Portal fibroblasts with mesenchymal stem cell features form a reservoir of proliferative myofibroblasts in liver fibrosis

Based on the identification of a transcriptomic signature, including Slit2, characterizing portal mesenchymal stem cells (PMSC) and derived myofibroblast (MF), we examined the gene expression profile of in liver tissue derived from multiple human liver disorders, including primary sclerosing cholangitis (PSC) (n=12), non-alcoholic steatohepatitis (NASH) (n=7) and other liver diseases (i.e., primary biliary cholangitis, autoimmune hepatitis, alcoholic liver disease and haemochromatosis) (n=8) and compared them to healthy controls (tumor free tissue from livers with metastasis from colorectal cancer) (n=5). We found that SLIT2 was overexpressed in the liver of patients with NASH, PSC and other chronic liver diseases. We also examined the microarray data of the human liver tissue samples for the transcriptomic signatures and found that in the different types of liver diseases the gene signature of PMSCs/PMSC-MFs was increased compared to normal liver, and correlated with the expression of ACTA2, COL1A1 and vWF. The RNA used for the microarray experiments was extracted from fresh frozen tissue obtained from explanted livers or diagnostic liver biopsies from 1) normal human liver tissue (tumor free tissue from livers with metastasis from colorectal cancer) (n=5) and 2) liver tissue from patients with chronic liver diseases, including primary sclerosing cholangitis (PSC) (n=12), non-alcoholic steatohepatitis (n=7) or other liver diseases (i.e., primary biliary cholangitis, autoimmune hepatitis, alcoholic liver disease and haemochromatosis) (n=8). The liver specimens were provided by the Norwegian biobank for primary sclerosing cholangitis, Oslo, Norway. The Affymetrix Human Gene 1.0 st array was used.