Common antigen of oval and biliary epithelial cells (A6) is a differentiation marker of epithelial and erythroid cell lineages in early development of the mouse

Engelhardt, Natalia V.; Factor, Valentina M.; Medvinsky, Alexander L.; Баранов, В. Н.; Lazareva, M. N.; Полторанина, В. С.

doi:10.1111/j.1432-0436.1993.tb00029.x

Cited by 48 publications

(38 citation statements)

References 9 publications

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“…31,35 In accordance with these findings, we found the presence of ES cell-derived bile duct structures expressing A6 antigen, a marker of hepatic oval and biliary epithelial cells. 36 These data suggest that a population of ES cellderived GFP ϩ cells may contain bipotential hepatic precursors that can differentiate into both hepatocytes and bile duct-like cells.…”

Section: Discussionmentioning

confidence: 97%

Hepatic precursors derived from murine embryonic stem cells contribute to regeneration of injured liver

et al. 2006

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We established an efficient system for differentiation, expansion and isolation of hepatic progenitor cells from mouse embryonic stem (ES) cells and evaluated their capacity to repopulate injured liver. Using mouse ES cells transfected with the green fluorescent protein (GFP) reporter gene regulated by albumin (ALB) enhancer/promoter, we found that a serum-free chemically defined medium supports formation of embryoid bodies (EBs) and differentiation of hepatic lineage cells in the absence of exogenous growth factors or feeder cell layers. The first GFP ؉ cells expressing ALB were detected in close proximity to "beating" myocytes after 7 days of EB cultures. GFP ؉ cells increased in number, acquired hepatocyte-like morphology and hepatocytespecific markers (i.e., ALB, AAT, TO, and G6P), and by 28 days represented more than 30% of cells isolated from EB outgrowths. The FACS-purified GFP ؉ cells developed into functional hepatocytes without evidence of cell fusion and participated in the repairing of diseased liver when transplanted into MUP-uPA/SCID mice. The ES cell-derived hepatocytes were responsive to normal growth regulation and proliferated at the same rate as the host hepatocytes after an additional growth stimulus from CCl 4 -induced liver injury. The transplanted GFP ؉ cells also differentiated into biliary epithelial cells. In conclusion, a highly enriched population of committed hepatocyte precursors can be generated from ES cells in vitro for effective cell replacement therapy. Supplementary material for this article can be found on the HEPATOLOGY website H epatocyte transplantation is an effective treatment for liver failure and/or end-stage liver disease. However, the shortage of donor organs and the difficulties of cyropreservation and long-term culturing of mature hepatocytes have limited the clinical application of cell-based therapy. Recently, the use of embryonic stem (ES) cells has attracted considerable interest for cell replacement therapy because of their capacity to proliferate indefinitely in vitro while retaining the potential to differentiate into all types of cells including hepatocytes. [1][2][3][4][5] Clinical application of ES cells requires a simple and efficient protocol for directing their differentiation into a specific cell type. Several studies have reported the induction of ES cell differentiation into hepatocytes both in vitro 6-9 and in vivo. 10 The in vitro approaches involve the formation of embryoid bodies (EBs) to re-create the inductive microenvironment required for liver organogenesis 11,12 or treatment with specific growth factors and cytokines critical for hepatocyte differentiation such as hepatocyte growth factor, fibroblast growth factor, and oncostatin. 1,13 Also, the introduction of genes promoting endodermal differentiation into ES cells, 14 modification of culture microenvironment by supplementation with extracellular matrix proteins or coculture with other cell types, 15,16 is used to direct ES cells toward a hepatocytic lineage. Nevertheless, these strategie...

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Section: Discussionmentioning

confidence: 97%

Hepatic precursors derived from murine embryonic stem cells contribute to regeneration of injured liver

et al. 2006

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“…Engelhardt et al 4 and Factor and Radaeva 5 described a Dipin/PHx model, and Rosenberg et al 20 described a cocaine-induced liver injury model to activate the oval cell compartment. Although these models did produce a small oval cell response, the models were showing that these cells are negative for A6 staining as well.…”

Section: Discussionmentioning

confidence: 99%

“…In normal adult liver, A6 immunohistochemistry is reported to stain only ductal epithelial cells with no other cell type showing reactivity to the epitope. Based on their conclusions, A6 4 showed that the adult bone marrow and spleen contained few A6ϩ cells, but they did not define which cells were positive in either organ. So, it is possible to speculate that the HSCs are A6ϩ.…”

Section: Discussionmentioning

confidence: 99%

“…However, this unique population of cells appears to stain positive for the A6 antigen. A6 is a monoclonal antibody previously described by Engelhardt et al 4 and Factor and Radaeva 5 that is specific for biliary cells and proliferating oval cells. The limitation of using A6 as an identifier of oval cells is that the antibody is not commercially available, thereby making it difficult to obtain for everyday use and characterization.…”

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Mouse A6–positive hepatic oval cells also express several hematopoietic stem cell markers

et al. 2003

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Hepatic oval cells (HOC) are thought to be a type of facultative stem cell that arises as a result of certain forms of hepatic injury. A new and more efficient model has been established to activate the oval cell compartment in mice by incorporating 3,5-diethoxycarbonyl-1,4-dihydro-collidine (DDC) in a standard chow at a concentration of 0.1%. At the present time, very few markers exist for the mouse oval cells. One accepted marker is A6, an uncharacterized epitope recognized by mouse hepatic oval cells and it is accepted to be an oval cell marker. Sca-1 is a cell surface marker used to identify hematopoietic stem cells in conjunction with Thy-1؉, CD34؉, and lineage-specific markers. Both the CD34 and Sca-1 antigens are not normally expressed in adult liver, but are expressed in fetal liver, presumably on the hematopoietic cells. We report herein that mouse oval cells express high levels of Sca-1 and CD34, as well as CD45 surface proteins. Immunohistochemistry revealed that the cells expressing Sca-1/CD34/CD45 were indeed oval cells because they co-expressed the oval cell-specific marker A6 (94.57% ؎ 0.033%), as well as alpha-fetoprotein (AFP) (75.92% ؎ 0.071%). By using Sca-1 antibody in conjunction with magnetic activated cell sorting (MACS), followed with a flow cytometric cell sorting (FACS) method for CD34 and CD45, we have developed a rapid oval cell isolation protocol with high yields of greater than 90%. In conclusion, we have an efficient murine model for the production and isolation of large numbers of highly purified oval cells. Our system works with most strains of mouse, which will facilitate both in vivo and in vitro studies of mouse hepatic oval cells. ( T he majority of the information on hepatic oval cells (HOCs) is derived from a series of highly reproducible rat models developed over the years. Until recently, murine models for oval cell activation and proliferation have been complicated and arduous, producing low numbers of oval cells with varying results. This has greatly limited the usefulness of mice as a genetic system to study the mechanisms of oval cell activation and differentiation. To take advantage of the immense power of mouse genetics we sought to define a reproducible, strain-independent, high-yield model for murine oval cell proliferation and purification. Recently, a method was described that is reproducible and generates large numbers of murine oval cells based on morphology. The model used to activate the oval cell compartment in mice is a diet of 3,5-diethoxycarbonyl-1,4-dihydro-collidine (DDC) at a concentration of 0.1% in a standard rodent chow for 4 to 6 weeks. Morphologically, the mouse oval cells share many similarities to rat oval cells; they are small in size (approximately 10 m), with a large nucleus to cytoplasm ratio. They radiate from the periportal region forming primitive ductular structures with poorly defined lumen, like that observed in the various rat models. [1][2][3] We used this diet, combined with antibody-based oval cell isolation techniques, to produce...

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Development and differentiation of bile ducts in the mammalian liver

Shiojiri

1997

Microsc. Res. Tech.

131

101

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Common antigen of oval and biliary epithelial cells (A6) is a differentiation marker of epithelial and erythroid cell lineages in early development of the mouse

Cited by 48 publications

References 9 publications

Hepatic precursors derived from murine embryonic stem cells contribute to regeneration of injured liver

Hepatic precursors derived from murine embryonic stem cells contribute to regeneration of injured liver

Mouse A6–positive hepatic oval cells also express several hematopoietic stem cell markers

Development and differentiation of bile ducts in the mammalian liver

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