Epithelial–mesenchymal transition contributes to portal tract fibrogenesis during human chronic liver disease

Liver precursor cells increase hepatic fibrosis induced by chronic carbon tetrachloride intoxication in rats

“…[51][52][53] The role of EMT in fibrosis was established in lung and kidney and, in the liver, transition of hepatocytes, biliary cells and HSC has also been already reported. [22][23][24][25][26] TGFb, which we found secreted by LPC, is a well-known EMT inducer 22,23,25 that could trigger LPC transition by an autocrine/paracrine pathway and provide a new potential mechanism of fibrosis. However, we could not demonstrate the expression of mesenchymal markers (ie aSMA, desmin and FSP1) in CK19-positive LPC cells from AAF/CCl 4 -treated rats in vivo.…”

“…1 Metabolism of CCl 4 into highly reactive CCl 3 radicals by cytochrome P450 is responsible for centrilobular hepatocellular necrosis, which triggers matrix deposition starting around the central veins, with gradual formation of septa bridging neighboring central veins, without any ductular reaction. 25 In our model, administration of AAF before and during CCl 4 treatment blocks the proliferative hepatocyte response caused by CCl 4 -induced necrosis 27 and leads to the emergence of an alternate regenerative pathway with expansion of LPC in periportal regions as commonly reported in human fibrosis of various etiologies. [12][13][14]28 Using this new model, we investigated the involvement of LPC activation in fibrosis development by comparing the fibrogenic response in rats treated with a combination of CCl 4 and AAF to that obtained in animals treated with either CCl 4 or AAF alone.…”

“…We also investigated whether LPC may directly participate to fibrogenesis and serve as a source of myofibroblasts through EMT as reported for hepatocytes and biliary cells. [22][23][24][25][26] …”

“…21 Among the large variety of factors secreted by myofibroblasts, transforming growth factor-b (TGFb), the most potent fibrogenic cytokine, is also a well-established mediator of epithelial-mesenchymal transition (EMT), which contributes to fibrosis following injury in several organs including the liver. [22][23][24][25][26] To investigate the fibrogenic potential of LPC, we established a new model in the rat in which persistent LPC expansion induced by a chronic 2-acetylaminofluorene (AAF) treatment was combined to the well-established model of liver fibrosis using chronic carbon tetrachloride (CCl 4 ) injection. 1 Metabolism of CCl 4 into highly reactive CCl 3 radicals by cytochrome P450 is responsible for centrilobular hepatocellular necrosis, which triggers matrix deposition starting around the central veins, with gradual formation of septa bridging neighboring central veins, without any ductular reaction.…”

β-Adrenoceptor blockade in sclerosing cholangitis of Mdr2 knockout mice: antifibrotic effects in a model of nonsinusoidal fibrosis

“…Thus, it is a point of discussion whether these myofibroblasts originate from cholangiocytes that have undergone epithelial-tomesenchymal transition. [28][29][30] However, S100A4 immunostainings demonstrated numerous fibroblasts that appear in the portal field and in the developing septae. Additionally, previous studies have demonstrated that S100A4-and CD45-positive fibrocytes, derived from bone marrow, infiltrate the injured liver.…”