly collected from patients undergoing surgery for colorectal cancer liver metastases.Their aim was to study to what extent a stem cell niche may exist, and to determine if physiological hepatocyte turnover in liver tissue homeostasis emanates from the PT, midzonal hepatocytes, or around the CV.(1) Elegantly, mutations permitting the histochemical identification of clonal patches of the mitochondrial enzyme cytochrome c oxidase (CCO) were used to trace the lineage of individual cell clones.11 Thus, in 17 human livers analysed, an average of 76.9% of patches were located closer to PTs than CVs,
Source: HAL
Institutions: Institut national de recherche en sciences et technologies du numérique, Centre Inria de Saclay, Leibniz Research Centre for Working Environment and Human Factors, SIMBIOTX: SImulations en Médecine, BIOtechnologie et ToXicologie de systèmes multicellulaires, Heidelberg University, Medizinische Fakultät Mannheim, Ghent University, University of Massachusetts Amherst
Language: English
Subfield: Hepatology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funder: Agence Nationale de la Recherche
OpenAlex ID: W4221152007