title: TNFalpha-mediated extracellular matrix remodeling is required for multiple division cycles in rat hepatocytes.
abstract: During liver regeneration, hepatocytes proliferate under the control of both proinflammatory cytokines such as tumor necrosis factor alpha (TNFalpha) and growth factors, in parallel to extracellular matrix remodeling. This study investigated mechanisms by which mitogen and extracellular matrix signals are linked for inducing proliferation of differentiated hepatocytes. The authors used adult rat hepatocytes in coculture with liver biliary cells, because cells are stably differentiated for several weeks, capable of extracellular matrix deposition, and unable to divide in response to growth factor alone. This work demonstrated that hepatocytes could undergo several proliferation waves without loss of differentiation by using alternating periods of TNFalpha/growth factor stimulation and deprivation. Three days after stimulation with TNFalpha and epidermal growth factor (EGF), up to 35% of hepatocytes divided. Demonstration was also provided that EGF alone only promoted cell progression up to late G(1), whereas TNFalpha was necessary for G(1)/S transition and Cdk1 induction. TNFalpha promoted an extracellular matrix (ECM) degradation that involved the matrix metalloproteinase MMP-9 induction through activation of NF-kappaB pathway. Finally, the authors showed that ECM remodeling signal was required for initiating any new hepatocyte division wave, in presence of mitogen. In conclusion, these results highlight that hepatocyte division is dependent on ECM deposition associated with differentiation status, and that ECM degradation signal is critical in controlling G(1)/S transition and Cdk1 induction. These results provide new insights for understanding the unique hepatocyte proliferation control and improving regeneration in patients suffering from liver damage.
authors.affiliation: INSERM U522, Hôpital Pontchaillou, Rennes, France.
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Sérandour
authors.forename: Pascal
authors.initials: P
authors.lastname: Loyer
authors.forename: Delphine
authors.initials: D
authors.lastname: Garnier
authors.forename: Brice
authors.initials: B
authors.lastname: Courselaud
authors.forename: Nathalie
authors.initials: N
authors.lastname: Théret
authors.forename: Denise
authors.initials: D
authors.lastname: Glaise
authors.forename: Christiane
authors.initials: C
authors.lastname: Guguen-Guillouzo
authors.forename: Anne
authors.initials: A
authors.lastname: Corlu
mesh_terms: D000818:Animals; D016203:CDC2 Protein Kinase / Q000096:biosynthesis; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation; D002478:Cells, Cultured; D004815:Epidermal Growth Factor / Q000494:pharmacology; D005109:Extracellular Matrix / Q000378:metabolism*; D022781:Hepatocytes / Q000166:cytology*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics; D016328:NF-kappa B / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D004815:Epidermal Growth Factor; D016203:CDC2 Protein Kinase; D020780:Matrix Metalloproteinase 9