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TISSUE-SPECIFIC STEM CELLS |
aDivision of Gastroenterology, Hepatology, and Nutrition, Childrens Hospital Los Angeles, Los Angeles, California, USA;
bDivision of Gastroenterology, Hepatology, and Nutrition, Penn State College of Medicine, Hershey, Pennsylvania, USA;
cGene, Immunology, and Stem Cell Program, and
dDivision of Research Immunology, Bone Marrow Transplant, Childrens Hospital Los Angeles, Los Angeles, California, USA
Key Words. CD133 • Oval cells • Adult stem cells • Cell surface markers • Fluorescence-activated cell sorting analysis Hepatic stem cells • Liver regeneration
Correspondence: C. Bart Rountree, M.D., Pediatric Gasteroenterology, Hepatology, and Nutrition, MCH 085, H7508, 500 University Drive, Hershey, Pennsylvania 17033, USA. Telephone: 717-531-0653; Fax: 717-531-5901; e-mail: brountree717{at}yahoo.com
Received on March 13, 2007;
accepted for publication on May 29, 2007.
First published online in STEM CELLS EXPRESS June 21, 2007.
Although oval cells are postulated to be adult liver stem cells, a well-defined phenotype of a bipotent liver stem cell remains elusive. The heterogeneity of cells within the oval cell fraction has hindered lineage potential studies. Our goal was to identify an enriched population of bipotent oval cells using a combination of flow cytometry and single cell gene expression in conjunction with lineage-specific liver injury models. Expression of cell surface markers on nonparenchymal, nonhematopoietic (CD45–) cells were characterized. Cell populations were isolated by flow cytometry for gene expression studies. 3,5-Diethoxycarbonyl-1,4-dihydrocollidine toxic injury induced cell cycling and expansion specifically in the subpopulation of oval cells in the periportal zone that express CD133. CD133+CD45– cells expressed hepatoblast and stem cell-associated genes, and single cells coexpressed both hepatocyte and cholangiocyte-associated genes, indicating bilineage potential. CD133+CD45– cells proliferated in response to liver injury. Following toxic hepatocyte damage, CD133+CD45– cells demonstrated upregulated expression of the hepatocyte gene Albumin. In contrast, toxic cholangiocyte injury resulted in upregulation of the cholangiocyte gene Ck19. After 21–28 days in culture, CD133+CD45– cells continued to generate cells of both hepatocyte and cholangiocyte lineages. Thus, CD133 expression identifies a population of oval cells in adult murine liver with the gene expression profile and function of primitive, bipotent liver stem cells. In response to lineage-specific injury, these cells demonstrate a lineage-appropriate genetic response. Disclosure of potential conflicts of interest is found at the end of this article.
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