Appearance of denuded hepatic stellate cells and their subsequent myofibroblast-like transformation during the early stage of biliary fibrosis in the rat

Abstract

To investigate the early in vivo response of hepatic stellate cells in biliary fibrosis, we examined rat livers during the first 7 days after bile duct ligation using light microscopy, immunohistochemistry, electron microscopy, and immunoelectron microscopy. At day 1 after bile duct ligation, alpha-smooth muscle actin-positive fibroblasts appeared and then increased in number around the proliferating bile ductules. With time, the destruction of the external limiting plate became accentuated because of the invasion of the proliferating bile ductules and periductural fibrosis. At day 7, stromal cells containing fat droplets appeared in the fibrous tissue adjacent to the periportal parenchyma; these are termed denuded hepatic stellate cells. In the fibrous tissue disconnected from the liver parenchyma, the denuded hepatic stellate cells were replaced by myofibroblast-like cells. Meanwhile, the expression of transforming growth factor-beta1 on biliary epithelial cells increased. These results indicate the dual origin of myofibroblasts in experimental biliary fibrosis, the periductural and periductal fibroblasts in the initial stage, and the denuded hepatic stellate cells in the subsequent stage. These two types of stromal cells may undergo myofibroblastic transformation by the transforming growth factor-beta1 secreted by the proliferating biliary epithelial cells.

Prominent contribution of portal mesenchymal cells to liver fibrosis in ischemic and obstructive cholestatic injuries

“…At early time points, combined expression of a-SMA and desmin was found at the interface of portal/septal ductules with the lobule. As it was previously shown by electron microscopy that at this time in BDL rats, fat dropletcontaining HSCs that were disconnected from the liver lobule (thus called denuded HSCs), congregated in the front of biliary fibrosis at the periportal fibrous tissue-lobular interface, 37 we may postulate that these cells comprised at least in part myofibroblastic HSCs. Nevertheless, time course analyses showed that the vast majority of a-SMA-labeled cells that co-localized with fibrosis became desmin-negative over time, suggesting that they derived mainly from portal mesenchymal cells distinct from HSCs, except for intralobular myofibroblastic HSCs detected in BDL cirrhotic liver.…”

TRAM2 Protein Interacts with Endoplasmic Reticulum Ca2+ Pump Serca2b and Is Necessary for Collagen Type I Synthesis

“…Molecular chaperones are necessary for folding of procollagen type I, and it has been documented that an increase in HSP47, a collagen-specific molecular chaperone, parallels the increase in collagen synthesis in various tissues (14,38,40,55). The number of translocons per cell must also increase during activation of HSCs, because rough ER becomes more prominent during their activation into myofibroblast-like cells (17,50). In our microarray study we detected upregulation of the Sec 10-like 1 gene and Sec 23 homolog B gene, encoding components of the protein secretion pathway.…”

Phagocytosis of apoptotic bodies by hepatic stellate cells induces NADPH oxidase and is associated with liver fibrosisin vivo

“…An increased amount of microfilaments is seen underneath the plasma membrane, a feature of myofibroblasts or activated HSC. 2,[24][25][26] Activated HSC localize in close proximity to collagen fibers. In vivo, engulfed AB become phagosomes, and at a later stage, phagolysosomes that are readily identified as double membrane-bound intracytoplasmic organelles containing remnants of cell organelles, and chromatin derived from apoptotic cells.…”