Intrahepatic bile ducts guide establishment of the intrahepatic nerve network in developing and regenerating mouse liver

Abstract

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 class III β-tubulin (TUBB3)+ nerve fibers are not distributed in intrahepatic tissue at embryonic day 17.5; they gradually extend along the periportal tissue, including intrahepatic bile ducts (IHBDs), after birth. Nerve growth factor (Ngf) expression increased in biliary epithelial cells (BECs) and mesenchymal cells next to BECs before nerve fiber extension, and Ngf was upregulated by Hes1. Ectopic NGF expression in mature hepatocytes induced nerve fiber extension into the parenchymal region, where they are normally excluded. Furthermore, after BECs were damaged by administration of 4,4-diaminodiphenylmethane, the nerve network appeared shrunken; however, it was reconstructed after IHBD regeneration, depending on the NGF signal. These results suggest that IHBDs guide extension of nerve fibers by secreting NGF during development and regeneration.