Bile ductules and stromal cells express hedgehog ligands and/or hedgehog target genes in primary biliary cirrhosis
Bile ductules and stromal cells express hedgehog ligands and/or hedgehog target genes in primary biliary cirrhosis
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DOI：
10.1002/hep.21660
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发表时间：
2007-05-01
期刊：
影响因子：
13.5
通讯作者：
Diehl, Anna Mae
中科院分区：
文献类型：
--
作者：
Jung, Youngmi;McCall, Shannon J.;Diehl, Anna Mae
Indian Hedgehog（Ihh）调节组织形态发生。Hedgehog（Hh）活性已在人胆管癌和肝细胞癌细胞系以及成年啮齿类动物肝脏的肌成纤维细胞和祖细胞中得到证实。我们评估了原发性胆汁性肝硬化（PBC）中Hh通路参与对胆汁损伤的反应。对3例PBC患者和3例无肝病对照者的肝切片进行了研究。免疫组织化学用于确定PBC肝脏中积聚的细胞是否表达Ihh或Hh靶基因，包括Hh受体Patched（Ptc）和Hh转录激活因子胶质母细胞瘤（Gli）2。通过细胞角蛋白（CK 19，一种胆管标记物，或OV 6，一种肝祖细胞标记物）的共染色进一步鉴定阳性细胞。在所有受试者中，Gli2和Ptc表达定位于汇管区。PBC患者Gli2或Ptc表达细胞/门静脉三联体的数量均为对照组的10倍（P <0.05）。PBC肝组织中部分CK19（+）细胞同时表达Gli2和Ptc。许多间质成纤维细胞也是Gli2（+）。Ihh在大多数胆管细胞中有较强的表达。散在的基质细胞也表达lhh。PBC组Ihh（+）细胞/门静脉三联体的数量是对照组的6倍（P <0.05）。PBC肝脏中的OV 6（+）祖细胞显着增加，其中一些细胞共表达lhh、Ptc和/或Gli2。结论：这是第一个直接的证据表明，非癌性的成年人肝脏含有几种类型的细胞，产生和/或响应Hh配体。这种Hh反应细胞在慢性胆汁淤积性肝损伤的纤维增生反应过程中积累，表明Hh信号在此过程中的作用。
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 fin-ther 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 lhh. 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 lhh, 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.