title: Triple Staining Including FOXA2 Identifies Stem Cell Lineages Undergoing Hepatic and Biliary Differentiation in Cirrhotic Human Liver.
abstract: Recent investigations have reported many markers associated with human liver stem/progenitor cells, "oval cells," and identified "niches" in diseased livers where stem cells occur. However, there has remained a need to identify entire lineages of stem cells as they differentiate into bile ducts or hepatocytes. We have used combined immunohistochemical staining for a marker of hepatic commitment and specification (FOXA2 [Forkhead box A2]), hepatocyte maturation (Albumin and HepPar1), and features of bile ducts (CK19 [cytokeratin 19]) to identify lineages of stem cells differentiating toward the hepatocytic or bile ductular compartments of end-stage cirrhotic human liver. We identified large clusters of disorganized, FOXA2 expressing, oval cells in localized liver regions surrounded by fibrotic matrix, designated as "micro-niches." Specific FOXA2-positive cells within the micro-niches organize into primitive duct structures that support both hepatocytic and bile ductular differentiation enabling identification of entire lineages of cells forming the two types of structures. We also detected expression of hsa-miR-122 in primitive ductular reactions expected for hepatocytic differentiation and hsa-miR-23b cluster expression that drives liver cell fate decisions in cells undergoing lineage commitment. Our data establish the foundation for a mechanistic hypothesis on how stem cell lineages progress in specialized micro-niches in cirrhotic end-stage liver disease.
authors.affiliation: Marion Bessin Liver Research Center, Division of Gastroenterology and Liver Disease, Departments of Medicine (CER, RB, JM, NP, SG, LER), Albert Einstein College of Medicine, Bronx, New York.|Departments of Genetics (CER), Albert Einstein College of Medicine, Bronx, New York.|Departments of Microbiology and Immunology (CER), Albert Einstein College of Medicine, Bronx, New York.
authors.forename: Charles E
authors.initials: CE
authors.lastname: Rogler
authors.affiliation: Marion Bessin Liver Research Center, Division of Gastroenterology and Liver Disease, Departments of Medicine (CER, RB, JM, NP, SG, LER), Albert Einstein College of Medicine, Bronx, New York.
authors.forename: Remon
authors.initials: R
authors.lastname: Bebawee
authors.affiliation: Marion Bessin Liver Research Center, Division of Gastroenterology and Liver Disease, Departments of Medicine (CER, RB, JM, NP, SG, LER), Albert Einstein College of Medicine, Bronx, New York.
authors.forename: Joe
authors.initials: J
authors.lastname: Matarlo
authors.affiliation: Division of Molecular Anatomic Pathology, Department of Pathology, University of Pittsburg, Pittsburg, Pennsylvania (JL).
authors.forename: Joseph
authors.initials: J
authors.lastname: Locker
authors.affiliation: Marion Bessin Liver Research Center, Division of Gastroenterology and Liver Disease, Departments of Medicine (CER, RB, JM, NP, SG, LER), Albert Einstein College of Medicine, Bronx, New York.|Montefiore Medical Center, Bronx, New York (NP).
authors.forename: Nicole
authors.initials: N
authors.lastname: Pattamanuch
authors.affiliation: Marion Bessin Liver Research Center, Division of Gastroenterology and Liver Disease, Departments of Medicine (CER, RB, JM, NP, SG, LER), Albert Einstein College of Medicine, Bronx, New York.|Departments of Pathology (SG), Albert Einstein College of Medicine, Bronx, New York.
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Gupta
authors.affiliation: Marion Bessin Liver Research Center, Division of Gastroenterology and Liver Disease, Departments of Medicine (CER, RB, JM, NP, SG, LER), Albert Einstein College of Medicine, Bronx, New York.
authors.forename: Leslie E
authors.initials: LE
authors.lastname: Rogler
mesh_terms: D000328:Adult; D000368:Aged; D001652:Bile Ducts / Q000166:cytology / Q000473:pathology*; D002454:Cell Differentiation; D019070:Cell Lineage; D005260:Female; D051542:Hepatocyte Nuclear Factor 3-beta / Q000032:analysis*; D022781:Hepatocytes / Q000166:cytology / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods*; D007223:Infant; D053539:Keratin-19 / Q000032:analysis; D008099:Liver / Q000166:cytology / Q000473:pathology*; D008297:Male; D013194:Staining and Labeling / Q000379:methods; D013234:Stem Cells / Q000166:cytology / Q000473:pathology*
chemical_list: C496502:FOXA2 protein, human; D053539:Keratin-19; D051542:Hepatocyte Nuclear Factor 3-beta
keywords: CK19; FOXA2; HepPar1; bile duct differentiation; hepatic differentiation; immunohistochemical stain; liver cirrhosis and fibrosis; oval cells; stem cell niche; stem/progenitor cells