Telomerase reconstitution immortalizes human fetal hepatocytes without disrupting their differentiation potential

Wege, Henning; Le, Hai Thanh; Chui, Michael S.; Liu, Li; Wu, Jian; Giri, Ranjit K.; Malhi, Harmeet; Sappal, Baljit S.; Kumaran, Vinay; Gupta, Sanjeev; Zern, Mark Α.

doi:10.1053/gast.2003.50064

Cited by 167 publications

(141 citation statements)

References 38 publications

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“…They are even able to give rise to two distinct cell types within a tissue. It may prove possible, by using similar strategies (15), to isolate such lines from other embryonic tissues, and other species including human, although immortalizing genes could be necessary (37,38). The use of cell lines for tissue repair would have many advantages in stem cell-based gene therapy.…”

Section: Discussionmentioning

confidence: 99%

Bipotential mouse embryonic liver stem cell lines contribute to liver regeneration and differentiate as bile ducts and hepatocytes

Strick‐Marchand

Morosan

Charneau

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

101

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Section: Discussionmentioning

confidence: 99%

Bipotential mouse embryonic liver stem cell lines contribute to liver regeneration and differentiate as bile ducts and hepatocytes

Strick‐Marchand

Morosan

Charneau

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

101

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“…FH cells were isolated and cultured as described (19), in DMEM containing 25 mM glucose and supplemented with 10% FBS, 100 units͞ml penicillin, 100 g͞ml streptomycin, 5 M hydrocortisone, and 5 g͞ml insulin. A subclone of FH cells that was stably transduced with hTERT, designated FH-B-hTERT (FH-B), was cultured in the same medium, as described (20). FH-B cells transduced with the Pdx1 gene (see below), designated FH-B-TPN cells, were maintained in the same culture medium, with the exception of hydrocortisone and insulin.…”

Section: Methodsmentioning

confidence: 99%

“…These cells express markers of hepatocytes, bile duct cells, and oval cells, and are capable of differentiating into mature hepatocytes in vivo (19). Moreover, FH cells were amenable to immortalization after retroviral introduction of the catalytic subunit of the human telomerase gene (FH-hTERT) (20). The replication potential of FH-hTERT cells was greatly enhanced, without evidence for neoplastic cell transformation, in either in vitro or in vivo assays.…”

mentioning

confidence: 99%

Reversal of hyperglycemia in mice by using human expandable insulin-producing cells differentiated from fetal liver progenitor cells

Zalzman

Gupta

Giri

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

246

148

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Beta-cell replacement is considered to be the most promising approach for treatment of type 1 diabetes. Its application on a large scale is hindered by a shortage of cells for transplantation. Activation of insulin expression, storage, and regulated secretion in stem͞progen-itor cells offers novel ways to overcome this shortage. We explored whether fetal human progenitor liver cells (FH) could be induced to differentiate into insulin-producing cells after expression of the pancreatic duodenal homeobox 1 (Pdx1) gene, which is a key regulator of pancreatic development and insulin expression in beta cells. FH cells possess a considerable replication capacity, and this was further extended by introduction of the gene for the catalytic subunit of human telomerase. Immortalized FH cells expressing Pdx1 activated multiple beta-cell genes, produced and stored considerable amounts of insulin, and released insulin in a regulated manner in response to glucose. When transplanted into hyperglycemic immunodeficient mice, the cells restored and maintained euglycemia for prolonged periods. Quantitation of human C-peptide in the mouse serum confirmed that the glycemia was normalized by the transplanted human cells. This approach offers the potential of a novel source of cells for transplantation into patients with type 1 diabetes.

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“…The telomerase immortalization is advantageous over other methods since the cells are less amenable to neoplastic transformation. The cells maintained contact inhibition and did not display characteristics of transformed cells in culture and upon transplantation in suitable recipients [Wege et al, 2003]. Although this work presents the creation of hepatocyte cell lines, the differentiation status of the cells is not clear.…”

Section: Liver Pathologies and Therapiesmentioning

confidence: 93%

“…SV40 T-antigen immortalized hepatocytes have been demonstrated to restore hepatic function when transplanted into animal models but carry a potential for increased malignant transformation [Nakamura et al, 1997;Tada et al, 1998;Cai et al, 2002]. In a recent publication, transduction of fetal human hepatocytes with the catalytic subunit of telomerase reverse transcriptase enabled them to divide for a longer period as compared to control cells [Wege et al, 2003]. The cells expressed functions normally associated with liver cells and upon transplantation to immunocompetent mice integrated and expressed RNA of hepatic genes.…”

Section: Liver Pathologies and Therapiesmentioning

confidence: 99%

Study of hepatocyte differentiation using embryonic stem cells

Lavon

Benvenisty

2005

J of Cellular Biochemistry

114

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The liver has many crucial functions including metabolizing dietary molecules, detoxifying compounds, and storing glycogen. The hepatocytes, comprising most of the liver organ, progressively modify their gene expression profile during the fetal development according to their roles in the different phases of development. Embryonic stem (ES) cells serve as a major tool in understanding liver development. These cells may also serve as a source of hepatic cells for cellular therapy. In this review, we aim to summarize the research that has been performed in the field of hepatocyte differentiation from mouse and human ES cells. We discuss the various methodologies for the differentiation of ES cells towards hepatic cells using either spontaneous or directed differentiation protocols. Although many protocols for differentiating ES cells to hepatic cells have been developed, the analysis of their status is not trivial and can lead to various conclusions. Hence, we discuss the issues of analyzing hepatocytes by means of the specificity of the markers for hepatocytes and the status of the cells as fetal or adult hepatocytes.

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Telomerase reconstitution immortalizes human fetal hepatocytes without disrupting their differentiation potential

Cited by 167 publications

References 38 publications

Bipotential mouse embryonic liver stem cell lines contribute to liver regeneration and differentiate as bile ducts and hepatocytes

Bipotential mouse embryonic liver stem cell lines contribute to liver regeneration and differentiate as bile ducts and hepatocytes

Reversal of hyperglycemia in mice by using human expandable insulin-producing cells differentiated from fetal liver progenitor cells

Study of hepatocyte differentiation using embryonic stem cells

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