Immunolocalization of OV-6, a putative progenitor cell marker in human fetal and diseased pediatric liver

Abstract

The existence of progenitor (stem) cells in the human liver remains a matter of debate. In rodent models of hepatocarcinogenesis and injury, oval cells proliferate in the periportal regions of the portal tracts and are suggested to derive from a stem cell compartment, because they are capable of differentiating into hepatocytes or biliary epithelial cells. In this study, the rat oval cell marker, OV-6 has been used to investigate the hypothesis that there are stem cells present in fetal and pediatric human liver. The pattern of OV-6 expression was compared with the established adult biliary cell markers human epithelial antigen-125 (HEA-125) and cytokeratin-19 (CK-19). In normal pediatric liver (n ‫؍‬ 7), bile ducts and ductules were immunostained with CK-19 and HEA-125, whereas OV-6 staining was consistently negative. In fetal tissue (n ‫؍‬ 10), ductal plate cells, primitive bile ducts, and hepatoblasts were stained with CK-19 and HEA-125 although only some of the ductal plate cells and hepatoblasts were OV-6 positive. In biliary atresia (n ‫؍‬ 6) and ␣1, anti-trypsin deficiency (␣1,AT) (n ‫؍‬ 4), CK-19 and HEA-125 immunostained ductular proliferative cells that tended to form finely anastomosing ductules, whereas OV-6 staining was found more on discrete cells confined to portal tract margins. Additionally, in diseased liver, OV-6 was strongly positive in hepatocyte lobules with greatest intensity in the periseptal regions. This widespread hepatocyte OV-6 positivity suggests that the antibody may identify cells of a less differentiated phenotype (transitional hepatocytes) that have replaced the mature cells. Therefore, it is proposed that in human liver, OV-6 is recognizing cells with a progenitor stem cell-like phenotype with the capacity to differentiate into OV-6 positive ductular cells or lobular hepatocytes. (HEPATOLOGY 1998;28:980-985.)Human liver organogenesis begins during the third or fourth week of gestation from endodermal cells lining the foregut. These endodermal cells give rise to hepatic cords representing liver progenitor cells (hepatoblasts), which are able to differentiate along biliary or hepatocyte lineages. 1

Two pathologic types of hepatocellular carcinoma with lymph node metastasis with distinct prognosis on the basis of CK19 expression in tumor

“…Despite that OV-6 was positive in some bile duct cells that always shared immunoreactivity for CK19 in cirrhotic liver, OV-6 was regarded as a specific marker of liver progenitor cells that have the capacity to differentiate into either hepatocytes or biliary cells. 8,[17][18][19][20][21] Moreover, increasing evidence indicated that HCC with ICC differentiation was derived from a hepatic progenitor cell. 4,17,20 During its neoplastic transformation the progenitor cell marker (OV-6) and biliary marker (CK19) could partially be retained in HCC cells, 6 which resemble hepatic progenitor cells with coexpression of CK19 and OV-6, 22 and was consistent with the present study.…”

“…8,[17][18][19][20][21] Moreover, increasing evidence indicated that HCC with ICC differentiation was derived from a hepatic progenitor cell. 4,17,20 During its neoplastic transformation the progenitor cell marker (OV-6) and biliary marker (CK19) could partially be retained in HCC cells, 6 which resemble hepatic progenitor cells with coexpression of CK19 and OV-6, 22 and was consistent with the present study. Therefore, CK19(1) HCC represents a distinct type of HCC with ICC-like differentiation with an increased risk for developing LNM.…”

Oval cell‐mediated liver regeneration: Role of cytokines and growth factors

“…52 Evidently, this situation also occurs in humans, as elevated levels of serum HGF are present in individuals with chronic hepatitis and cirrhosis, [55][56][57] both conditions in which oval cell proliferation is well documented. 7,18,38,40,58,59 In situ hybridization has revealed that oval cells and basophilic hepatocytes, in addition to hepatic stellate cells, express aFGF transcripts. 60 A marked increase in hepatic aFGF levels has been reported at the peak of oval cell proliferation in the 2-AAF/PH model, and levels greatly exceeded those observed after PH alone, suggesting a more prominent role for aFGF in oval cellmediated regeneration.…”

Persistent Elevation of Hepatocyte Growth Factor Activator Inhibitors in Cholangiopathies Affects Liver Fibrosis and Differentiation

“…They were further divided into two groups retrospectively according to the clinical features at the end of 12-month follow-up after the Kasai operation: three patients (patients 6-8) who were jaundice free and with good bile flow (BA1) and six patients (patients 9-14) who had jaundice and finally underwent liver transplantation (BA2). In addition, liver tissues were also obtained from six children (Supporting Table 1, patients [15][16][17][18][19][20] with advanced-stage BA at the time of liver transplantation (LT). Near-normal liver tissues were the nontumor parts of surgically removed liver tissues from two patients with colon cancer metastasized to the liver.…”

“…15 Striking similarities have been reported between proliferative bile ductules and developing bile ducts in human fetus. 16 Because there are increased numbers of both proliferating ductular cells and newly regenerating hepatocytes in BA livers, 17 it has been suggested that both types of cells may differentiate from HSCs activated in BA livers. 17 Based on these observations, here we explored the mechanisms controlling the activation and differentiation of cells in ductular reactions and their possible relationship to HAI-1 and -2-related ECM remodeling and fibrosis progression in livers with BA or other cholangiopathies.…”