The hepatic stem cell niche: Identification by... : Hepatology (original) (raw)

Liver Injury/Regeneration

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

Kuwahara, Reiichiro1; Kofman, Alexander V.1; Landis, Charles S.2; Swenson, Scott E.3; Barendswaard, Els1; Theise, Neil D.1,4*

1_Department of Medicine, Division of Digestive Diseases, Beth Israel Medical Center—Albert Einstein College of Medicine, New York, NY_

2_Department of Medicine, Albert Einstein College of Medicine, Bronx, NY_

3_Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT_

4_Department of Pathology, Beth Israel Medical Center, Albert Einstein College of Medicine, New York, NY_

*Address reprint requests to: Division of Digestive Diseases, Beth Israel Medical Center, First Avenue at 16th Street, New York NY 10003

Email:[email protected]

Received 8 November 2007; Accepted 7 January 2008

Published online in Wiley InterScience (www.interscience.wiley.com).

Grant sponsor: National Institutes of Health; Grant Number: R01 DK58559; Grant sponsor: John J. Gerard Foundation.

Potential conflict of interest: Nothing to report.

These authors contributed equally to this work.

fax: 212-420-4373.

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.

Abbreviations: APAP, acetaminophen (N-acetyl-p-aminophenol); BrdU, 5-bromo-2′-deoxyuridine; CoH, Canal of Hering; HSPC, hepatic stem/progenitor cells; LRC, label-retaining cell; OVc, oval cells; panK, pan-keratin; PBS, phosphate-buffered saline.