- Meeting ID: 867 6409 6440
- passcode: 149120
13h00 - 13h50 – Matthieu Bougueon (UCL Cancer Institute)
A rule-based multiscale model of hepatic stellate cell plasticity: critical role of the inactivation loop in fibrosis progression
Hepatic stellate cells (HSCs) are the source of the extracellular matrix (ECM) whose accumulation leads to fibrosis, a condition that impairs liver function in chronic liver disease. Understanding HSC dynamics will enable the development of new therapeutic approaches. Few computational models have been proposed for hepatic fibrosis, and none take into account the heterogeneity of HSC phenotypes recently highlighted by single-cell RNA-sequencing analyses. The aim of this study is to develop a rule-based model to study HSC dynamics during fibrosis progression and reversion. Using Kappa, a graph rewriting language, we build models and using the KaSim tool, simulations are performed, based on Gillespie’s stochastic simulation algorithm. We generate biological data from a mouse model of CCl4-induced liver fibrosis to validate the selected model, and use RNA sequencing data from fibrosis patients to verify predictions. We are developing the first rule-based multiscale model of HSC that incorporates seven HSC states and their interaction with TGFB1 molecules that regulate HSC activation and the secretion of type I collagen, the main component of ECM. Simulation studies highlight the critical role of HSC inactivation during fibrosis progression and reversion. While inactivation allows the elimination of activated HSCs during reversion steps, reactivation loops of inactivated HSCs (iHSC) are required to maintain fibrosis. We also demonstrated the model’s sensitivity to TGFB1 parameters, suggesting its adaptability to a variety of pathophysiological conditions in which TGFB1 release associated with the inflammatory response differs. Thus, our model predicts the accumulation of iHSCs during chronic liver disease, a prediction confirmed by RNA sequencing data from patients with hepatic fibrosis. Overall, our study provides the first model of HSC dynamics during hepatic fibrosis and its reversion, enabling exploration of the regulatory role of HSCs in hepatic homeostasis. Thus, our model provides predictions that show the critical role of the inactivation loop in the development of hepatic fibrosis and identifies HSCi as potential new markers of fibrosis progression.
Dernière modification le 07/02/2025