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

Abstract

Molecular mechanisms of human ductal plate (DP) development and differentiation (DD) are unclear. The author immunohistochemically investigated expressions of cholangiocellular antigens (CEA, CA19-9, EMA, MUC1, MUC2, MUC5AC, MUC6, mucins, CK7, and CK19), hepatocellular antigens (HepPar1, AFP, CK8, and CK18), hepatic stellate/progenitor cell (HSC) antigens or stem cell (SC) antigens (C-erbB2, CD56, chromogranin, synaptophysin, bcl2, NSE, NCAM, KIT, and PDGFRA), and proliferating antigen (Ki67) in 32 human fetal livers (HFL). The DD of human intrahepatic bile duct (IBD) could be categorized into four stages: DP, remodeling DP, remodeled DP, and immature IBD. All the molecules examined were expressed in the DP and DP derivatives. These results suggest that human DP or DP derivatives have capacities to differentiate into cholangiocellular, hepatocellular, HSC, SC, and neuroendocrine lineages. The data also suggest that NCAM, KIT/SC factor-signaling, NSE, HGF/MET signaling, PDGFa/PDGFRA signaling, chromogranin, synaptophysin, and CD56 play important roles in DD of DP and biliary cells of HFL. DP, DP derivatives, and IBD in HFL have proliferative capacity.

Keywords: Human; development; differentiation; ductal plate; embryo; fetus.

Figure 1

The HE histologies of ductal plate and intrahepatic biliary cells in human fetal livers. (a) The ductal plate is composed of single or double-layered cylindrical structures located in the interface between hepatoblasts and mesenchyme of the portal tract (arrows: 8 gestational weeks (GW)). (b) The ductal plate is composed of single or double-layered cuboidal cells (arrows, 9 GW). (c) The remodeling ductal plate shows disappearance of some cells of the ductal plate and development of tubular structures of future bile ducts, which is moving into the portal mesenchyme. (c, arrows, 14 GW). (d) PAS-positive products are seen in the ductal plate (arrows, 9 GW). (e) Cytokeratin 18 is positive in hepatoblasts and ductal plate (arrows, 10 GW). (f) Cytokeratin 19 is seen mainly in the ducts but is also present faintly in periportal hepatocytes and ductal plate (arrows) HE stain. (a) HE, × 40. (b) HE, × 350. (c) HE, × 150. (d) PAS, × 200. (e) CK18, × 200. (f) CK7, × 200. (A color version of this figure is available in the online journal.)

Figure 2

(a) NCAM is always expressed in some cells of ductal plate (9 gestational weeks (GW)). (b) KIT expression is seen in some hepatoblasts and hematopoietic progenitor cells of the parenchyma (arrows, 12 GW). (c) The cells of ductal plate (arrows) are strongly positive for MET (9 GW). (d): The cells of remodeling ductal plate (arrows) indicated by arrows are strongly positive for PDGFRA (13 GW). The staining pattern is mostly membranous. (a, d) × 200. (b, c) × 400. (A color version of this figure is available in the online journal.)

Figure 3

MUC1 (a, 13 gestational weeks (GW)), CEA (b, 11 GW), CA19-9 (c, 12 GW), EMA (d, 10 GW), cytokeratin 7(e, 11 GW), and HepPar1 (f, 8 GW) are expressed in ductal plate. (a–f) × 200. HepPar1 is expressed in hepatoblasts ductal plate; however, HepPar1 is expressed weakly in cells of portal mesenchyme. The staining pattern is mostly cytoplasmic. (A color version of this figure is available in the online journal.)

Figure 4

Positive expression of ErbB-1 (a, 7 GW), bcl2 (b, 14 GW), NSE (c, 16 GW), CD56 (d, 11 GW), chromogranin A (e, 13 GW), and Ki67 (9 GW) in human ductal plate. a, b, d: × 200. c,d, f: × 350. The expression pattern was cytoplasmic with membranous accentuation. (A color version of this figure is available in the online journal.)