title: Immunohistochemical Analysis of the Stem Cell Marker LGR5 in Pediatric Liver Disease.
abstract: Aims In regenerating liver, hepatic progenitor cells (HPCs) are recruited in response to injury; however, few highly specific human HPC markers exist for the hepatocyte lineage. Leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5), a Wnt-associated stem cell marker, has been extensively studied in intestinal stem cells, but little is known about its expression in human liver. We hypothesized that LGR5+ HPCs are induced in the regenerative response to pediatric liver injury. Methods and results Immunohistochemistry was used to characterize LGR5 expression in pediatric liver explants (n = 36). We found cytoplasmic LGR5 expression in all cases; although, much less was observed in acute hepatic necrosis compared to chronic liver diseases. In the latter cases, >50% of hepatocytes were LGR5+, signifying a robust regenerative response mainly in the periphery of regenerative nodules. Only weak LGR5 staining was noted in bile ducts, suggesting hepatocyte-specific expression at the interface. Conclusions Although we observed some degree of regenerative response in all cases, LGR5 was highly expressed in chronic liver disease, possibly due to alternate regeneration and reprogramming pathways. LGR5 is predominant in peri-septal hepatocytes rather than epithelial cell adhesion molecule (EpCAM) positive ductular reactions in chronic pediatric liver diseases and may represent a transitional HPC phenotype for the hepatocyte lineage. These studies are the first to support a unique role for LGR5 in human hepatocyte regeneration and as a potential predictive biomarker for recovery of liver function in children. Future work will also investigate the molecular mechanisms behind LGR5 expression.
authors.affiliation: 1 Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania, USA.|2 McGowan Institute for Regenerative Medicine, Pittsburgh, Pennsylvania, USA.|3 Department of Pathology, Pittsburgh Liver Research Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
authors.forename: Zahida
authors.initials: Z
authors.lastname: Khan
authors.affiliation: 3 Department of Pathology, Pittsburgh Liver Research Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
authors.forename: Anne
authors.initials: A
authors.lastname: Orr
authors.affiliation: 2 McGowan Institute for Regenerative Medicine, Pittsburgh, Pennsylvania, USA.|3 Department of Pathology, Pittsburgh Liver Research Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
authors.forename: George K
authors.initials: GK
authors.lastname: Michalopoulos
authors.affiliation: 3 Department of Pathology, Pittsburgh Liver Research Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.|4 Department of Pathology, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania, USA.
authors.forename: Sarangarajan
authors.initials: S
authors.lastname: Ranganathan
mesh_terms: D000208:Acute Disease; D015415:Biomarkers / Q000378:metabolism; D002648:Child; D002908:Chronic Disease; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008107:Liver Diseases / Q000378:metabolism* / Q000473:pathology; D008115:Liver Regeneration / Q000502:physiology*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*
chemical_list: D015415:Biomarkers; C116884:LGR5 protein, human; D043562:Receptors, G-Protein-Coupled
keywords: alpha-1 antitrypsin deficiency; biliary atresia; hepatic progenitor cell; progressive familial intrahepatic cholestasis; reprogramming; transdifferentiation