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A multiscale agent-based in silico model of liver fibrosis progression

Dutta-Moscato, J and Solovyev, A and Mi, Q and Nishikawa, T and Soto-Gutierrez, A and Fox, IJ and Vodovotz, Y (2014) A multiscale agent-based in silico model of liver fibrosis progression. Frontiers in Bioengineering and Biotechnology, 2 (MAY).

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Chronic hepatic inflammation involves a complex interplay of inflammatory and mechanical influences, ultimately manifesting in a characteristic histopathology of liver fibrosis. We created an agent-based model (ABM) of liver tissue in order to computationally examine the consequence of liver inflammation. Our liver fibrosis ABM (LFABM) is comprised of literature-derived rules describing molecular and histopathological aspects of inflammation and fibrosis in a section of chemically injured liver. Hepatocytes are modeled as agents within hexagonal lobules. Injury triggers an inflammatory reaction, which leads to activation of local Kupffer cells and recruitment of monocytes from circulation. Portal fibroblasts and hepatic stellate cells are activated locally by the products of inflammation. The various agents in the simulation are regulated by above-threshold concentrations of pro- and anti-inflammatory cytokines and damage-associated molecular pattern molecules. The simulation progresses from chronic inflammation to collagen deposition, exhibiting periportal fibrosis followed by bridging fibrosis, and culminating in disruption of the regular lobular structure. The ABM exhibited key histopathological features observed in liver sections from rats treated with carbon tetrachloride (CCl4). An in silico "tension test" for the hepatic lobules predicted an overall increase in tissue stiffness, in line with clinical elastography literature and published studies in CCl4-treated rats. Therapy simulations suggested differential anti-fibrotic effects of neutralizing tumor necrosis factor alpha vs. enhancing M2 Kupffer cells. We conclude that a computational model of liver inflammation on a structural skeleton of physical forces can recapitulate key histopathological and macroscopic properties of CCl4-injured liver. This multiscale approach linking molecular and chemomechanical stimuli enables a model that could be used to gain translationally relevant insights into liver fibrosis.


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Dutta-Moscato, J
Solovyev, A
Mi, Qqim3@pitt.eduQIM3
Nishikawa, T
Soto-Gutierrez, A
Fox, IJijf5@pitt.eduIJF5
Vodovotz, Yvodovotz@pitt.eduVODOVOTZ
Centers: Other Centers, Institutes, Offices, or Units > McGowan Institute for Regenerative Medicine
Other Centers, Institutes, Offices, or Units > Thomas E. Starzl Transplantation Institute
Date: 1 January 2014
Date Type: Publication
Journal or Publication Title: Frontiers in Bioengineering and Biotechnology
Volume: 2
Number: MAY
DOI or Unique Handle: 10.3389/fbioe.2014.00018
Schools and Programs: Dietrich School of Arts and Sciences > Mathematics
School of Health and Rehabilitation Sciences > Sports Medicine and Nutrition
School of Medicine > Biomedical Informatics
School of Medicine > Pathology
School of Medicine > Surgery
Refereed: Yes
Date Deposited: 22 May 2015 21:26
Last Modified: 29 Apr 2022 11:55


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