Origin and characterization of a human bipotent liver progenitor cell line☆

Parent, Romain; Marion, Marie‐Jeanne; Furio, Laetitia; Trépo, Christian; Petit, Marie-Anne

doi:10.1053/j.gastro.2004.01.002

Cited by 204 publications

(190 citation statements)

References 33 publications

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“…35 Moreover, these gradual appearances of liver-specific functions were associated with rapid disappearance of stem cell markers. These last observations contrasted with the results of Parent et al 17 indicating that differentiated HepaRG cells preserved an immature phenotype characterized by maintenance of oval-cell markers. This discrepancy could be partly explained because DMSO exposure enhanced sev- eral liver-specific functions 18 and unexpectedly re-induced stem cell marker expression, such as CD34 in HepaRG cells as in normal adult human hepatocytes (unpublished results).…”

Section: Discussioncontrasting

confidence: 97%

“…They constitutively and synchronously display both hepatocyte-like and biliary-like epithelial phenotypes at confluence, indicating they may have bipotent progenitor features. 16,17 When optimally differentiated, HepaRG cells support HBV infection 16 and express a large panel of liver-specific genes, including those expressing drug metabolizing enzymes. 18 In this work, we analyze the possible transdifferentiation process of human liver cells using the HepaRG cell line, define the sequential expression of hepatocyte nuclear factor (HNF) family transcription factors, and identify associated signaling mechanisms involved in this process.…”

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confidence: 99%

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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: Discussioncontrasting

confidence: 97%

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confidence: 99%

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

et al. 2007

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“…Nevertheless, transition of LPC to myofibroblasts after treatment with TGFb has indeed been previously obtained in vitro, using LPC isolated from rats fed a choline-deficient diet supplemented with ethionine. 53 In a search of the capability of LPC to undergo EMT into HSC, we cultured human HepaRG LPC 54 and followed their epithelial and fibroblastic phenotypic characteristics in response to TGFb. HepaRG underwent a phenotypic change from epithelial to mesenchymal-like cells in vitro on the basis of an increased expression of snail, aSMA and collagens and a paralleled decrease of E-cadherin (unpublished data) as observed by Wang et al 53 on rat LPC.…”

Section: Discussionmentioning

confidence: 99%

Liver precursor cells increase hepatic fibrosis induced by chronic carbon tetrachloride intoxication in rats

Chobert

Couchie

Fourcot

et al. 2012

Laboratory Investigation

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“…Several attempts have been made to isolate LPCs from diseased adult human liver [1][2][3][4][5][6]. To date, only one liver progenitor cell line has been established from a cirrhotic liver cancer patient following chronic HCV infection [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

“…LPCs offer a major therapeutic opportunity in fi elds as diverse as gene therapy, initiation of liver repair, and biological liver support systems. To realize this potential, it is necessary to identify suitable sources of LPCs, establish reproducible methods for their isolation, and defi ne conditions for their expansion and subsequent culture, differentiation, and maturation into functional hepatocytes and cholangiocytes.Several attempts have been made to isolate LPCs from diseased adult human liver [1][2][3][4][5][6] …”

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Human Liver Progenitor Cell Lines Are Readily Established From Non-Tumorous Tissue Adjacent to Hepatocellular Carcinoma

Zhang

London

Schulz

et al. 2010

Stem Cells and Development

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Non-tumorous liver tissue removed during surgery to resect hepatocellular carcinoma (HCC) is potentially a useful source of material from which cells, particularly liver progenitor/stem cells (LPCs), can be isolated to establish cell lines. The purpose of this study was to evaluate the applicability of the "plate-and-wait" method to derive LPCs from resections to remove HCC. Three independent non-tumorous liver samples from HCC resection and 3 samples from liver donors were used for LPC isolation. Staining for LPC markers, OV6, CK19, and EpCAM, in the above liver samples demonstrated staining in only 2 of the non-tumorous samples. We isolated 2 human liver epithelial cell lines (HLECs) from these 2 samples. These HLECs were positive for general stem cell markers CD133, EpCAM, and Oct4. They expressed the liver progenitor cell markers OV6, CK14, and M2PK but not CK19. They also expressed the hepatocellular markers albumin, CK8, CK18, HNF4-α, and the drug-metabolizing gene CYP3A4. These cells accumulated glycogen, indocyanine green, and synthesized urea. They produced colonies in soft agar that showed anchorage-independent growth and their tumorigenic status was confi rmed when they produced tumors following transfer to athymic nude mice. In contrast, the third nontumorous tissue and 3 normal liver samples did not produce cell lines. This study establishes a correlation between the presence of LPCs in the source liver tissue and the ability to derive cell lines from these tissues. The phenotypic similarities between the LPCs and the HLECs suggest that a precursor-product relationship may exist between the 2 cell types. IntroductionT he principal treatment modality of end-stage liver disease is orthotopic liver transplantation. The paucity of available organs is driving research to seek alternative therapies. One approach is cell therapy, and the use of hepatocytes has been evaluated with limited success, partly due to their fragility that makes them diffi cult to isolate and store. Liver progenitor/stem cells (LPCs) offer the advantage of being extremely robust, rapidly propagated and able to generate both hepatocytes and cholangiocytes. LPCs offer a major therapeutic opportunity in fi elds as diverse as gene therapy, initiation of liver repair, and biological liver support systems. To realize this potential, it is necessary to identify suitable sources of LPCs, establish reproducible methods for their isolation, and defi ne conditions for their expansion and subsequent culture, differentiation, and maturation into functional hepatocytes and cholangiocytes.Several attempts have been made to isolate LPCs from diseased adult human liver [1][2][3][4][5][6] ZHANG ET AL. 1278non-specifi c binding and intrinsic peroxidase activity, the sections were incubated with a primary monoclonal antibody overnight at 4°C. After washes, the sections were incubated with the secondary antibody (peroxidase-labeled; Bio-Rad, Hercules, CA) for 60 min. The staining reaction was developed with DAB substrate (DAKO, Glostrup, Denmark). Con...

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Origin and characterization of a human bipotent liver progenitor cell line☆

Cited by 204 publications

References 33 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

Liver precursor cells increase hepatic fibrosis induced by chronic carbon tetrachloride intoxication in rats

Human Liver Progenitor Cell Lines Are Readily Established From Non-Tumorous Tissue Adjacent to Hepatocellular Carcinoma

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