Heterogeneity of liver cells expressing procollagen types I and IV in vivo

Abstract

 The extracellular matrix of fibrotic liver is predominantly produced by mesenchymal cells, the in vivo phenotype of which is poorly defined. We report on the application of combined immunohistology and in situ hybridization with [³⁵S]-labeled α1(I) and α1(IV) procollagen RNA probes. In CCl₄-treated rats, all α1(I) procollagen-producing cells were vimentin positive but cytokeratin negative; over 90% expressed desmin, a marker of rat liver stellate cells. α1(I) Procollagen-expressing, desmin-negative cells were confined to portal tract and perivascular stroma. Similarly, α1(I) procollagen gene transcripts were, in all instances, colocalized with vimentin in human liver. In fibrotic specimens, over 70% of these cells expressed α-actin. Antibodies against epithelial, endothelial, and Kupffer cells, granulocytes, and lymphocytes did not react with α1(I) procollagen RNA-expressing cells. Localization, morphology, and immunophenotype of α1(I) procollagen-expressing cells indicated stellate cells and portal/vascular fibroblasts, but not epithelial cells, to be sources of hepatic interstitial collagen. However, most α1(IV)-expressing human liver cells were identified as endothelial cells, the remaining cells were (myo-)fibroblastic and bile duct epithelial cells, but not hepatocytes. This indicates synthesis of procollagen type IV from both sides of the basement membrane and suggests an active participation of endothelial cells in the process of sinusoidal capillarization.