Expression of transforming growth factor-alpha and its receptor during human liver development and maturation

Abstract

We investigated the expression of transforming growth factor-alpha (TGF-alpha) and its receptor during human liver development and maturation, using immunohistochemistry. In the fetal liver, strong immunoreactivity for TGF-alpha and its receptor was noted in intrahepatic bile duct cells of various developmental stages; moderate immunoreactivity for TGF-alpha and mild immunoreactivity for TGF-alpha receptor were found in immature hepatocytes. In the postnatal liver, reactivity for TGF-alpha in hepatocytes decreased gradually and was negative or only weakly positive in the adult liver, while reactivity for TGF-alpha receptor in hepatocytes increased gradually and was strongly positive in the adult liver. In contrast, immunoreactivity of TGF-alpha and its receptor in intrahepatic bile duct cells persisted in the postnatal liver and was positive in the adult liver. These data suggest that the system of TGF-alpha and its receptor has an important role in the proliferation and differentiation of intrahepatic biliary cells and hepatocytes in the fetal liver. The decreasing expression of TGF-alpha in hepatocytes in the postnatal liver may indicate that proliferative activity of hepatocytes gradually decreases with liver maturation. The presence of TGF-alpha and its receptor in intrahepatic bile ducts in the postnatal liver suggests that the system of TGF-alpha and TGF-alpha receptor is operative postnatally.

Human ductal plate and its derivatives express antigens of cholangiocellular, hepatocellular, hepatic stellate/progenitor cell, stem cell, and neuroendocrine lineages, and proliferative antigens

“…This work of TGFa/TGFR signaling 16 was the first report of growth factor/receptor signaling in human liver development. In the present study, MET and PDGFRA were investigated in HFLs.…”

“…54 In humans, the author demonstrated that human DP cells have features of HSC, MUC apomucins-positive mucin producing epithelial cells, glandular epithelial cells, periportal hepatocytes, and growth factor/receptor signaling. These studies by demonstrated positive reactions for KIT, NCAM, hepatocyte paraffin 1, AFP, MUC apomucins, mucins histochemistry, CEA, CA19-9, MET, PDGFRA, TGF-a, 16 and MIB-1 in human IBD development including the DP. Thus, it is suggested that cells of human DP are HSC and have these phenotypes, and the DP may give rise to hepatocytes, mucin-producing epithelial cells, and glandular epithelial cells in addition to cholangiocytes.…”

“…The author proved that mesenchymal-DP or mesenchymal-IBD interactions are important to the normal development of DP and IBDs. 3,8,12,16 The author demonstrated that mesenchymal elements such as type IV collagen, laminin, tenascin, matrix proteinases, E-cadherin, catenins, and apoptosis-related proteins were present in portal mesenchyme of HFL and that these molecules may induce transformation of neighboring hepatoblasts into the DP in HFL. 3,4,8,12,16 The strong expression of MET in the DP and IBDs just adjacent to the portal mesemchyme in HFL also suggest that HGF may be produced by the portal mesenchyma and directly act the neighboring DP and IBDs.…”

“…The author has already proved that transforming growth factor-a and its receptor (TGFa/TGFR signaling) may play an important role during human liver development and maturation, 16 prior to the present work. This work of TGFa/TGFR signaling 16 was the first report of growth factor/receptor signaling in human liver development.…”

“…1,5,6 The author demonstrated that the process of normal DD of human fetal IBD involves many molecular mechanisms including apoptosis, apoptosis-related proteins, DP cell proliferation, pancreatic digestive enzymes, such as aamylase, trypsinogen, and lipase, some proteinases including matrix metalloproteinases and tissue inhibitors of matrix metalloproteinases, peribiliary vascular plexus, carbohydrate structures of many glycoproteins, mucin core antigen (MUC) apomucin expression, expression of cytokeratin (CK), E-cadherin-catenin systems, doublestranded RNA-activated protein kinase, midkine, truncated midkine, type IV collagen, laminin, tenascin, trypsin, chymotrypsin, transforming growth factor-a and its receptor, and pancreatic amylase mRNA. [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17] The developmental failures of these human fetal IBD or DP give rise to the persistence of biliary structures in postnatal human livers. Such structures are called DP malformations (DPM) or hepatobiliary fibropolycystic disease, which involves congenital hepatic fibrosis, polycystic diseases (adult and infantile) of the liver and kidneys, congenital biliary atresia, von-Meyenburg complex, and Caroli's disease.…”