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Review
, 27 (3), 268-75

Hedgehog Signaling in Cholangiocytes

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Review

Hedgehog Signaling in Cholangiocytes

Alessia Omenetti et al. Curr Opin Gastroenterol.

Abstract

Purpose of review: Cells lining the biliary tree are targets of injury, but also orchestrate liver repair. The latter involves autocrine/paracrine signaling that enhances the viability and growth of residual ductular cells and promotes accumulation of inflammatory and myofibroblastic cells. The mechanisms mediating this so-called 'ductular reaction' need to be better understood to improve injury outcomes. Studies are revealing that ductular cells produce and respond to hedgehog (Hh) ligands, developmental morphogens that control progenitor cell fate and tissue construction during embryogenesis. Because this has potential implications for liver repair, this review will summarize current knowledge about Hh signaling and cholangiocytes.

Recent findings: Diverse types of liver injury stimulate cholangiocytes to generate Hh ligands, and cholangiocyte-derived Hh ligands interact with receptors on cholangiocytes and neighboring cells to modulate virtually every aspect of the ductular reaction to injury. Excessive Hh signaling promotes dysfunctional repair and results in chronic hepatic inflammation, fibrogenesis, and carcinogenesis.

Summary: The Hh pathway is part of the complex signaling network that orchestrates liver repair. How other pathways and posttranscriptional mechanisms modulate Hh signaling in ductular cells remains unclear. Further research in this area may identify novel therapeutic targets for the treatment of cholangiopathies and cholangiocarcinoma.

Figures

Figure 1
Figure 1. Hedgehog Pathway components in hepatoblasts, hepatoblast-derivates and mature liver epithelial cells
(A–B) Liver progenitor cells give rise to progeny that eventually differentiate into either hepatocytes or cholangiocytes. Herein we refer to both rodent and human bipotent progenitor cells as hepatoblasts (lower level), and their immature progeny as hepatoblast-derivatives (middle level). Small hepatocytes and immature ductular cells are hepatoblast-derivatives. Both hepatoblasts and hepatoblast-derivatives express Hh ligands and Hh target genes. (A) In uninjured livers, mature cholangiocytes exhibit weak expression of both Hh ligands and Hh target genes, whereas these factors are never demonstrated in mature hepatocytes (B) In injured livers, cholangiocytes begin to produce Hh ligands and strongly express Hh target genes, while hepatocytes acquire the ability to release Hh ligands.
Figure 1
Figure 1. Hedgehog Pathway components in hepatoblasts, hepatoblast-derivates and mature liver epithelial cells
(A–B) Liver progenitor cells give rise to progeny that eventually differentiate into either hepatocytes or cholangiocytes. Herein we refer to both rodent and human bipotent progenitor cells as hepatoblasts (lower level), and their immature progeny as hepatoblast-derivatives (middle level). Small hepatocytes and immature ductular cells are hepatoblast-derivatives. Both hepatoblasts and hepatoblast-derivatives express Hh ligands and Hh target genes. (A) In uninjured livers, mature cholangiocytes exhibit weak expression of both Hh ligands and Hh target genes, whereas these factors are never demonstrated in mature hepatocytes (B) In injured livers, cholangiocytes begin to produce Hh ligands and strongly express Hh target genes, while hepatocytes acquire the ability to release Hh ligands.
Figure 2
Figure 2. Hedgehog Pathway intracellular signaling
(A) PATHWAY OFF. In absence of Hedgehog ligands (Hh), Patched (Ptc), a membrane-spanning receptor on the surface of Hh-responsive cells, keeps the co-receptor Smoothened (Smo) in its inactive form. “Free”-Ptc silences the Smo-dependent down-stream intracellular signaling, and Hh-regulated transcription factors undergo multiple phosphorylations, leading to their inactivation and proteasome degradation. Thus, nuclear translocation of Hh-regulated transcription factors is prevented, and the pathway is OFF. (B) PATHWAY ON. When the extracellular microenviroment becomes enriched with soluble HH ligands, they bind to the receptor PTC and this interaction SMO, which turns into its active form. Activation of Smo inhibits Hh transcription factor degradation, leading to an intracellular signaling cascade that ultimately drives the activation and nuclear translocation of Gli family zinc-finger transcription factors, which induce the expression of Hh target genes (e.g. Glis, Ptc, Smo and Hh interactive protein, Hhip).
Figure 3
Figure 3. Hedgehog Pathway and cholangiocyte reactive phenotype
When an insult occurs, cholangiocytes acquire the so called “reactive phenotype” which has 4 key features: (1) reduced apoptosis/increased proliferation (which results in the expansion of ductular cell populations); (2) enhanced secretion of chemokines and cytokines (which recruit immune cells promoting periductular inflammation); (3) generation of pro-fibrogenic factors such as PDGFBB (that drive the accumulation and activation of matrix producing myofibroblasts); (4) loss of epithelial features and gain of more mesenchymal phenotype, so-called Epithelial-to-Mesenchymal Transition, EMT (which blocks epithelial differentiation and contributes to biliary fibrosis). These reactive cholangiocytes and the cells that they recruited produce Hh ligands. The Hh ligands, in turn, feedback and re-enforce the reactive ductular phenotype by acting as a) profibrogenic, b) proinflammatory, c) trophic, and d) EMT inducing signals. The Hh-enriched microenvironment thus perpetuates the ductular reaction. Because the Hh pathway drives the acquisition/perpetuation of a reactive phenotype in cholangiocytes, it is now recognized as a key player in all conditions characterized by cholangiocyte activation and ductular reaction.

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