Hedgehog activity, epithelial-mesenchymal transitions, and biliary dysmorphogenesis in biliary atresia

Abstract

Biliary atresia (BA) is notable for marked ductular reaction and rapid development of fibrosis. Activation of the Hedgehog (Hh) pathway promotes the expansion of populations of immature epithelial cells that coexpress mesenchymal markers and may be profibrogenic. We examined the hypothesis that in BA excessive Hh activation impedes ductular morphogenesis and enhances fibrogenesis by promoting accumulation of immature ductular cells with a mesenchymal phenotype. Livers and remnant extrahepatic ducts from BA patients were evaluated by quantitative reverse‐transcription polymerase chain reaction (QRT‐PCR) and immunostaining for Hh ligands, target genes, and markers of mesenchymal cells or ductular progenitors. Findings were compared to children with genetic cholestatic disease, age‐matched deceased donor controls, and adult controls. Ductular cells isolated from adult rats with and without bile duct ligation were incubated with Hh ligand‐enriched medium ± Hh‐neutralizing antibody to determine direct effects of Hh ligands on epithelial to mesenchymal transition (EMT) marker expression. Livers from pediatric controls showed greater innate Hh activation than adult controls. In children with BA, both intra‐ and extrahepatic ductular cells demonstrated striking up‐regulation of Hh ligand production and increased expression of Hh target genes. Excessive accumulation of Hh‐producing cells and Hh‐responsive cells also occurred in other infantile cholestatic diseases. Further analysis of the BA samples demonstrated that immature ductular cells with a mesenchymal phenotype were Hh‐responsive. Treating immature ductular cells with Hh ligand‐enriched medium induced mesenchymal genes; neutralizing Hh ligands inhibited this. Conclusion: BA is characterized by excessive Hh pathway activity, which stimulates biliary EMT and may contribute to biliary dysmorphogenesis. Other cholestatic diseases show similar activation, suggesting that this is a common response to cholestatic injury in infancy. (HEPATOLOGY 2011;)

The expression of epithelial–mesenchymal transition–related proteins in biliary epithelial cells is associated with liver fibrosis in biliary atresia

“…However, several recent studies have suggested that some alternative mechanisms might also contribute to the expansion of myofibroblastic populations in BA (14,15,19). Here, we found and confirmed evidence for EMT in BA and showed that bile duct epithelia underwent EMT and transdifferentiated into myofibroblasts; thus, these cells might be an additional and significant source of fibroblasts in BA.…”

Taurocholate Induces Biliary Differentiation of Liver Progenitor Cells Causing Hepatic Stellate Cell Chemotaxis in the Ductular Reaction

“…This has led to the hypothesis that the two processes of LPC expansion and HSC activation with the resultant DR and fibrosis, respectively, are closely related. While histological evidence of a DR has previously been demonstrated in children with extrahepatic biliary atresia 16,17 , the potential role of LPCs driving HSC activation and fibrosis via development of the DR has not previously been assessed in CFLD.…”

Sonic Hedgehog Signaling Mediates Epithelial–Mesenchymal Communication and Promotes Renal Fibrosis

“…13,14 Shh expression is upregulated in chronic liver and lung diseases, and it promotes epithelial to mesenchymal transition during biliary fibrosis. 13,15,16 However, whether hedgehog signaling plays a role in the pathogenesis of renal fibrosis, or kidney diseases in general, is completely unknown.…”