Department of Tissue Development and Regeneration, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, S-1, W-17, Chuo-ku, Sapporo, 060-8556, Japan.
Division of Regenerative Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-0071, Japan.
Sci Rep. 2023 May 1;13(1):7084. doi: 10.1038/s41598-023-33882-w.
Intrahepatic nerves are involved in the regulation of metabolic reactions and hepatocyte-based regeneration after surgical resection, although their contribution to chronic liver injury remains unknown. Given that intrahepatic nerves are abundant in the periportal tissue, they may be correlated also with cholangiocyte-based regeneration. Here we demonstrate that isoproterenol (ISO), a β-adrenergic receptor agonist, promoted ductular expansion induced by 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) in vivo. Immunofluorescence analysis shows that nerve fibers positive for tyrosine hydroxylase form synaptophysin-positive nerve endings on epithelial cell adhesion molecule-positive (EpCAM) cholangiocytes as well as on Thy1 periportal mesenchymal cells (PMCs) that surround bile ducts, suggesting that the intrahepatic biliary tissue are targeted by sympathetic nerves. In vitro analyses indicate that ISO directly increases cAMP levels in cholangiocytes and PMCs. Mechanistically, ISO expands the lumen of cholangiocyte organoids, resulting in promotion of cholangiocyte proliferation, whereas it increases expression of fibroblast growth factor 7, a growth factor for cholangiocytes, in PMCs. Taken together, the results indicate that intrahepatic sympathetic nerves regulate remodeling of bile ducts during DDC-injury by the activation of β-adrenergic receptors on cholangiocytes and PMCs.
肝内神经参与手术切除后代谢反应和肝细胞再生的调节，尽管它们对慢性肝损伤的贡献尚不清楚。由于肝内神经在门脉周围组织中丰富，它们可能也与胆管细胞为基础的再生有关。在这里，我们证明了异丙肾上腺素（ISO），一种β-肾上腺素能受体激动剂，促进了体内 3,5-二乙氧羰基-1,4-二氢吡啶（DDC）诱导的胆小管扩张。免疫荧光分析表明，酪氨酸羟化酶阳性的神经纤维与上皮细胞黏附分子阳性（EpCAM）胆管细胞以及围绕胆管的 Thy1 门脉周围间充质细胞（PMCs）上的突触素阳性神经末梢形成突触，表明肝内胆管组织是由交感神经靶向的。体外分析表明，ISO 直接增加胆管细胞和 PMCs 中的 cAMP 水平。从机制上讲，ISO 扩张胆管细胞类器官的腔，导致胆管细胞增殖的促进，而在 PMCs 中增加了成纤维细胞生长因子 7（一种胆管细胞的生长因子）的表达。总之，这些结果表明，肝内交感神经通过激活胆管细胞和 PMCs 上的β-肾上腺素能受体，调节 DDC 损伤期间胆管的重塑。
