Bouguéon, Matthieu

Boutillier, Pierre

Feret, Jerome

Hazard, Octave

Theret, Nathalie

Oral presentation during the GT-biossInternational audienc

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HAL Id: hal-03545569https://hal.inria.fr/hal-03545569Submitted on 27 Jan 2022HAL is a multi-disciplinary open accessarchive for the deposit and dissemination of sci-entific research documents, whether they are pub-lished or not. The documents may come fromteaching and research institutions in France orabroad, or from public or private research centers.L’archive ouverte pluridisciplinaire HAL, estdestinée au dépôt et à la diffusion de documentsscientifiques de niveau recherche, publiés ou non,émanant des établissements d’enseignement et derecherche français ou étrangers, des laboratoirespublics ou privés.A Kappa model for hepatic stellate cells activation byTGFB1Matthieu Bouguéon, Pierre Boutillier, Jerome Feret, Octave Hazard, NathalieTheretTo cite this version:Matthieu Bouguéon, Pierre Boutillier, Jerome Feret, Octave Hazard, Nathalie Theret. A Kappa modelfor hepatic stellate cells activation by TGFB1. GT-Bioss 2021 - Biologie systémique symbolique, Nov2021, Lyon, France. pp.1-23. ￿hal-03545569￿Matthieu Bougueon, Pierre Boutillier, Jérome Feret, Octave Hazard and Nathalie Theret.A Kappa model for hepatic stellate cells activation by TGBF11,2,3123GT Bioss 2021Liver Fibrosis Multiples causeExtracellular matrix (ECM) accumulatioReversible1 Cordero-Espinoza The Journal of clinical investigation 128.1 (2018): 85-96Hepatic FibrosisLiver injury induces inflammatory response leading to release of TGFB which activates quiescent qHSC towards a MFB phenotype promoting tissue repairMFB are eliminated either by apoptosis/senescence pathways or by inactivation towards a inactivated HSC state.The inactivated iHSC can be reactivated upon TGF-b stimulation in a faster manner Upon chronic injuries, the dynamics of the system is modifief and MFB escaped to the elimination pathways leading to ECM accumulation2ObjectivesA)  Develop a Kappa-based model to analyze the dynamics of hepatic stellate cells upon TGF-beta stimulationB) Identify the regulators of equilibrium between repair and fibrosis by integrating the matrix environmentC) While the equilibrium breaking is clearly the fibrosis threshold, founding target inhibiting TGF-β is the final aims of this project3KappaWalter FontanaPierre BoutillierJerome FeretJean Krivinehttps://kappalanguage.org/4KappaRules based language created in 2004 (V.Damos)Rules describe agent behavior modifing state of site of this agent.Exemple:s site of the agent A will become redand the site r will be bound to the site x of B.5Kappa   Rules based language using agent   Rules based    VS    Agent Based6all conformations of the agents or the processus must be describeonly information on the modified part KappaKappa is a graphs rewritting language, meaning a model is a graph where Agent are nodes and interaction are edges  A model is a graph composed of multiple graphs modified each time a rules is firedChemistry syntaxe:A + B -> C + D7‘Ka’'HSC(state{quiescent} TGFBR1_2{membrane}[.]), TGFB1(cell[.] state{active}) -> HSC(state{quiescent} TGFBR1_2{intern}[1]), TGFB1(cell[1] state{active}) @ ‘Ka’Kappa rulesRule describing TGFB binding to quiescent cell.Interaction possible only if occurences of HSC have their receptors in a membrane state and free.8‘Ka’Kappa ToolsKaSim KaSaSpatial KappaCausality AnalyzerStochastic Simulator using Gillespie algorithm.Static analyzer gives informations onlink between agents,Impact of the state of site on linkdouble link formationExtension introducing spatial information and compartmentalization in KappaSorokina O. Bioinformatics. 2013Understanding the impact between rules, what conditions must be met to allow another rule to be triggered.910Model 1 Agent HSC with 7 state (quiescent, activated ...) and 1 site (TGFBR73 rulesParameters:EnvironnementNumber of HSC: 100Number of receptor: 10000qHSChalf life: 54.93dactivation speed: 1hProliferationHSC proliferation half-time: 13.75hMFB proliferation half-time: 886.9h ActivationqHSC -> aHSC: 84haHSC -> MFB : 84hMFBhalf-life: 3.76dInactivation: 5diHSCreactivation: 42hiHSC half life: 54.93d11ReceptorRecycling rate: 30 minReceptor production Rate: 4 minConstitutive degradation rate: 36minLigand induced degradation rate :4 minTGFBTGFB1 half life 3min TGBF wave: 5000 * number of HSCSimulations protocolPerform multiple simulations to test the impact of the inpuTGFB concentratioFrequence of TGFB inpuNumber of TGFB input12dT between inputNumber of inputTGFB concentrationqHSCT0 6 monthqHSC, aHSC, MFB, iHSC, aHSC reactivated, MFB reactivatedParameters:[TGFB]: 5000number of input: 8dT: 90h and 24h13SimulationsParameters:[TGFB]: 5000number of input: 8 and 16dT between input: 90h14SimulationsParameters:[TGFB]: 5000 and 1000number of input: 8dT between input: 90h15SimulationsSimulationsParameters: [TGFB]: 5000, number of input: 8, dT between input: 90h2 stimulations separate by 6 months16Analysis- Despite the heterogeneity of the different source of data, we observed a recovery time  consistent with the experimental data- Chronic TGFb stimulation did not lead to accumulation of MFB that promote fibrosis- Hypothesis; The extracellular matrix produced by activate hepatic stellate cells might contribute to the disequilibrium towards fibrosis17Extracellular Matrix- provides physical support for cells  - establishes separation and maintenance of differentiated tissues - regulates growth factors and receptor abundance- maintains the level of hydration and the pH of the local environment18Source: Michael W. King: Integrative Medical Biochemistry Examination and Board Review,www.accesspharmacy.com  Copyright © McGraw-Hill Education. All rights reservedExtracellular MatrixThe components of ECM- are mainly secreted by activated hepatic stellate cells- the stiffness of ECM promotes activation of HSC- the remodeling of ECM depends on protease activities also secreted by activated HSC- increased stiffness of liver tissues is associated with the progression of fibrosis from stage 1 to stage 419Source: Michael W. King: Integrative Medical Biochemistry Examination and Board Review,www.accesspharmacy.com  Copyright © McGraw-Hill Education. All rights reservedPerspectivesA)  Integration of the mechanical effect of ECM on HSC activation by introducing the main driver of stiffness, the type I collagen that is produced by activated HSC and MFBB)  Comparative study of the use of molecules (TGFbeta receptor, collagen) as groups (token) or as individual agent. Computational challenge ?20AcknowledgementsThis work was support by a travel grant by the SFBIMy supervisorsNathalie Theret; Irset, InsermAnne Siegel; Irisa, InriaJérome Feret; Team Antique, InriaPierre Boutillier; Nomadic LabOctave Hazard; Team Antique, InriaThank you!Any questions?Matthieu Bougueon | matthieu.bougueon@irisa.fr 

Modelling hepatic stellate cells activation by TGFB1 using Kappa language

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A Kappa model for hepatic stellate cells activation by TGFB1

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