Triple Staining Including FOXA2 Identifies Stem Cell Lineages Undergoing Hepatic and Biliary Differentiation in Cirrhotic Human Liver

Charles E. Rogler, Remon Bebawee, Joe Matarlo, Joseph Locker, Nicole Pattamanuch, Sanjeev Gupta, Leslie E. Rogler

Research output: Contribution to journalArticle

2 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)33-46
Number of pages14
JournalJournal of Histochemistry and Cytochemistry
Volume65
Issue number1
DOIs
StatePublished - Jan 1 2017

Keywords

  • CK19
  • FOXA2
  • HepPar1
  • bile duct differentiation
  • hepatic differentiation
  • immunohistochemical stain
  • liver cirrhosis and fibrosis
  • oval cells
  • stem cell niche
  • stem/progenitor cells

ASJC Scopus subject areas

  • Anatomy
  • Histology

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