Survival of liver failure pigs by transplantation of reversibly immortalized human hepatocytes with Tamoxifen-mediated self-recombination

Totsugawa, Toshinori; Chen, Yong; Rivas‐Carrillo, Jorge David; Soto-Gutiérrez, Alejandro; Navarro-Alvarez, Nalú; Noguchi, Hirofumi; Okitsu, Teru; Westerman, Karen A.; Kohara, Michinori; Reth, Michael; Tanaka, Noriaki; Leboulch, Philippe; Kobayashi, Naoya

doi:10.1016/j.jhep.2007.02.019

Cited by 40 publications

(47 citation statements)

References 25 publications

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“…The strategy of "Cre/LoxP-based reversible immortalization with specific immortalizing genes" has emerged as a promising way to overcome the cellular senescence of primary cell cultures, for their further use in fundamental studies and clinical research (Kobayashi et al, 2000;Totsugawa et al, 2007). However, to remove the potential tumorigenic dangers of the immortalizing genes, a secondary virus-mediated gene transfer for Cre expression is usually utilized.…”

Section: Discussionmentioning

confidence: 99%

“…However, these approaches are limited by cellular senescence and the partial loss of differentiated function. The transfer of specific oncogenes into primary cells can enable the generation of cell populations, a process known as cell immortalization (Counter et al, 1992;Kobayashi et al, 2000;Matsumura et al, 2004;Totsugawa et al, 2007). Primary cells that are transduced by simian virus 40 large T antigen (SV40LTAg) have a higher replicative ability than their parent cells.…”

Section: Introductionmentioning

confidence: 99%

“…To recover the functions of the cells and remove the potential tumorigenic dangers of the immortalizing genes, a "Cre/LoxP-based reversible immortalization" procedure has been applied in a series of studies to obtain "reverted cells" (i.e., cells after the removal of the immortalizing genes) (Kobayashi et al, 2000;Totsugawa et al, 2007). However, the requirement for the expression of the Cre recombinase at the completion of the expansion phase in order to trigger the excision of the integrated immortalizing genes necessitates a secondary virus-mediated gene transfer in a large number of cells.…”

Section: Introductionmentioning

confidence: 99%

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Reversible immortalization of rat pancreatic β cells with a novel immortalizing and tamoxifen-mediated self-recombination tricistronic vector

Wang

Zhang

et al. 2011

Journal of Biotechnology

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Reversible immortalization of rat pancreatic β cells with a novel immortalizing and tamoxifen-mediated self-recombination tricistronic vector

Wang

Zhang

et al. 2011

Journal of Biotechnology

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“…Our group also showed the reversible immortalization of human hepatocytes using a retroviral vector expressing a catalytic subunit of hTERT flanked by a pair of LoxP recombination targets [17]. One of the 24 clones was further subjected to transfection with the plasmid pCAGMerCreMer/Puro R , which expresses a Cre recombinase protein fused to two mutant estrogen-receptor ligand-binding domains (MerCreMer), under the control of the CAG promoter.…”

Section: Reversibly Immortalized Human Hepatocytesmentioning

confidence: 99%

Controlled Expansion of Mammalian Cell Populations by Reversible Immortalization

Noguchi¹,

Kobayashi²

2013

J Biotechnol Biomaterial

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In 1996, reversible immortalization using SV40 large T antigens and the Cre/LoxP system was successfully achieved with primary human fibroblasts. The concept of reversible immortalization involves introducing an immortalizing agent, SV40 large T antigens, into primary cells, expanding the cells in the culture, and finally, efficiently removing the immortalizing agent using Cre/LoxP site-specific recombination. The resulting cell population is essentially identical to the initial primary cells, but greatly increased in number. Since this report, reversible immortalization has been realized with hepatocytes, pancreatic β-cells, hepatic stellate cells, endothelial cells, renal epithelial cells and myogenic cells. This method facilitates the study of cell transplantation as well as cell differentiation, the cell cycle and senescence, by allowing one to control cell proliferation.

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“…Thus, theoretically speaking, the cells could not only proliferate but also do so without increasing the risk of tumor growth. Kobayashi has made an important contribution to this respect [11][12][13]. Another problem concerning immortalized hepatocyte lines is the insertion of the immortalized gene, which makes the cell proliferate continually, but also leads the cells to gradually lose their expression of hepatocyte-specific functions as less mRNA is made from the genes of differentiated liver cells and more is made from the genes of dedifferentiated liver cells.…”

Section: Cell Sourcesmentioning

confidence: 99%

Bioartificial liver devices: Perspectives on the state of the art

Ding

Shi

2010

Front. Med.

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Acute liver failure remains a significant cause of morbidity and mortality. Bioartificial liver (BAL) devices have been in development for more than 20 years. Such devices aim to temporarily take over the metabolic and excretory functions of the liver until the patients' own liver has recovered or a donor liver becomes available for transplant. The important issues include the choice of cell materials and the design of the bioreactor. Ideal BAL cell materials should be of good viability and functionality, easy to access, and exclude immunoreactive and tumorigenic cell materials. Unfortunately, the current cells in use in BAL do not meet these requirements. One of the challenges in BAL development is the improvement of current materials; another key point concerning cell materials is the coculture of different cells. The bioreactor is an important component of BAL, because it determines the viability and function of the hepatocytes within it. From the perspective of bioengineering, a successful and clinically effective bioreactor should mimic the structure of the liver and provide an in vivo-like microenvironment for the growth of hepatocytes, thereby maintaining the cells' viability and function to the maximum extent. One future trend in the development of the bioreactor is to improve the oxygen supply system. Another direction for future research on bioreactors is the application of biomedical materials. In conclusion, BAL is, in principle, an important therapeutic strategy for patients with acute liver failure, and may also be a bridge to liver transplantation. It requires further research and development, however, before it can enter clinical practice.

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Survival of liver failure pigs by transplantation of reversibly immortalized human hepatocytes with Tamoxifen-mediated self-recombination

Abstract: Here we demonstrate the usefulness of Cre/LoxP -mediated reversible immortalization of human hepatocytes with Tamoxifen-mediated self-recombination.

Cited by 40 publications

References 25 publications

Reversible immortalization of rat pancreatic β cells with a novel immortalizing and tamoxifen-mediated self-recombination tricistronic vector

Reversible immortalization of rat pancreatic β cells with a novel immortalizing and tamoxifen-mediated self-recombination tricistronic vector

Controlled Expansion of Mammalian Cell Populations by Reversible Immortalization

Bioartificial liver devices: Perspectives on the state of the art

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