Sonic Hedgehog Pathway

Omenetti, Alessia; Diehl, Anna Mae

doi:10.1007/978-3-642-00150-5_26

Cited by 2 publications

(1 citation statement)

References 62 publications

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“…The Hedgehog (Hh) pathway is critically important in organogenesis and tissue remodeling, and Hh activation appears to be involved in fibrogenesis in hepatobiliary disease 3, 4. Furthermore, Hh signaling regulates epithelial‐mesenchymal transitions (EMT; expression of typically mesenchymal markers in epithelial cell types; Table 1) of cholangiocytes in experimental obstructive cholestasis, and intrahepatic bile ducts in primary biliary cirrhosis (PBC) patients show evidence of EMT 5.…”

Section: Markers Of Hh Signaling and Emt Examinedmentioning

confidence: 99%

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

Omenetti

Bass

Anders³

et al. 2011

Hepatology

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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;)

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Section: Markers Of Hh Signaling and Emt Examinedmentioning

confidence: 99%

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

Omenetti

Bass

Anders³

et al. 2011

Hepatology

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Sonic hedgehog promotes generation and maintenance of human forebrain Olig2 progenitors

Ortega

Radonjic

Zečević

2013

Front. Cell. Neurosci.

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Function of oligodendrocytes (OLs), myelin forming cells in the CNS, is disrupted in demyelinating diseases such as periventricular leukomalacia or multiple sclerosis. It is, thus, important to better understand factors that can affect generation or differentiation of human OLs. In rodents, Sonic hedgehog (Shh) is influencing expression of Olig2, a helix-loop-helix transcription factor required for development of OLs. In humans, Olig2 is present in cortical progenitors at midgestation, however the role of Shh in the specification of human OLs, including Olig2 positive (Olig2+) progenitors, is not fully understood. Here we studied in vitro effects of Shh signaling on proliferation and specification of human cortical Olig2+ progenitors at midgestation. First, we established that the spatial pattern of Olig2 expression in the human developing CNS, described on cryosections, was preserved in mixed and enriched radial glia cell (RGC) cultures. Next, we demonstrated that in vitro treatment with Shh induced an increase in the number of Olig2+ progenitors. Shh treatment increased the density of early oligodendrocyte progenitors (OPCs) at the expense of RGC, while the number of late OPCs, did not change. However, inhibition of endogenous Shh with cyclopamine did not reduce the density of Olig2+ cells, implying the presence of an additional Shh-independent mechanism for OLs generation in vitro. These results suggest that the primary role of Shh signaling in the human dorsal oligodendrogenesis is the expansion and specification of multipotent radial glia progenitors into Olig2+ early OPCs. These results obtained in vitro are relevant to understand primary myelination during CNS development, as well as remyelination in demyelinating diseases.

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Sonic Hedgehog Pathway

Cited by 2 publications

References 62 publications

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

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

Sonic hedgehog promotes generation and maintenance of human forebrain Olig2 progenitors

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