Vasoactive Intestinal Peptide Derived From Liver Mesenchymal Cells Mediates Tight Junction Assembly in Mouse Intrahepatic Bile Ducts
Vasoactive Intestinal Peptide Derived From Liver Mesenchymal Cells Mediates Tight Junction Assembly in Mouse Intrahepatic Bile Ducts
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DOI：
10.1002/hep4.1459
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发表时间：
2019-12-24
影响因子：
5.1
通讯作者：
Watanabe, Mamoru
中科院分区：
文献类型：
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作者：
Sato, Ayako;Kakinuma, Sei;Watanabe, Mamoru
肝内胆管(IHBD)的形成与其微环境有关。特别是，门静脉周围的间充质细胞调节发育中的肝脏胆管细胞的分化和管状形态的发生；然而，需要进一步的研究来充分了解IHBD在连续的分级网络中的排列。本研究旨在阐明在IHBD形成过程中胆管和肝脏间充质细胞之间的相互作用。为了确定导致这种细胞-细胞相互作用的候选因素，从胎龄16.5天的基质金属蛋白酶14(MMP14)缺陷(基因敲除[KO])小鼠的肝脏中分离出间充质细胞，并与野生型(WT)小鼠的间质细胞进行比较。WT间充质细胞显著促进由肝母细胞来源的胆管细胞(胆管细胞囊)组成的管腔结构的形成，而MMP14-KO间充质细胞不能促进囊性结构的形成。综合分析发现，血管活性肠肽(VIP)在MMP14-KO间充质细胞中的表达受到明显抑制。在IHBD发生过程中，VIP和VIP受体1(VIPR1)分别主要在门静脉周围间充质细胞和胆管祖细胞表达。在体外，VIP/VIPR1信号显著促进胆管细胞囊泡的形成，上调紧密连接蛋白1、囊性纤维化跨膜传导调节因子和水通道蛋白1的表达。VIP拮抗剂显著抑制了IHBD体内发育过程中的紧密连接组装和离子/水转运体的上调。在成年小鼠胆汁淤积性损伤模型中，外源性VIP可促进受损胆管紧密连接的修复，改善高胆红素血症。结论：VIP由门静脉周围间充质细胞在围产期产生。它通过建立紧密的连接和上调胆管细胞内的离子/水转运体来支持胆管的发育。VIP通过在胆管内建立紧密连接，有助于迅速从胆汁淤积损伤中恢复过来。
Formation of intrahepatic bile ducts (IHBDs) proceeds in accordance with their microenvironment. Particularly, mesenchymal cells around portal veins regulate the differentiation and ductular morphogenesis of cholangiocytes in the developing liver; however, further studies are needed to fully understand the arrangement of IHBDs into a continuous hierarchical network. This study aims to clarify the interaction between biliary and liver mesenchymal cells during IHBD formation. To identify candidate factors contributing to this cell-cell interaction, mesenchymal cells were isolated from embryonic day 16.5 matrix metalloproteinase 14 (MMP14)-deficient (knockout [KO]) mice livers, in which IHBD formation is retarded, and compared with those of the wild type (WT). WT mesenchymal cells significantly facilitated the formation of luminal structures comprised of hepatoblast-derived cholangiocytes (cholangiocytic cysts), whereas MMP14-KO mesenchymal cells failed to promote cyst formation. Comprehensive analysis revealed that expression of vasoactive intestinal peptide (VIP) was significantly suppressed in MMP14-KO mesenchymal cells. VIP and VIP receptor 1 (VIPR1) were mainly expressed in periportal mesenchymal cells and cholangiocytic progenitors during IHBD development, respectively, in vivo. VIP/VIPR1 signaling significantly encouraged cholangiocytic cyst formation and up-regulated tight junction protein 1, cystic fibrosis transmembrane conductance regulator, and aquaporin 1, in vitro. VIP antagonist significantly suppressed the tight junction assembly and the up-regulation of ion/water transporters during IHBD development in vivo. In a cholestatic injury model of adult mice, exogenous VIP administration promoted the restoration of damaged tight junctions in bile ducts and improved hyperbilirubinemia. Conclusion: VIP is produced by periportal mesenchymal cells during the perinatal stage. It supports bile duct development by establishing tight junctions and up-regulating ion/water transporters in cholangiocytes. VIP contributes to prompt recovery from cholestatic damage through the establishment of tight junctions in the bile ducts.