{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T02:56:00Z","timestamp":1787021760892,"version":"3.56.0"},"update-to":[{"DOI":"10.1371\/journal.pcbi.1011858","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2024,8,8]],"date-time":"2024-08-08T00:00:00Z","timestamp":1723075200000}}],"reference-count":83,"publisher":"Public Library of Science (PLoS)","issue":"7","license":[{"start":{"date-parts":[[2024,7,29]],"date-time":"2024-07-29T00:00:00Z","timestamp":1722211200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001677","name":"Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100001677","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100012950","name":"Institut national de recherche en informatique et en automatique","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100012950","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004794","name":"Centre National de la Recherche Scientifique","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100004794","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Universit\u00e9 de Rennes"},{"DOI":"10.13039\/501100001677","name":"Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100001677","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001677","name":"Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100001677","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>\n                    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 (TGF\n                    <jats:italic>\u03b2<\/jats:italic>\n                    1) 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\u2019s sensitivity to (TGF\n                    <jats:italic>\u03b2<\/jats:italic>\n                    1) parameters, suggesting its adaptability to a variety of pathophysiological conditions for which levels of (TGF\n                    <jats:italic>\u03b2<\/jats:italic>\n                    1) 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.\n                  <\/jats:p>","DOI":"10.1371\/journal.pcbi.1011858","type":"journal-article","created":{"date-parts":[[2024,7,29]],"date-time":"2024-07-29T15:38:32Z","timestamp":1722267512000},"page":"e1011858","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":14,"title":["A rule-based multiscale model of hepatic stellate cell plasticity: Critical role of the inactivation loop in fibrosis 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Biochemical Reaction Rules with Constraints. In: Programming Languages and Systems\u201420th European Symposium on Programming, ESOP 2011, Held as Part of the Joint European Conferences on Theory and Practice of Software, ETAPS 2011, Saarbr\u00fccken, Germany, March 26-April 3, 2011. Proceedings. vol. 6602 of Lecture Notes in Computer Science. Springer; 2011. p. 338\u2013357. 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A potential mechanism of self perpetuation in liver fibrogenesis","volume":"89","author":"MG Bachem","year":"1992","journal-title":"J Clin Invest"},{"issue":"1","key":"pcbi.1011858.ref071","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/S0168-8278(05)80008-X","article-title":"The response of rat liver perisinusoidal lipocytes to polypeptide growth regulator changes with their transdifferentiation into myofibroblast-like cells in culture","volume":"18","author":"MG Bachem","year":"1993","journal-title":"Journal of hepatology"},{"issue":"5","key":"pcbi.1011858.ref072","doi-asserted-by":"crossref","first-page":"1094","DOI":"10.1053\/he.2000.6126","article-title":"Modulation of transforming growth factor \u03b2 response and signaling during transdifferentiation of rat hepatic stellate cells to myofibroblasts","volume":"31","author":"S Dooley","year":"2000","journal-title":"Hepatology"},{"issue":"14","key":"pcbi.1011858.ref073","doi-asserted-by":"crossref","first-page":"10551","DOI":"10.1016\/S0021-9258(17)34095-4","article-title":"Modulation of transforming growth factor beta receptors of rat lipocytes during the hepatic wound healing response. Enhanced binding and reduced gene expression accompany cellular activation in culture and in vivo","volume":"269","author":"SL Friedman","year":"1994","journal-title":"Journal of Biological Chemistry"},{"issue":"1","key":"pcbi.1011858.ref074","doi-asserted-by":"crossref","first-page":"e3","DOI":"10.1371\/journal.pcbi.0020003","article-title":"Signal processing in the TGF-\u03b2 superfamily ligand-receptor network","volume":"2","author":"JMG Vilar","year":"2006","journal-title":"PLoS computational biology"},{"issue":"5","key":"pcbi.1011858.ref075","first-page":"1319","article-title":"Spatial and temporal dynamics of hepatic stellate cell activation during oxidant-stress-induced fibrogenesis","volume":"152","author":"G Montosi","year":"1998","journal-title":"Am J Pathol"},{"issue":"3","key":"pcbi.1011858.ref076","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1007\/s40139-013-0018-7","article-title":"Reversibility of liver fibrosis and inactivation of fibrogenic myofibroblasts","volume":"1","author":"X Liu","year":"2013","journal-title":"Current pathobiology reports"},{"issue":"6B","key":"pcbi.1011858.ref077","doi-asserted-by":"crossref","first-page":"1726","DOI":"10.1111\/j.1582-4934.2009.00801.x","article-title":"Interleukin-33 overexpression is associated with liver fibrosis in mice and humans","volume":"14","author":"P Marvie","year":"2010","journal-title":"J Cell Mol Med"},{"issue":"3","key":"pcbi.1011858.ref078","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1016\/j.jhep.2009.12.009","article-title":"Fibrillar collagen scoring by second harmonic microscopy: a new tool in the assessment of liver fibrosis","volume":"52","author":"L Gailhouste","year":"2010","journal-title":"Journal of hepatology"},{"issue":"43","key":"pcbi.1011858.ref079","doi-asserted-by":"crossref","first-page":"15545","DOI":"10.1073\/pnas.0506580102","article-title":"Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles","volume":"102","author":"A Subramanian","year":"2005","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"3","key":"pcbi.1011858.ref080","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1038\/ng1180","article-title":"PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes","volume":"34","author":"VK Mootha","year":"2003","journal-title":"Nat Genet"},{"issue":"D1","key":"pcbi.1011858.ref081","doi-asserted-by":"crossref","first-page":"D933","DOI":"10.1093\/nar\/gkac958","article-title":"Ensembl 2023","volume":"51","author":"FJ Martin","year":"2023","journal-title":"Nucleic Acids Res"},{"issue":"12","key":"pcbi.1011858.ref082","first-page":"1","article-title":"Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2","volume":"15","author":"MI Love","year":"2014","journal-title":"Genome biology"},{"issue":"1","key":"pcbi.1011858.ref083","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1145\/2976758","article-title":"Exponential laws of computing growth","volume":"60","author":"PJ Denning","year":"2016","journal-title":"Communications of the ACM"}],"updated-by":[{"DOI":"10.1371\/journal.pcbi.1011858","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2024,8,8]],"date-time":"2024-08-08T00:00:00Z","timestamp":1723075200000}}],"container-title":["PLOS Computational Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1011858","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,8,8]],"date-time":"2024-08-08T14:22:05Z","timestamp":1723126925000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1011858"}},"subtitle":[],"editor":[{"given":"Philip K","family":"Maini","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2024,7,29]]},"references-count":83,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2024,7,29]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pcbi.1011858","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2024.01.24.577157","asserted-by":"object"}]},"ISSN":["1553-7358"],"issn-type":[{"value":"1553-7358","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,7,29]]}}}