Hepatic Oval Cells Have the Side Population Phenotype Defined by Expression of ATP-Binding Cassette Transporter ABCG2/BCRP1

Shimano, Koichi; Satake, Makoto; Okaya, Atsuhito; Kitanaka, Junichi; Kitanaka, Nobue; Takemura, Masashi; Sakagami, Masafumi; Terada, Nobuyuki; Tsujimura, Tohru

doi:10.1016/s0002-9440(10)63624-3

Cited by 185 publications

(135 citation statements)

References 22 publications

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“…27 The high proliferation potential and low apoptotic activity of purified differentiated cells could also be associated with a transdifferentiation program when cells were seeded at low density, leading to disruption of cell-cell communications. Cells transdifferentiated through a bipotent progenitor characterized by major oval-like cell markers expression such as CK19, CK18, ␥GT, ABCG2/ BRCP1, 28 NCAM, 29 Thy1, CD34, Flt-3, and at a weaker level c-Kit. [30][31][32] In addition, they expressed various receptors, adhesion molecules, lymphoid and myeloid markers, and exhibited nuclear accumulation of ␤-catenin.…”

Section: Discussionmentioning

confidence: 99%

Transdifferentiation of hepatocyte‐like cells from the human hepatoma HepaRG cell line through bipotent progenitor†

et al. 2007

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Hepatic tumors, exhibiting mature hepatocytes and undifferentiated cells merging with cholangiocyte and hepatocyte phenotypes, are frequently described. The mechanisms by which they occur remain unclear. We report differentiation and transdifferentiation behaviors of human HepaRG cells isolated from a differentiated tumor developed consecutively to chronic HCV infection. We demonstrate that, in vitro, proliferating HepaRG cells differentiate toward hepatocyte-like and biliary-like cells at confluence. If hepatocyte-like cells are selectively isolated and cultured at high cell density, they proliferate and preserve their differentiation status. However, when plated at low density, they transdifferentiate into hepatocytic and biliary lineages through a bipotent progenitor. In accordance, transplantation of either undifferentiated or differentiated HepaRG cells in uPA/SCID mouse damaged liver gives rise mainly to functional human hepatocytes infiltrating mouse parenchyma. Analysis of the differentiation/transdifferentiation process reveals that: (1) H epatic tumors with combined hepatocellular cholangiocarcinoma have been frequently described for instance, hepatoblastoma with cholangioblastic features in young patients 1 and HCCs with dual expression of hepatocyte and bile duct markers in adult patients suffering from diseases related to HCV and/or HBV infection. 2 Such tumors usually contain mature hepatocytes and so-called transitional areas that consist of undifferentiated cells that have morphological and immunological features of both hepatocytes and cholangiocytes. 3 Co-expression of hepatocytic and biliary markers suggests involvement of hepatic progenitor cells in development of these human tumors and supports the concept of genetic events to explain their abnormal growth during tumor formation. 4 However, mechanisms of occurrence of these progenitors and abnormal control of their expansion and differentiation are still unclear.Hepatic progenitor cells, also referred to as oval cells in rodents, have been defined as immature epithelial cells able to differentiate toward both biliary and hepatocytic lineages. The smallest ramification of the biliary tree in adult liver, the canal of Hering, may constitute the niche for these hepatic progenitor cells. 5 They are few in number, and because bile ductular and hepatocytic cells have a tremendous capacity to proliferate and differentiate, heAbbreviations: BrdU, bromodeoxyuridine; HNF, hepatocyte nuclear factor; RT, reverse transcription.

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Section: Discussionmentioning

confidence: 99%

Transdifferentiation of hepatocyte‐like cells from the human hepatoma HepaRG cell line through bipotent progenitor†

et al. 2007

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“…Recently, SP cells have also been identified in the hematopoietic compartments of different species [14,15], and have been isolated from various other adult tissues including the liver [16], skeletal muscle [17], brain [18], pancreas [19], and lung [20]. These findings suggest that the SP phenotype represents a common feature of adult tissue-specific stem cells.…”

Section: Introductionmentioning

confidence: 99%

Rat limbal epithelial side population cells exhibit a distinct expression of stem cell markers that are lacking in side population cells from the central cornea

et al. 2005

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The side population (SP) phenotype is shared by stem cells in various tissues and species. Here we demonstrate SP cells with Hoechst dye efflux were surprisingly collected from the epithelia of both the rat limbus and central cornea, unlike in human and rabbit eyes. Our results show that rat limbal SP cells have a significantly higher expression of the stem cell markers ABCG2, nestin, and notch 1, compared to central corneal SP cells. Immunohistochemistry also revealed that ABCG2 and the epithelial stem/progenitor cell marker p63 were expressed only in basal limbal epithelial cells. These results demonstrate that ABCG2 expression is closely linked to the stem cell phenotype of SP cells.

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“…Recently, however, it has become clear that another ABC transporter, Breast Cancer Resistance Protein (BCRP/ABCG2), is mainly responsible for the SP phenotype, at least in bone marrow [2][3][4][5][6]. Based on the initial findings in the hematopoietic compartment, SP cells have now been identified in many other tissues including the mammary gland [7][8][9], skeletal muscle, pancreas, lung, retina, liver, testis, heart, and epidermis [10][11][12][13][14][15][16][17]. In addition to normal tissues, it has further been demonstrated that cancer cell lines and primary tumor cells contain an SP [18][19][20].…”

Section: Introductionmentioning

confidence: 99%

Contribution of the ABC Transporters Bcrp1 and Mdr1a/1b to the Side Population Phenotype in Mammary Gland and Bone Marrow of Mice

et al. 2005

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The ability of cells to export Hoechst 33342 can be used to identify a subpopulation of cells (side population [SP]) with characteristics of stem cells in many tissues. The ATP-binding cassette transporters Bcrp1 (Abcg2) and Mdr1a/1b (Abcb1a/1b) have been implicated as being responsible for this phenotype. To further explore the involvement of these transporters in the SP phenotype, we have generated Bcrp1/ Mdr1a/1b triple knockout mice and studied the effect of their absence on the SP in bone marrow and mammary gland.Whereas in bone marrow Bcrp1 was almost exclusively responsible for the SP, both transporters contributed to the SP phenotype in the mammary gland, where their combined absence resulted in a nearly complete loss of SP. Interestingly, bone marrow of Mdr1a/1b −/− mice frequently displayed an elevated SP, which was reversible by the Bcrp1 inhibitor Ko143, suggesting that Bcrp1 can compensate for the loss of Mdr1a/1b in bone marrow. Stem Cells 2005;23:1059-1065

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Hepatic Oval Cells Have the Side Population Phenotype Defined by Expression of ATP-Binding Cassette Transporter ABCG2/BCRP1

Cited by 185 publications

References 22 publications

Transdifferentiation of hepatocyte‐like cells from the human hepatoma HepaRG cell line through bipotent progenitor†

Transdifferentiation of hepatocyte‐like cells from the human hepatoma HepaRG cell line through bipotent progenitor†

Rat limbal epithelial side population cells exhibit a distinct expression of stem cell markers that are lacking in side population cells from the central cornea

Contribution of the ABC Transporters Bcrp1 and Mdr1a/1b to the Side Population Phenotype in Mammary Gland and Bone Marrow of Mice

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