Human and Rat Hepatic Stellate Cells Express Neurotrophins and Neurotrophin Receptors

The expression of neurotrophins and neurotrophin receptors in non–neural tissue is related to tissue remodeling, differentiation, proliferation and migration of target cells. The literature yields contradictory results on neurotrophin and neurotrophin receptor expression in the liver. We show immunoreactivity to antibodies to nerve growth factor (NGF), brain–derived neurotrophin (BDNF), neurotrophin 3 (NT–3), neurotrophin 4/5 (NT–4/5), the low–affinity nerve growth factor receptor p75 and the high–affinity tyrosine kinase receptors (Trk) B and C in hepatic stellate cells and weak reactivity for BDNF, NT–3, and NT–4/5 in hepatocytes, in cryosections of human and rat liver, in normal and varying pathologic conditions. Immunoreactivity is unequivocally localized to hepatic stellate cells by double staining with α–smooth muscle actin (α–SMA) and desmin, studied by confocal laser scanning microscopy. Finally, the presence of mRNA transcripts for the different neurotrophins and neurotrophin receptors, with the exception of Trk–B, is shown by reverse transcription polymerase chain reaction (RT–PCR) on RNA extracted from freshly isolated rat hepatic stellate cells, compared with hepatocyte RNA. Hepatocyte RNA was found to contain BDNF, NT–3, NT–4/5 mRNA (which is compatible with the immunohistochemical findings) and Trk–A mRNA. In conclusion, hepatic stellate cells are a source of several neurotrophins in the liver and they express neurotrophin receptors. These findings correspond with the known involvement of hepatic stellate cells in tissue remodeling, their production of extracellular matrix components and their proliferation in acute necrotizing liver pathology. In analogy with findings in other organs and systems, neurotrophins are hypothesized to play a role in the pathophysiology of liver disease.