Stage-specific regulation of adhesion molecule expression segregates epithelial stem/progenitor cells in fetal and adult human livers
Stage-specific regulation of adhesion molecule expression segregates epithelial stem/progenitor cells in fetal and adult human livers
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DOI：
10.1007/s12072-007-9023-4
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发表时间：
2008-03-01
影响因子：
6.6
通讯作者：
Gupta, Sanjeev
中科院分区：
文献类型：
--
作者：
Inada, Mari;Benten, Daniel;Gupta, Sanjeev
目的调节细胞粘附分子的表达对干/祖细胞的增殖、隔离和维持至关重要。因此，我们确定胎儿和成人的特定阶段的作用，细胞粘附在肝细胞compartments.Methods我们进行免疫染色的粘附分子，E-钙粘蛋白和Ep-CAM，相关蛋白，β-连环蛋白和α-辅肌动蛋白，肝胆标志物，白蛋白，甲胎蛋白，细胞角蛋白-19，和增殖标志物，Ki-67。结果在胎肝中，成肝细胞广泛增殖，E-cadherin、beta-catenin和alpha-actinin广泛表达，但Ep-CAM在这些细胞中的表达强度较低，且集中在细胞膜上，表明细胞粘附力较弱。胆管板和胆管中的成肝细胞增殖较少，Ep-CAM在这些细胞中强烈表达，遍及细胞膜，表明强粘附。在一些导管板细胞中，β-连环蛋白另外存在于细胞质和细胞核中，表明粘附分子的活性细胞信号传导。在成人肝脏中，细胞不再增殖，E-钙粘蛋白，β-连环蛋白和α-辅肌动蛋白在整个肝细胞中表达，而EpCAM仅在胆管细胞中表达。一些细胞在成人肝脏的导管结构与Ep-CAM共表达白蛋白和细胞角蛋白-19，表明持久性的胎儿样干/祖细胞。结论调节表达的Ep-CAM支持增殖胎儿肝母细胞通过弱粘附，并有助于在胆管形态发生，促进更强的粘附在肝母细胞在此过程中。限制Ep-CAM表达的胆管在成人肝脏大概促进隔离的干/祖细胞。粘附分子的这种阶段特异性和细胞区室相关的调节应该与定义肝干/祖细胞在健康和疾病期间如何进入、退出和保持在肝小生境中有关。
Purpose Regulated expression of cell adhesion molecules could be critical in the proliferation, sequestration, and maintenance of stem/progenitor cells. Therefore, we determined fetal and adult stage-specific roles of cell adhesion in liver cell compartments.Methods We performed immunostaining for the adhesion molecules, E-cadherin and Ep-CAM, associated proteins, beta-catenin and alpha-actinin, hepatobiliary markers, albumin, alpha-fetoprotein, and cytokeratin-19, and the proliferation marker, Ki-67. Expression of albumin was verified by in situ mRNA hybridization.Results In the fetal liver, hepatoblasts showed extensive proliferation with wide expression of E-cadherin, beta-catenin, and alpha-actinin, although Ep-CAM was expressed in these cells less intensely and focally in the cell membrane to indicate weak cell adhesion. Hepatoblasts in ductal plate and bile ducts showed less proliferation and Ep-CAM was intensely expressed in these cells throughout the cell membrane, indicating strong adhesion. In some ductal plate cells, beta-catenin was additionally in the cytoplasm and nucleus, suggesting active cell signaling by adhesion molecules. In adult livers, cells were no longer proliferating and E-cadherin, beta-catenin, and alpha-actinin were expressed in hepatocytes throughout, whereas EpCAM was expressed in only bile duct cells. Some cells in ductal structures of the adult liver with Ep-CAM coexpressed albumin and cytokeratin-19, indicating persistence of fetal-like stem/progenitor cells.Conclusions Regulated expression of Ep-CAM supported proliferation in fetal hepatoblasts through weak adhesion and helped in biliary morphogenesis by promoting stronger adhesion in hepatoblasts during this process. Restriction of Ep-CAM expression to bile ducts in the adult liver presumably facilitated sequestration of stem/progenitor cells. This stage-specific and cell compartment-related regulation of adhesion molecules should be relevant for defining how liver stem/progenitor cells enter, exit, and remain in hepatic niches during both health and disease.