Ontogeny of human intrahepatic innervation

Intrahepatic nerves serve important metabolic, sensory and motor functions. Their ontogeny in human liver has not been elucidated. We aimed to characterise the ontogeny of human intrahepatic innervation, to assess its relationship with biliary structures and to examine the distribution and nature of peptidergic nerves during development. We used immunohistochemistry on archival normal human liver tissue from 63 fetuses [8-40 gestational weeks (gw)] and 10 adults with antibodies to pan-neural markers and neuropeptides. Few nerve fibers appeared in portal tracts at 8 gw. Their density increased gradually from 12 gw and reached adult levels at 32-33 gw. Rare intra-acinar nerves, restricted to periportal areas, appeared at 40 gw. Galanin-, somatostatin- and calcitonin-gene-related peptide-positive nerve fibers were noted only in portal tracts from 22, 26 and 32 gw, respectively. In human adult liver, dense portal and intra-acinar neural supply was observed. Human fetal liver contains a neural network distributed mainly in portal tracts with a density that increases progressively towards term. Intra-acinar innervation appears at term, suggesting that is not required for normal liver function during development, while peptidergic nerves are important for intrauterine liver functions. Developmentally regulated expression of galanin and somatostatin may play a role in liver morphogenesis.