title: Podoplanin discriminates distinct stromal cell populations and a novel progenitor subset in the liver.
abstract: Podoplanin/gp38(+) stromal cells present in lymphoid organs play a central role in the formation and reorganization of the extracellular matrix and in the functional regulation of immune responses. Gp38(+) cells are present during embryogenesis and in human livers of primary biliary cirrhosis. Since little is known about their function, we studied gp38(+) cells during chronic liver inflammation in models of biliary and parenchymal liver fibrosis and steatohepatitis. Gp38(+) cells were analyzed using flow cytometry and confocal microscopy, and the expression of their steady state and inflammation-associated genes was evaluated from healthy and inflamed livers. Gp38(+) cells significantly expanded in all three models of liver injury and returned to baseline levels during regression of inflammation. Based on CD133 and gp38 expression in the CD45(-)CD31(-)Asgpr1(-) liver cell fraction, numerous subsets could be identified that were negative for CD133 (gp38(hi)CD133(-), gp38(low)CD133(-), and gp38(-)CD133(-)). Moreover, among the CD133(+) cells, previously identified as progenitor population in injured liver, two subpopulations could be distinguished based on their gp38 expression (gp38(-)CD133(+) and CD133(+)gp38(+)). Importantly, the distribution of the identified subsets in inflammation illustrated injury-specific changes. Moreover, the gp38(+)CD133(+) cells exhibited liver progenitor cell characteristics similar to the gp38(-)CD133(+) population, thus representing a novel subset within the classical progenitor cell niche. Additionally, these cells expressed distinct sets of inflammatory genes during liver injury. Our study illuminates a novel classification of the stromal/progenitor cell compartment in the liver and pinpoints a hitherto unrecognized injury-related alteration in progenitor subset composition in chronic liver inflammation and fibrosis.
authors.affiliation: Department of Medicine II, Saarland University Medical Center, Homburg, Germany;
authors.forename: Christoph
authors.initials: C
authors.lastname: Eckert
authors.affiliation: Institute of Translational Immunology and Research Center for Immunotherapy, University Medical Center, Johannes Gutenberg University, Mainz, Germany;
authors.forename: Yong Ook
authors.initials: YO
authors.lastname: Kim
authors.affiliation: Department of Medicine II, Saarland University Medical Center, Homburg, Germany;
authors.forename: Henrike
authors.initials: H
authors.lastname: Julich
authors.affiliation: Department of Medicine II, Saarland University Medical Center, Homburg, Germany;
authors.forename: Eva-Carina
authors.initials: EC
authors.lastname: Heier
authors.affiliation: Department of Medicine II, Saarland University Medical Center, Homburg, Germany;
authors.forename: Niklas
authors.initials: N
authors.lastname: Klein
authors.affiliation: Department of Physiology, Center for Integrative Physiology and Molecular Medicine, University of Saarland, Saarland, Germany.
authors.forename: Elmar
authors.initials: E
authors.lastname: Krause
authors.affiliation: Insitute of Anatomy and Cell Biology, University of Saarland, Saarland, Germany; and.
authors.forename: Thomas
authors.initials: T
authors.lastname: Tschernig
authors.affiliation: Department of Medicine II, Saarland University Medical Center, Homburg, Germany;
authors.forename: Miroslaw
authors.initials: M
authors.lastname: Kornek
authors.affiliation: Department of Medicine II, Saarland University Medical Center, Homburg, Germany;
authors.forename: Frank
authors.initials: F
authors.lastname: Lammert
authors.affiliation: Institute of Translational Immunology and Research Center for Immunotherapy, University Medical Center, Johannes Gutenberg University, Mainz, Germany;
authors.forename: Detlef
authors.initials: D
authors.lastname: Schuppan
authors.affiliation: Department of Medicine II, Saarland University Medical Center, Homburg, Germany; lukacsver@aol.com.
authors.forename: Veronika
authors.initials: V
authors.lastname: Lukacs-Kornek
mesh_terms: D000071916:AC133 Antigen; D018435:ATP Binding Cassette Transporter, Subfamily B / Q000172:deficiency / Q000235:genetics; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D002469:Cell Separation / Q000379:methods; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D006023:Glycoproteins / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008105:Liver Cirrhosis, Biliary / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D065626:Non-alcoholic Fatty Liver Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010455:Peptides / Q000378:metabolism; D010641:Phenotype; D013234:Stem Cells / Q000378:metabolism* / Q000473:pathology; D017154:Stromal Cells / Q000378:metabolism* / Q000473:pathology; D000097202:ATP-Binding Cassette Sub-Family B Member 4; D000098853:Podoplanin
chemical_list: D000071916:AC133 Antigen; D018435:ATP Binding Cassette Transporter, Subfamily B; D015703:Antigens, CD; D015415:Biomarkers; D006023:Glycoproteins; D018836:Inflammation Mediators; D008562:Membrane Glycoproteins; D010455:Peptides; D000097202:ATP-Binding Cassette Sub-Family B Member 4; C490441:Pdpn protein, mouse; D000098853:Podoplanin; C000606023:PROM1 protein, human; C000606024:Prom1 protein, mouse
keywords: NASH; fibrosis; inflammation; oval cells