Isolation of multipotent progenitor cells from human fetal liver capable of differentiating into liver and mesenchymal lineages

Dan, Yock Young; Riehle, Kimberly J.; Lázaro, Catherine A.; Teoh, Narcissus; Haque, Jamil; Campbell, Jean S.; Fausto, Nelson

doi:10.1073/pnas.0603824103

Cited by 290 publications

(263 citation statements)

References 36 publications

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“…In conclusion, the human HepaRG cells display unique features because they share with the human fetal liver multipotent progenitor cells, recently isolated and characterized by Dan et al 45 : (1) a high proliferative ability; (2) differentiation potential toward biliary and hepatocytic lineage; and (3) the capacity to differentiate into functional hepatocytes in vivo. Moreover, probably related to their tumor origin, HepaRG cells exhibit a transdifferentiation potential through a hepatic bipotent progenitor.…”

Section: Discussionmentioning

confidence: 83%

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: 83%

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

et al. 2007

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“…Intriguingly, mesenchymal cell-like endothelial cells and hepatic satellite cells do not show this replicative senescence (Dan et al, 2006). The replicative senescence in hepatocytes is probably in part the result of continued proliferation during 20 -30 years of chronic liver diseases.…”

Section: Non-haematopoietic Stem Cellsmentioning

confidence: 94%

Telomere and telomerase in stem cells

2007

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Telomeres, guanine-rich tandem DNA repeats of the chromosomal end, provide chromosomal stability, and cellular replication causes their loss. In somatic cells, the activity of telomerase, a reverse transcriptase that can elongate telomeric repeats, is usually diminished after birth so that the telomere length is gradually shortened with cell divisions, and triggers cellular senescence. In embryonic stem cells, telomerase is activated and maintains telomere length and cellular immortality; however, the level of telomerase activity is low or absent in the majority of stem cells regardless of their proliferative capacity. Thus, even in stem cells, except for embryonal stem cells and cancer stem cells, telomere shortening occurs during replicative ageing, possibly at a slower rate than that in normal somatic cells. Recently, the importance of telomere maintenance in human stem cells has been highlighted by studies on dyskeratosis congenital, which is a genetic disorder in the human telomerase component. The regulation of telomere length and telomerase activity is a complex and dynamic process that is tightly linked to cell cycle regulation in human stem cells. Here we review the role of telomeres and telomerase in the function and capacity of the human stem cells.

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“…CD90 (Thy-1) is a 25-to 37-kDa cell-surface-anchored glycoprotein (Rege and Hagood, 2006). Its expression has been found in bone marrowderived mesenchymal stem cells (Dennis et al, 2007), hepatic stem/progenitor cells (La´zaro et al, 2003;Dan et al, 2006;Herrera et al, 2006), hematopoietic stem cells and keratinocytic stem cells (Nakamura et al, 2006;Araki et al, 2007;Haack-Sorensen et al, 2007). It has also been identified in human liver CSCs, murine breast CSCs and primarily cultured CD133 þ glioblastoma CSCs (Liu et al, 2006;Cho et al, 2008;Yang et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Trastuzumab (herceptin) targets gastric cancer stem cells characterized by CD90 phenotype

et al. 2011

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Identification and characterization of cancer stem cells (CSCs) in gastric cancer are difficult owing to the lack of specific markers and consensus methods. In this study, we show that cells with the CD90 surface marker in gastric tumors could be enriched under non-adherent, serumfree and sphere-forming conditions. These CD90 þ cells possess a higher ability to initiate tumor in vivo and could re-establish the cellular hierarchy of tumors from singlecell implantation, demonstrating their self-renewal properties. Interestingly, higher proportion of CD90 þ cells correlates with higher in vivo tumorigenicity of gastric primary tumor models. In addition, it was found that ERBB2 was overexpressed in about 25% of the gastric primary tumor models, which correlates with the higher level of CD90 expression in these tumors. Trastuzumab (humanized anti-ERBB2 antibody) treatment of hightumorigenic gastric primary tumor models could reduce the CD90 þ population in tumor mass and suppress tumor growth when combined with traditional chemotherapy. Moreover, tumorigenicity of tumor cells could also be suppressed when trastuzumab treatment starts at the same time as cell implantation. Therefore, we have identified a CSC population in gastric primary tumors characterized by their CD90 phenotype. The finding that trastuzumab targets the CSC population in gastric tumors suggests that ERBB2 signaling has a role in maintaining CSC populations, thus contributing to carcinogenesis and tumor invasion. In conclusion, the results from this study provide new insights into the gastric tumorigenic process and offer potential implications for the development of anticancer drugs as well as therapeutic treatment of gastric cancers.

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Isolation of multipotent progenitor cells from human fetal liver capable of differentiating into liver and mesenchymal lineages

Cited by 290 publications

References 36 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†

Telomere and telomerase in stem cells

Trastuzumab (herceptin) targets gastric cancer stem cells characterized by CD90 phenotype

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