Potential hepatic stem cells reside in EpCAM+ cells of normal and injured mouse liver.
Hepatic oval cells are considered to be facultative hepatic stem cells (HSCs) that differentiate into hepatocytes and cholangiocytes in severely injured liver. Hepatic oval cells have also been implicated in tumorigenesis. However, their nature and origin remain elusive. To isolate and characterize mouse oval cells, we searched for cell surface molecules expressed on oval cells and analyzed their nature at the single-cell level by flow cytometric analysis and in the in vitro colony formation assay. We demonstrate that epithelial cell adhesion molecule (EpCAM) is expressed in both mouse normal cholangiocytes and oval cells, whereas its related protein, TROP2, is expressed exclusively in oval cells, establishing TROP2 as a novel marker to distinguish oval cells from normal cholangiocytes. EpCAM(+) cells isolated from injured liver proliferate to form colonies in vitro, and the clonally expanded cells differentiate into hepatocytes and cholangiocytes, suggesting that the oval cell fraction contains potential HSCs. Interestingly, such cells with HSC characteristics exist among EpCAM(+) cells of normal liver. Intriguingly, comparison of the colony formation of EpCAM(+) cells in normal and injured liver reveals little difference in the number of potential HSCs, strongly suggesting that most proliferating mouse oval cells represent transit-amplifying cells rather than HSCs.
Laboratory of Cell Growth and Differentiation, Institute of Molecular and Cellular Biosciences, The University of Tokyo, Tokyo 113-0032, Japan.
Mayuko
M
Okabe
Yuko
Y
Tsukahara
Minoru
M
Tanaka
Kaori
K
Suzuki
Shigeru
S
Saito
Yoshiko
Y
Kamiya
Tohru
T
Tsujimura
Koji
K
Nakamura
Atsushi
A
Miyajima
D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism; D000951:Antigens, Neoplasm / Q000378:metabolism*; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D000071858:Epithelial Cell Adhesion Molecule; D022781:Hepatocytes / Q000166:cytology* / Q000378:metabolism; D008099:Liver / Q000166:cytology* / Q000293:injuries* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D011506:Proteins / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism
D000943:Antigens, Differentiation; D000951:Antigens, Neoplasm; D015815:Cell Adhesion Molecules; D000071858:Epithelial Cell Adhesion Molecule; D011506:Proteins; C544766:TROP2 protein, mouse