A CD133 Expressing Murine Liver Oval Cell Population with Bi-lineage Potential

¹ Division of Gastroenterology, Hepatology, and Nutrition; Childrens Hospital Los Angeles, Los Angeles, California, USA; Division of Gastroenterology, Hepatology, and Nutrition; Penn State College of Medicine, Hershey, Pennsylvania, USA; Gene, Immunology, and Stem Cell Program; Childrens Hospital Los Angeles, Los Angeles, California, USA
² Gene, Immunology, and Stem Cell Program; Division of Research Immunology, BMT; Childrens Hospital Los Angeles, Los Angeles, California, USA

^* To whom correspondence should be addressed. E-mail: brountree717{at}yahoo.com.

	Abstract

Although oval cells (OCs) 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 non-parenchymal, non-hematopoietic (CD45-) cells were characterized. Cell populations were isolated by flow cytometry for gene expression studies. 3,5-diethoxycarbonyl-1, 4-dihydro-collidine (DDC) 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 co-expressed both hepatocyte and cholangiocyte associated genes, indicating bi-lineage potential. CD133+CD45- cells proliferated in response to liver injury. Following toxic hepatocyte damage, CD133+CD45- cells demonstrated up-regulated 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, bi-potent liver stem cells. In response to lineage specific injury, these cells demonstrate a lineage appropriate genetic response.

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