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
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.
Development. 2018 Apr 25;145(9):dev159095. doi: 10.1242/dev.159095.
Epithelial organs consist of multiple tissue structures, such as epithelial sheets, blood vessels and nerves, which are spatially organized to achieve optimal physiological functions. The hepatic nervous system has been implicated in physiological functions and regeneration of the liver. However, the processes of development and reconstruction of the intrahepatic nerve network and its underlying mechanisms remain unknown. Here, we demonstrate that neural class III β-tubulin (TUBB3) nerve fibers are not distributed in intrahepatic tissue at embryonic day 17.5; instead, they gradually extend along the periportal tissue, including intrahepatic bile ducts (IHBDs), after birth. Nerve growth factor () expression increased in biliary epithelial cells (BECs) and mesenchymal cells next to BECs before nerve fiber extension, and was upregulated by hairy enhancer of slit 1 (Hes family bHLH transcription factor 1; Hes1). Ectopic NGF expression in mature hepatocytes induced nerve fiber extension into the parenchymal region, from where these fibers are normally excluded. Furthermore, after BECs were damaged by the administration of 4,4-diaminodiphenylmethane, the nerve network appeared shrunken; however, it was reconstructed after IHBD regeneration, which depended on the NGF signal. These results suggest that IHBDs guide the extension of nerve fibers by secreting NGF during nerve fiber development and regeneration.
上皮器官由多种组织结构组成，如上皮片、血管和神经，它们在空间上组织起来以实现最佳的生理功能。肝神经系统参与肝脏的生理功能和再生。然而，肝内神经网络的发育和重建过程及其潜在机制尚不清楚。在这里，我们证明神经 III 类 β-微管蛋白（TUBB3）神经纤维在胚胎第 17.5 天不在肝内组织中分布；相反，它们在出生后沿着门周组织（包括肝内胆管（IHBD））逐渐延伸。神经生长因子（NGF）的表达在胆管上皮细胞（BECs）和 BEC 旁边的间充质细胞中增加，然后在神经纤维延伸之前增加，并且由毛状增强子 slit1（Hes 家族 bHLH 转录因子 1；Hes1）上调。成熟肝细胞中异位 NGF 表达诱导神经纤维延伸到实质区域，而这些纤维通常被排除在该区域之外。此外，在用 4,4-二氨基二苯甲烷处理 BEC 后，神经网络似乎缩小；然而，在 IHBD 再生后，它被重建，这取决于 NGF 信号。这些结果表明，IHBD 通过在神经纤维发育和再生过程中分泌 NGF 来引导神经纤维的延伸。
