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TISSUE-SPECIFIC STEM CELLS

Long-Term Culture of Postnatal Mouse Hepatic Stem/Progenitor Cells and Their Relative Developmental Hierarchy

^aDepartment of Pediatrics, Graduate School of Medicine, Kyoto University, Kyoto, Japan;
^bDivision of Gastroenterology and Hepatology, Graduate School of Medical and Dental Science, Niigata University, Niigata, Japan;
^cDepartment of Gastroenterology, Juntendo University School of Medicine, Izunokuni, Japan

Key Words. Side population cells • Sca-1+ cells • Serum-free medium • Long-term culture Fluorescence-activated cell sorting analysis • Hepatic stem cells

Correspondence: Tatsutoshi Nakahata, M.D., Department of Pediatrics, Graduate School of Medicine, Kyoto University, 54 Kawara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan. Telephone: +81-75-751-3290; Fax: +81-75-752-2361; e-mail: tnakaha{at}kuhp.kyoto-u.ac.jp

Received September 3, 2006; accepted for publication December 27, 2006.
First published online in STEM CELLS EXPRESS   January 11, 2007.



Few studies on the long-term culture of postnatal mouse hepatic stem/progenitor cells have been reported. We successfully adapted a serum-free culture system that we employed previously to expand fetal mouse hepatic stem/progenitor cells and maintained them in culture over long periods. The expanded postnatal cells contained immature -fetoprotein-positive cells along with hepatocytic and cholangiocytic lineage-committed cells. These cells expressed CD49f but not CD45, CD34, Thy-1, c-kit, CD31, or flk-1, and oncostatin M induced their differentiation. This heterogeneous population contained side population (SP) cells, which express the ATP-binding cassette transporter ABCG2, and sca-1+ cells. As mice aged, the frequency of SP and sca-1+ cells decreased along with the ability of cultured cells to expand. Approximately 20%–40% of the SP cells expressed sca-1, but only a few sca-1+ cells were also SP cells. Analysis of colonies derived from single SP or sca-1+ cells revealed that, although both cells had dual differentiation potential and self-renewal ability, SP cells formed colonies more efficiently and gave rise to SP and sca-1+ cells, whereas sca-1+ cells generated only sca-1+ progeny. Thus, SP cells are more characteristic of stem cells than are sca-1+ cells. In regenerating livers, ABCG2+ cells and sca-1+ cells were detected around or in the portal area (the putative hepatic stem cell niche). The expanded cells share many features of fetal hepatic stem/progenitor cells or oval cells and may be useful in determining the mechanisms whereby hepatic stem cells self-renew and differentiate.

Disclosure of potential conflicts of interest is found at the end of this article.