Biliary epithelial‐mesenchymal transition in posttransplantation recurrence of primary biliary cirrhosis†‡

Abstract

Primary biliary cirrhosis (PBC) recurs in the allograft after liver transplantation. Study of early tissue changes in the time-course of disease recurrence provides a unique insight into the initial stages of the disease process, which, in nontransplant patients, occurs long before clinical presentation. We describe a patient who developed classical clinical, biochemical, immunological, and histological features of PBC within 9 months after transplantation. Use of tissue from this patient before and during the development of PBC allowed us to identify biliary epithelial cell (BEC) epithelial-mesenchymal transition (EMT) as a key pathogenetic process. BEC expression of S100A4 (an early fibroblast lineage marker established as a robust marker of EMT), vimentin, and pSmad 2/3 [a marker of transforming growth factor beta (TGF-␤) pathway signaling] were identified immunohistochemically in most BECs in liver tissue from this patient at the point of diagnosis of recurrent disease. BEC expression of S100A4 and pSmad 2/3 was seen as early as 24 days after orthotopic liver transplantation (OLT), although no other features of recurrent PBC were present at this time. Conclusion: S100A4, vimentin, and pSmad 2/3 expression in early recurrent PBC after OLT suggests that BEC EMT is occurring (potentially explaining BEC loss) and that this process is driven by TGF-␤. S100A4 expression by BEC appears to occur before the development of any other features of recurrent PBC, suggesting that EMT may be an initiating event. (HEPATOLOGY 2007;45:977-981.)

Accumulation of Hedgehog-Responsive Progenitors Parallels Alcoholic Liver Disease Severity in Mice and Humans

“…To characterize better the phenotypes of Hh-responsive ductular-appearing cells, serial sections were evaluated for expression of α-SMA, vimentin, and CK-7. Gli-2-expressing cells were demonstrated in ductular structures that expressed the mesenchymal markers α-SMA ( Figure 6D) 31 and vimentin ( Figure 6E) 37 as well as the epithelial progenitor marker CK-7 ( Figure 6F). These results indicate that the ductular response that accompanies severe alcohol-induced liver damage in humans includes populations of Hh-responsive immature cells that may be undergoing epithelial-mesenchymal transitions.…”

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

“…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.…”

Interleukin-17A-Induced Epithelial-Mesenchymal Transition of Human Intrahepatic Biliary Epithelial Cells: Implications for Primary Biliary Cirrhosis

“…stages (II-III) of PBC and may be relatively infrequent in the earlier stages (Robertson et al 2007;Jones 2008). The previous study from a PBC-recurred patient after liver transplantation revealed that HIBECs-EMT may predominate in very early process of PBC (Robertson et al 2007). Thus in this study, we examined if IBECs underwent EMT in livers of patients at the early stage of PBC.…”

“…A previous case report has revealed IBECs-EMT in transplanted liver tissues of a PBC patient, suggesting that IBECs-EMT might occur at early stage of PBC (Robertson et al 2007). However, it has been unclear if IBECs-EMT occurs in primary PBC patients.…”

“…The mechanisms that trigger IBECs loss in PBC have been subjected to intensive studies (Kaplan and Gershwin 2005;Lindor et al 2009). One potential mechanism for IBECs loss is epithelial to mesenchymal transition (EMT), in which epithelial cells undergo phenotypic reprogram, leading to loss of epithelial markers and properties but gain of features related to fibroblasts (Robertson et al 2007).…”