The hepatic stem cell niche: Identification by label-retaining cell assay

TLDR

Label retention assays are the gold standard for locating intraorgan epithelial stem cell niches in situ and in vivo, yet they have not been applied to the liver because of its slow cell turnover. We labeled potential hepatic stem cells by giving mice a sublethal dose of acetaminophen with bromodeoxyuridine, then administered a second sublethal acetaminophen chase to wash out label from transit‑amplifying cells. Four hepatic stem cell niches were identified—the canal of Hering, intralobular bile ducts, periductal “null” mononuclear cells, and peribiliary hepatocytes—demonstrating that liver regeneration is governed by a multi‑tiered, flexible system rather than a single stem cell location.

Abstract

Label retention assays remain the state-of-the-art approach to identify the location of intraorgan epithelial stem cell niches, in situ and in vivo . They are commonly used in organs with rapid cell turnover but have not been applied to the liver, where cell turnover is very slow. We used a sublethal dose of acetaminophen administered coincident with bromodeoxyuridine to load possible hepatic stem cells in mice with label and then administered a second, sublethal chase of acetaminophen to accomplish “washout” of label from transit amplifying cell populations. Conclusion: Four possible hepatic stem cell niches are identified by this approach: the canal of Hering (proximal biliary tree), intralobular bile ducts, periductal “null” mononuclear cells, and peribiliary hepatocytes. These results confirm several different and often contradictory lines of investigation regarding the intrahepatic location of stem/progenitor cells and suggest that the liver has a multi-tiered, flexible system of regeneration rather than a single stem/progenitor cell location.