Computational simulation of liver fibrosis dynamics

Yoshizawa, Misa; Sugimoto, Masahiro; Tanaka, Minoru; Sakai, Yusuyuki; Nishikawa, Masaki

doi:10.1038/s41598-022-18123-w

Cited by 5 publications

(2 citation statements)

References 50 publications

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“…Computational models and in silico approaches have acquired great importance along with the evolution of computers and the rising relevance of data science, which allows researchers to investigate large databases in a high-throughput, fast manner. In silico strategies have been developed to study food-drug interactions, liver metabolism modeling, and fibrotic process simulation that recapitulate collagen deposition and inflammatory processes in central venous regions [102][103][104]. However, Drug-Induced Liver Injury (DILI) research stands out as one of the most benefitted areas when it comes to computational models.…”

Section: Computational Modelsmentioning

confidence: 99%

The 3Rs in Experimental Liver Disease

Martinez-Lopez,

Angel-Gomis,

Sanchez-Ardid

et al. 2023

Animals

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Patients with cirrhosis present multiple physiological and immunological alterations that play a very important role in the development of clinically relevant secondary complications to the disease. Experimentation in animal models is essential to understand the pathogenesis of human diseases and, considering the high prevalence of liver disease worldwide, to understand the pathophysiology of disease progression and the molecular pathways involved, due to the complexity of the liver as an organ and its relationship with the rest of the organism. However, today there is a growing awareness about the sensitivity and suffering of animals, causing opposition to animal research among a minority in society and some scientists, but also about the attention to the welfare of laboratory animals since this has been built into regulations in most nations that conduct animal research. In 1959, Russell and Burch published the book “The Principles of Humane Experimental Technique”, proposing that in those experiments where animals were necessary, everything possible should be done to try to replace them with non-sentient alternatives, to reduce to a minimum their number, and to refine experiments that are essential so that they caused the least amount of pain and distress. In this review, a comprehensive summary of the most widely used techniques to replace, reduce, and refine in experimental liver research is offered, to assess the advantages and weaknesses of available experimental liver disease models for researchers who are planning to perform animal studies in the near future.

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Section: Computational Modelsmentioning

confidence: 99%

The 3Rs in Experimental Liver Disease

Martinez-Lopez,

Angel-Gomis,

Sanchez-Ardid

et al. 2023

Animals

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“…The model integrated parenchymal cells, inflammatory cells, collagen-producing cells and molecular regulatory agents, with rules defining the properties and interactions between all agents [13]. This model was then modified by preventing the migration of collagen-producing cells, thus providing a more accurate dynamic of collagen deposition [14]. The Dutta-Moscato model has also been extended and modified by Wand and Jiang [15] to include information about lipid accumulation induced by CCl4 treatment, making it possible to study the progression of liver fibrosis in presence or absence of steatosis.…”

Section: Introductionmentioning

confidence: 99%

A rule-based multiscale model of hepatic stellate cell plasticity: critical role of the inactivation loop in fibrosis progression

Bougueon,

Legagneux,

Hazard

et al. 2024

Preprint

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Hepatic stellate cells (HSC) are the source of extracellular matrix (ECM) whose overproduction leads to fibrosis, a condition that impairs liver functions in chronic liver diseases. Understanding the dynamics of HSCs will provide insights needed to develop new therapeutic approaches. Few models of hepatic fibrosis have been proposed, and none of them include the heterogeneity of HSC phenotypes recently highlighted by single-cell RNA sequencing analyses. Here, we developed rule-based models to study HSC dynamics during fibrosis progression and reversion. We used the Kappa graph rewriting language, for which we used tokens and counters to overcome temporal explosion. HSCs are modeled as agents that present seven physiological cellular states and that interact with (TGFβ1) molecules which regulate HSC activation and the secretion of type I collagen, the main component of the ECM. Simulation studies revealed the critical role of the HSC inactivation process during fibrosis progression and reversion. While inactivation allows elimination of activated HSCs during reversion steps, reactivation loops of inactivated HSCs (iHSCs) are required to sustain fibrosis. Furthermore, we demonstrated the model’s sensitivity to (TGFβ1) parameters, suggesting its adaptability to a variety of pathophysiological conditions for which levels of (TGFβ1) production associated with the inflammatory response differ. Using new experimental data from a mouse model of CCl4-induced liver fibrosis, we validated the predicted ECM dynamics. Our model also predicts the accumulation of iHSCs during chronic liver disease. By analyzing RNA sequencing data from patients with non-alcoholic steatohepatitis (NASH) associated with liver fibrosis, we confirmed this accumulation, identifying iHSCs as novel markers of fibrosis progression. Overall, our study provides the first model of HSC dynamics in chronic liver disease that can be used to explore the regulatory role of iHSCs in liver homeostasis. Moreover our model can also be generalized to fibroblasts during repair and fibrosis in other tissues.

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A rule-based multiscale model of hepatic stellate cell plasticity: Critical role of the inactivation loop in fibrosis progression

Bouguéon,

Legagneux,

Hazard

et al. 2024

PLoS Comput Biol

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Hepatic stellate cells (HSC) are the source of extracellular matrix (ECM) whose overproduction leads to fibrosis, a condition that impairs liver functions in chronic liver diseases. Understanding the dynamics of HSCs will provide insights needed to develop new therapeutic approaches. Few models of hepatic fibrosis have been proposed, and none of them include the heterogeneity of HSC phenotypes recently highlighted by single-cell RNA sequencing analyses. Here, we developed rule-based models to study HSC dynamics during fibrosis progression and reversion. We used the Kappa graph rewriting language, for which we used tokens and counters to overcome temporal explosion. HSCs are modeled as agents that present seven physiological cellular states and that interact with (TGFβ1) molecules which regulate HSC activation and the secretion of type I collagen, the main component of the ECM. Simulation studies revealed the critical role of the HSC inactivation process during fibrosis progression and reversion. While inactivation allows elimination of activated HSCs during reversion steps, reactivation loops of inactivated HSCs (iHSCs) are required to sustain fibrosis. Furthermore, we demonstrated the model’s sensitivity to (TGFβ1) parameters, suggesting its adaptability to a variety of pathophysiological conditions for which levels of (TGFβ1) production associated with the inflammatory response differ. Using new experimental data from a mouse model of CCl4-induced liver fibrosis, we validated the predicted ECM dynamics. Our model also predicts the accumulation of iHSCs during chronic liver disease. By analyzing RNA sequencing data from patients with non-alcoholic steatohepatitis (NASH) associated with liver fibrosis, we confirmed this accumulation, identifying iHSCs as novel markers of fibrosis progression. Overall, our study provides the first model of HSC dynamics in chronic liver disease that can be used to explore the regulatory role of iHSCs in liver homeostasis. Moreover, our model can also be generalized to fibroblasts during repair and fibrosis in other tissues.

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Computational simulation of liver fibrosis dynamics

Cited by 5 publications

References 50 publications

The 3Rs in Experimental Liver Disease

The 3Rs in Experimental Liver Disease

A rule-based multiscale model of hepatic stellate cell plasticity: critical role of the inactivation loop in fibrosis progression

A rule-based multiscale model of hepatic stellate cell plasticity: Critical role of the inactivation loop in fibrosis progression

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