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 collagenproducing 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 collagenproducing 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.tumor microenvironment

Cardiac fibroblasts in pressure overload hypertrophy: the enemy within?

“…Together, in healthy ventricles, 95% of all GFP + fibroblasts were of endocardial or epicardial origin, and none of them were hematopoietically derived, as the Vav-Cre driver exclusively labeled CD45 + or PECAM1 + cells. After aortic bending, both epicardial-and endocardial-derived fibroblasts underwent transient proliferaOn the other hand, FSP1, which is frequently used as a cardiac fibroblast marker (10), was almost exclusively expressed in CD45 + cells, with no expression detected in interstitial GFP + fibroblasts and a limited presence in perivascular GFP + fibroblasts; therefore, similar to previous studies (11,12), FSP1 preferentially labeled immune cells. Hence, Moore-Morris et al have identified collagen1a1-GFP as a robust and specific marker of cardiac fibroblasts in both healthy and pressureoverloaded hearts.…”

S100A4 promotes colon inflammation and colitis-associated colon tumorigenesis

“…Recently, it was found that S100A4 + cells in liver were a subtype of macrophages. 23 However, it seems that S100A4 is expressed in different types of cells in various tissues. 45 , 46 The cellular origin of S100A4 in the colon is not clear.…”

“…17 , 18 Previous studies have reported that S100A4 is expressed in a variety of cells, such as fibroblasts, macrophages, and malignant cells, and plays a crucial role in mediating tumor-stromal interplay. 19-23 S100A4 functions as both intracellular and extracellular forms. 24 , 25 Intracellular S100A4 is involved in a wide range of biological functions, such as the regulation of angiogenesis, cell survival, motility, invasion or metastasis.…”

Cellular and molecular mechanisms in liver fibrogenesis

“…The real involvement of EMT as a pathogenic mechanism contributing to liver fibrogenesis in CLDs is then more than controversial, with accumulating evidence deposing against EMT from either hepatocytes or cholangiocytes [31][32][33][34][35][36]. Along these lines, an excellent very recent fate tracing study from the laboratory of Robert Schwabe, performed using a novel Cre-transgenic mouse that marks 99% of hepatic stellate cells, has shown that HSCs give rise to 82-96% of myofibroblasts in models of toxic, cholestatic and fatty liver disease [37].…”