title: Fibroblast-specific protein 1 identifies an inflammatory subpopulation of macrophages in the liver.
abstract: Cirrhosis is the end result of chronic liver disease. Hepatic stellate cells (HSC) are believed to be the major source of collagen-producing myofibroblasts in cirrhotic livers. Portal fibroblasts, bone marrow-derived cells, and epithelial to mesenchymal transition (EMT) might also contribute to the myofibroblast population in damaged livers. Fibroblast-specific protein 1 (FSP1, also called S100A4) is considered a marker of fibroblasts in different organs undergoing tissue remodeling and is used to identify fibroblasts derived from EMT in several organs including the liver. The aim of this study was to characterize FSP1-positive cells in human and experimental liver disease. FSP1-positive cells were increased in human and mouse experimental liver injury including liver cancer. However, FSP1 was not expressed by HSC or type I collagen-producing fibroblasts. Likewise, FSP1-positive cells did not express classical myofibroblast markers, including αSMA and desmin, and were not myofibroblast precursors in injured livers as evaluated by genetic lineage tracing experiments. Surprisingly, FSP1-positive cells expressed F4/80 and other markers of the myeloid-monocytic lineage as evaluated by double immunofluorescence staining, cell fate tracking, flow cytometry, and transcriptional profiling. Similar results were obtained for bone marrow-derived and peritoneal macrophages. FSP1-positive cells were characterized by increased expression of COX2, osteopontin, inflammatory cytokines, and chemokines but reduced expression of MMP3 and TIMP3 compared with Kupffer cells/macrophages. These findings suggest that FSP1 is a marker of a specific subset of inflammatory macrophages in liver injury, fibrosis, and cancer.
authors.affiliation: Department of Medicine, University of California at San Diego, La Jolla, CA 92093, USA. christoph.oesterreicher@meduniwien.ac.at
authors.forename: Christoph H
authors.initials: CH
authors.lastname: Österreicher
authors.forename: Melitta
authors.initials: M
authors.lastname: Penz-Österreicher
authors.forename: Sergei I
authors.initials: SI
authors.lastname: Grivennikov
authors.forename: Monica
authors.initials: M
authors.lastname: Guma
authors.forename: Ekaterina K
authors.initials: EK
authors.lastname: Koltsova
authors.forename: Christian
authors.initials: C
authors.lastname: Datz
authors.forename: Roman
authors.initials: R
authors.lastname: Sasik
authors.forename: Gary
authors.initials: G
authors.lastname: Hardiman
authors.forename: Michael
authors.initials: M
authors.lastname: Karin
authors.forename: David A
authors.initials: DA
authors.lastname: Brenner
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism*; D019070:Cell Lineage; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D020869:Gene Expression Profiling; D055166:Hepatic Stellate Cells / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D008099:Liver / Q000473:pathology*; D008103:Liver Cirrhosis / Q000378:metabolism*; D008113:Liver Neoplasms / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D046228:Microarray Analysis; D058628:Myofibroblasts / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins; C470944:S100a4 protein, mouse