Adult Mouse Liver Contains Two Distinct Populations of Cholangiocytes

Abstract

Summary: The biliary system plays an important role in several acquired and genetic disorders of the liver. We have previously shown that biliary duct epithelium contains cells giving rise to proliferative Lgr5+ organoids in vitro. However, it remained unknown whether all biliary cells or only a specific subset had this clonogenic activity. The cell surface protease ST14 was identified as a positive marker for the clonogenic subset of cholangiocytes and was used to separate clonogenic and non-clonogenic duct cells by fluorescence-activated cell sorting. Only ST14hi duct cells had the ability to generate organoids that could be serially passaged. The gene expression profiles of clonogenic and non-clonogenic duct cells were similar, but several hundred genes were differentially expressed. RNA fluorescence in situ hybridization showed that clonogenic duct cells are interspersed among regular biliary epithelium at a ∼1:3 ratio. We conclude that adult murine cholangiocytes can be subdivided into two populations differing in their proliferative capacity. : In this article, Grompe and colleagues show that the cholangiocyte compartment of adult liver is heterogeneous. Their work shows conclusively that they differ in their clonogenic potential in the “Clevers” organoid assay and that they have a distinct gene expression profile. Keywords: bile duct, biliary tree, liver, progenitor, cholangiocyte, liver regeneration, organoid, clonogenic assay