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Bile ductules and stromal cells express hedgehog ligands and/or hedgehog target genes in primary biliary cirrhosis
Author(s) -
Jung Youngmi,
McCall Shan J.,
Li YinXiong,
Diehl Anna Mae
Publication year - 2007
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.21660
Subject(s) - hedgehog , patched , hedgehog signaling pathway , progenitor cell , primary biliary cirrhosis , stromal cell , biology , gli2 , smoothened , pathology , cancer research , medicine , stem cell , endocrinology , microbiology and biotechnology , immunology , signal transduction
Indian Hedgehog (Ihh) regulates tissue morphogenesis. Hedgehog (Hh) activity has been demonstrated in human cholangiocarcinoma and hepatocellular carcinoma lines, and in myofibroblasts and progenitors from adult rodent livers. We evaluated Hh pathway involvement in the response to biliary injury in primary biliary cirrhosis (PBC). Liver sections from 3 PBC patients and 3 controls without liver disease were studied. Immunohistochemistry was used to determine if cells that accumulate in PBC livers express Ihh or Hh‐target genes including the Hh‐receptor, Patched (Ptc), and the Hh‐transcriptional activator glioblastoma (Gli) 2. Positive cells were further identified by costaining for cytokeratin (CK) 19, a biliary marker, or OV6, a hepatic progenitor marker. In all subjects, Gli2 and Ptc expression localized in portal areas. The numbers of Gli2‐ or Ptc‐expressing cells/portal triad were each 10‐fold greater in patients with PBC than in controls ( P < 0.05). In PBC livers, some CK19(+) cells coexpressed Gli2 or Ptc. Many stromal fibroblastic cells were also Gli2(+). Strong Ihh expression was detected in most bile ductular cells. Scattered stromal cells also expressed Ihh. The number of Ihh(+) cells/portal triad was 6‐fold greater in PBC livers than controls ( P < 0.05). OV6(+) progenitors increased significantly in PBC livers, and some of these cells coexpressed Ihh, Ptc, and/or Gli2. Conclusion: This is the first direct evidence that noncancerous, adult human livers harbor several types of cells that produce and/or respond to Hh ligands. Such Hh‐responsive cells accumulate during the fibroproliferative response to chronic cholestatic liver injury, suggesting a role for Hh signaling in this process. (H EPATOLOGY 2007;45:1091–1096.)