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Telomerase reconstitution immortalizes human fetal hepatocytes without disrupting their differentiation potential

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Telomerase reconstitution immortalizes human fetal hepatocytes without disrupting their differentiation potential. / Wege, Henning; Le, Hai T; Chui, Michael S; Liu, Li; Wu, Jian; Giri, Ranjit; Malhi, Harmeet; Sappal, Baljit S; Kumaran, Vinay; Gupta, Sanjeev; Zern, Mark A.

In: GASTROENTEROLOGY, Vol. 124, No. 2, 01.02.2003, p. 432-44.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Wege, H, Le, HT, Chui, MS, Liu, L, Wu, J, Giri, R, Malhi, H, Sappal, BS, Kumaran, V, Gupta, S & Zern, MA 2003, 'Telomerase reconstitution immortalizes human fetal hepatocytes without disrupting their differentiation potential', GASTROENTEROLOGY, vol. 124, no. 2, pp. 432-44. https://doi.org/10.1053/gast.2003.50064

APA

Wege, H., Le, H. T., Chui, M. S., Liu, L., Wu, J., Giri, R., Malhi, H., Sappal, B. S., Kumaran, V., Gupta, S., & Zern, M. A. (2003). Telomerase reconstitution immortalizes human fetal hepatocytes without disrupting their differentiation potential. GASTROENTEROLOGY, 124(2), 432-44. https://doi.org/10.1053/gast.2003.50064

Vancouver

Wege H, Le HT, Chui MS, Liu L, Wu J, Giri R et al. Telomerase reconstitution immortalizes human fetal hepatocytes without disrupting their differentiation potential. GASTROENTEROLOGY. 2003 Feb 1;124(2):432-44. https://doi.org/10.1053/gast.2003.50064

Bibtex

@article{1218a95464c647b092166b96d018deb0,
title = "Telomerase reconstitution immortalizes human fetal hepatocytes without disrupting their differentiation potential",
abstract = "BACKGROUND & AIMS: The availability of in vitro expandable human hepatocytes would greatly advance liver-directed cell therapies. Therefore, we examined whether human fetal hepatocytes are amenable to telomerase-mediated immortalization without inducing a transformed phenotype and disrupting their differentiation potential. Telomerase is a ribonucleoprotein that plays a pivotal role in maintaining telomere length and chromosome stability. Human somatic cells, including hepatocytes, exhibit no telomerase activity. Consequently, their telomeres progressively shorten with each cell cycle until critically short telomeres trigger replicative senescence.METHODS: The catalytic subunit, telomerase reverse transcriptase, was expressed in human fetal hepatocytes. Transduced cells were characterized for telomerase activity, telomere length, proliferative capacity, hepatocellular functions, oncogenicity, and their in vivo maturation potential.RESULTS: The expression of human telomerase reverse transcriptase restored telomerase activity in human fetal hepatocytes. Telomerase-reconstituted cells were capable of preserving elongated telomeres, propagated in culture beyond replicative senescence for more than 300 cell doublings (to date), and maintained their liver-specific nature, as analyzed by a panel of hepatic growth factors, growth factor receptors, and transcription factors as well as albumin, glucose-6-phosphatase, glycogen synthesis, cytochrome P450 (CYP) expression profiles, and urea production. Moreover, the immortalized cells exhibited no oncogenicity, and no up-regulation of c-Myc was detected. The cells engrafted and survived in the liver of immunodeficient mice with hepatocellular gene expression.CONCLUSIONS: Reconstitution of telomerase activity induces indefinite replication in human fetal hepatocytes and offers unique opportunities for examining basic biologic mechanisms and for considering development of stable cell lines for liver-directed therapies.",
keywords = "Animals, Cell Differentiation, Cell Line, Transformed, DNA-Binding Proteins, Female, Fetus, Hepatocytes, Humans, Mice, Neoplasms, Pregnancy, Telomerase, Telomere, Transduction, Genetic",
author = "Henning Wege and Le, {Hai T} and Chui, {Michael S} and Li Liu and Jian Wu and Ranjit Giri and Harmeet Malhi and Sappal, {Baljit S} and Vinay Kumaran and Sanjeev Gupta and Zern, {Mark A}",
year = "2003",
month = feb,
day = "1",
doi = "10.1053/gast.2003.50064",
language = "English",
volume = "124",
pages = "432--44",
journal = "GASTROENTEROLOGY",
issn = "0016-5085",
publisher = "W.B. Saunders Ltd",
number = "2",

}

RIS

TY - JOUR

T1 - Telomerase reconstitution immortalizes human fetal hepatocytes without disrupting their differentiation potential

AU - Wege, Henning

AU - Le, Hai T

AU - Chui, Michael S

AU - Liu, Li

AU - Wu, Jian

AU - Giri, Ranjit

AU - Malhi, Harmeet

AU - Sappal, Baljit S

AU - Kumaran, Vinay

AU - Gupta, Sanjeev

AU - Zern, Mark A

PY - 2003/2/1

Y1 - 2003/2/1

N2 - BACKGROUND & AIMS: The availability of in vitro expandable human hepatocytes would greatly advance liver-directed cell therapies. Therefore, we examined whether human fetal hepatocytes are amenable to telomerase-mediated immortalization without inducing a transformed phenotype and disrupting their differentiation potential. Telomerase is a ribonucleoprotein that plays a pivotal role in maintaining telomere length and chromosome stability. Human somatic cells, including hepatocytes, exhibit no telomerase activity. Consequently, their telomeres progressively shorten with each cell cycle until critically short telomeres trigger replicative senescence.METHODS: The catalytic subunit, telomerase reverse transcriptase, was expressed in human fetal hepatocytes. Transduced cells were characterized for telomerase activity, telomere length, proliferative capacity, hepatocellular functions, oncogenicity, and their in vivo maturation potential.RESULTS: The expression of human telomerase reverse transcriptase restored telomerase activity in human fetal hepatocytes. Telomerase-reconstituted cells were capable of preserving elongated telomeres, propagated in culture beyond replicative senescence for more than 300 cell doublings (to date), and maintained their liver-specific nature, as analyzed by a panel of hepatic growth factors, growth factor receptors, and transcription factors as well as albumin, glucose-6-phosphatase, glycogen synthesis, cytochrome P450 (CYP) expression profiles, and urea production. Moreover, the immortalized cells exhibited no oncogenicity, and no up-regulation of c-Myc was detected. The cells engrafted and survived in the liver of immunodeficient mice with hepatocellular gene expression.CONCLUSIONS: Reconstitution of telomerase activity induces indefinite replication in human fetal hepatocytes and offers unique opportunities for examining basic biologic mechanisms and for considering development of stable cell lines for liver-directed therapies.

AB - BACKGROUND & AIMS: The availability of in vitro expandable human hepatocytes would greatly advance liver-directed cell therapies. Therefore, we examined whether human fetal hepatocytes are amenable to telomerase-mediated immortalization without inducing a transformed phenotype and disrupting their differentiation potential. Telomerase is a ribonucleoprotein that plays a pivotal role in maintaining telomere length and chromosome stability. Human somatic cells, including hepatocytes, exhibit no telomerase activity. Consequently, their telomeres progressively shorten with each cell cycle until critically short telomeres trigger replicative senescence.METHODS: The catalytic subunit, telomerase reverse transcriptase, was expressed in human fetal hepatocytes. Transduced cells were characterized for telomerase activity, telomere length, proliferative capacity, hepatocellular functions, oncogenicity, and their in vivo maturation potential.RESULTS: The expression of human telomerase reverse transcriptase restored telomerase activity in human fetal hepatocytes. Telomerase-reconstituted cells were capable of preserving elongated telomeres, propagated in culture beyond replicative senescence for more than 300 cell doublings (to date), and maintained their liver-specific nature, as analyzed by a panel of hepatic growth factors, growth factor receptors, and transcription factors as well as albumin, glucose-6-phosphatase, glycogen synthesis, cytochrome P450 (CYP) expression profiles, and urea production. Moreover, the immortalized cells exhibited no oncogenicity, and no up-regulation of c-Myc was detected. The cells engrafted and survived in the liver of immunodeficient mice with hepatocellular gene expression.CONCLUSIONS: Reconstitution of telomerase activity induces indefinite replication in human fetal hepatocytes and offers unique opportunities for examining basic biologic mechanisms and for considering development of stable cell lines for liver-directed therapies.

KW - Animals

KW - Cell Differentiation

KW - Cell Line, Transformed

KW - DNA-Binding Proteins

KW - Female

KW - Fetus

KW - Hepatocytes

KW - Humans

KW - Mice

KW - Neoplasms

KW - Pregnancy

KW - Telomerase

KW - Telomere

KW - Transduction, Genetic

U2 - 10.1053/gast.2003.50064

DO - 10.1053/gast.2003.50064

M3 - SCORING: Journal article

C2 - 12557149

VL - 124

SP - 432

EP - 444

JO - GASTROENTEROLOGY

JF - GASTROENTEROLOGY

SN - 0016-5085

IS - 2

ER -