title: Kupffer cells influence parenchymal invasion and phenotypic orientation, but not the proliferation, of liver progenitor cells in a murine model of liver injury.
abstract: Activation of myofibroblasts (MF) and extracellular matrix (ECM) deposition predispose the expansion and differentiation of liver progenitor cells (LPC) during chronic liver injury. Because Kupffer cells (KC) are active modulators of tissue response and fibrosis, we analyzed their role in a model of LPC proliferation. A choline-deficient diet, supplemented by ethionine (CDE) was administrated to C57Bl/6J mice that were depleted of KC by repeated injections of clodronate (CLO) and compared to PBS-injected mice. On CDE, massive KC activation was observed in the PBS group, but this was blunted in CLO-treated mice. The depletion of KC did not influence LPC proliferation but reduced their invasive behavior. Instead of being found far into the parenchyma, as was found in the PBS group (mean distance from portal vein: 209 μm), LPC of CLO mice remained closer to the portal area (138 μm), forming aggregates and phenotypically resembling cells of biliary lineage. Notably, removal of KC was also associated with a significant decrease in amount of MF and ECM and in the expression of profibrotic factors. Thus, besides ECM and MF, KC are also a significant component of the microenvironmental changes preceding LPC expansion. Depletion of KC may limit the LPC parenchymal invasion through a deficiency in chemoattracting factors, reduced activation of MF, and/or a paucity of the ECM framework necessary for cell motility.
authors.affiliation: Laboratory of Hepato-Gastroenterology, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain (UCL), Brussels, Belgium.
authors.forename: Noémi
authors.initials: N
authors.lastname: Van Hul
authors.forename: Nicolas
authors.initials: N
authors.lastname: Lanthier
authors.forename: Regina
authors.initials: R
authors.lastname: Español Suñer
authors.forename: Jorge
authors.initials: J
authors.lastname: Abarca Quinones
authors.forename: Nico
authors.initials: N
authors.lastname: van Rooijen
authors.forename: Isabelle
authors.initials: I
authors.lastname: Leclercq
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002794:Choline / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D004032:Diet; D004195:Disease Models, Animal; D005001:Ethionine / Q000494:pharmacology; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism; D055166:Hepatic Stellate Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007728:Kupffer Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008099:Liver / Q000473:pathology*; D008107:Liver Diseases / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D058628:Myofibroblasts / Q000473:pathology; D010641:Phenotype; D013234:Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*
chemical_list: D016207:Cytokines; D002794:Choline; D005001:Ethionine