Neighbor of Punc E 11: Expression Pattern of the New Hepatic Stem/Progenitor Cell Marker During Murine Liver Development

Abstract

We have previously identified Neighbor of Punc E 11 (Nope) as a specific cell surface marker of stem/progenitor cells in the murine fetal liver that is also expressed in hepatocellular carcinoma. Here, we focus on the differential expression pattern of Nope during murine fetal and postnatal liver development as well as in a normal and regenerating adult liver including oval cell activation. In the fetal liver, Nope shows a constantly high expression level and is a useful surface marker for the identification of Dlk, E-cadherin, and CD133-positive hepatoblasts by flow cytometry. Postnatally, Nope expression declines rapidly and remains barely detectable in the adult liver as shown by quantitative real-time reverse-transcriptase polymerase chain reaction and western blot analyses. Immunohistochemically, costainings for Nope- and epithelial-specific markers (E-cadherin), markers of early hepatoblasts (alpha-fetoprotein), and biliary marker proteins (CK19) demonstrate that Nope is initially expressed on bipotent hepatoblasts and persists thereafter on commited hepatocytic as well as cholangiocytic progenitor cells during late fetal liver development. Postnatally, Nope loses its circular expression pattern and is specifically directed to the sinusoidal membrane of early hepatocytes. While Nope is only weakly expressed on cholangiocytes in the normal adult liver, activated stem/progenitor (oval) cells clearly coexpress Nope together with the common markers A6, EpCAM, and CD24 in the 3,5-diethoxycarbonyl-1,4-dihydrocollidine mouse model. In conclusion, Nope should be most useful in future research to define the differentiation stage of hepatic-specified cells of various sources and is a promising candidate to identify and isolate hepatic stem cells from the adult liver.

IMP2/p62 induces genomic instability and an aggressive hepatocellular carcinoma phenotype

“… 10 , 13 Another gene of the same imprinted gene cluster, 12 DLK1 , represents a marker of hepatic stem cells. 15 DLK1 was significantly overexpressed and its promoter was hypomethylated in human tumor tissue compared with normal samples ( P =1.3e −7 ; Figure 1a and b ) and strongly correlated with IMP2 ( R 2 =0.548; P <2.2e −16 ) and AFP ( R 2 =0.535; P <2.2e −16 ).…”

“…Interestingly, we observed a correlation of IMP2 expression with the oval/stem cell marker DLK1 . 15 DLK1 was previously shown to correspond with poor survival in HCC. 34 Oval cells share phenotypic markers with embryonic hepatoblasts, in which DLK1 is also highly expressed.…”

Expansion of prominin-1-expressing cells in association with fibrosis of biliary atresia

“…During the early stages of hepatogenesis, PROM1 pos progenitor cells are more abundant than shortly after birth, indicating either cellular attrition or loss of PROM1 expression . Within 2 weeks after RRV challenge, there is a clear reemergence of PROM1 pos cells.…”

The Progress and Prospects of Putative Biomarkers for Liver Cancer Stem Cells in Hepatocellular Carcinoma

“…By quantitative real-time RT-PCR and Western blot analyses, Nope expression declined rapidly and remained barely detectable in the adult liver postnatally. Using immunohistochemical costainings for Nope- and epithelial-specific markers (E-cadherin), early hepatoblasts markers (AFP) and biliary marker proteins (CK19) revealed that Nope was initially expressed on bipotent hepatoblasts and persisted thereafter on committed hepatocytic as well as cholangiocytic progenitor cells during late fetal liver development [105]. The results indicate that Nope is a promising candidate to identify and isolate LCSCs from the adult liver.…”