Immunohistochemical Analysis of LGR5 Expression in Pediatric Liver Disease

Abstract

BACKGROUNDIn regenerating liver, hepatic progenitor cells (HPCs) are recruited in response to liver injury; however, there is a lack of highly specific human HPC markers for the hepatocyte lineage. LGR5, a Wnt‐associated adult stem cell marker, has been extensively studied in intestinal stem cells. Although LGR5 appears to be exclusively expressed by HPCs in mice, little is known about its expression in human liver. We hypothesized that LGR5+ cells are induced in the regenerative response to liver injury to potentially rescue dysfunctional hepatocytes.METHODSUsing immunohistochemistry, we characterized LGR5 expression in pediatric liver diseases, using mainly liver explants (n=36 cases total).RESULTSWe found cytoplasmic LGR5 over‐expression in all 36 pediatric cases, including acute hepatic necrosis and cholestatic liver diseases. In 44% of cases, >50% of hepatocytes were LGR5+, signifying a robust regenerative response. In contrast, there was only weak staining in bile ducts, suggesting hepatocyte‐specific expression. Marked peri‐portal expression was prominent in cholestatic diseases, consistent with known patterns of regeneration. Comparison to other regeneration markers will further characterize this hepatocyte progenitor cell phenotype.CONCLUSIONSAlthough we observed some degree of regenerative response in all cases examined, LGR5 was highly expressed in cholestatic liver diseases, possibly due to alternate regeneration pathways. These studies are the first to support a unique role for LGR5 in human hepatocyte regeneration and as a potential predictive marker for recovery of liver function in children. LGR5 INTENSITY TOTAL CASES WEAK + 1+ 2+ 3+ A1AT Deficiency (ATD) 15 0 2 5 8 Biliary Atresia (BA) 5 0 0 2 3 PFIC 10 1 1 5 3 Acute Hepatic Necrosis (ALF) 6 1 4 1 0 TOTAL CASES 36 2 7 13 14 imageimage