Integrated spatial-temporal model for the prediction of interplay between biomechanics and cell kinetics in fibrotic wall formation

Upon different types of liver injury, there are distinct patterns of hepatic fibrosis developed, such as ECM septa (fibrotic walls) connecting pericentral (CV) areas due to toxic injury or septa connecting portal (PV) compartments due to cholestatic injury. Since liver fibrosis is a multi-cellular process and difficult to capture for biological in vivo and in vitro models, computational models may shed light on exploring the mechanisms behind particular pattern formation. In this work, we present a novel computational liver model that permits to assess the potential role of biomechanics in the formation of fibrotic walls. It for the first time studies the orchestration of cell types during fibrosis development and the interaction of cell populations with the ECM network mechanics in a liver lobule. Our model results are quantitatively confronted with experimental findings. The determination of the pattern-characterizing parameters in this study e.g. the density of hepatic stellate cells (HSC) and macrophages (MC) were obtained through image analysis of 2D and 3D images from mouse experiments. Together with a model of ECM networks, these non-parenchymal cells and their intercellular signaling were integrated as new elements into computational model of basic liver micro-architecture that included hepatocytes (the main parenchymal liver cell), sinusoids, CV and PV. The new model is applied to test possible mechanisms of how the fibrotic wall may form during liver fibrosis in space and time. Using this strategy we proposed a potential scenario distinguishing regeneration after acute toxic insult and repeated toxic exposure leading to formation of characteristic fibrotic walls:

1. The spatial pattern of CYP2E1 expression (key metabolic enzyme) indicated the location for the deposition of fibrotic collagens. Briefly, the spatial-temporal pattern of certain signaling molecules are governed by the spatial distribution of CYP2E1-positive hepatocytes, and this leads to attraction of activated HSC and MC;

2. The proliferating hepatocytes surrounding the CYP2E1 positive region compress the fibrotic collagen network into “wall”-like shape. Model simulations of specific perturbations permit its validation.

Publication History

Article published online:
07 September 2021