A human β-cell line for transplantation therapy to control type 1 diabetes

Michiki Narushima; Naoya Kobayashi; Teru Okitsu; Yoshihito Tanaka; Shun Ai Li; Yong Chen; Atsushi Miki; Kimiaki Tanaka; Shuhei Nakaji; Kohji Takei; Alejandro Soto Gutierrez; Jorge David Rivas-Carrillo; Nalu Navarro-Álvarez; Hee Sook Jun; Karen A. Westerman; Hirofumi Noguchi; Jonathan R.T. Lakey; Philippe Leboulch; Noriaki Tanaka; Ji Won Yoon

doi:10.1038/nbt1145

A human β-cell line for transplantation therapy to control type 1 diabetes

Michiki Narushima, Naoya Kobayashi, Teru Okitsu, Yoshihito Tanaka, Shun Ai Li, Yong Chen, Atsushi Miki, Kimiaki Tanaka, Shuhei Nakaji, Kohji Takei, Alejandro Soto Gutierrez, Jorge David Rivas-Carrillo, Nalu Navarro-Álvarez, Hee Sook Jun, Karen A. Westerman, Hirofumi Noguchi, Jonathan R.T. Lakey, Philippe Leboulch, Noriaki Tanaka, Ji Won Yoon

Research output: Contribution to journal › Article › peer-review

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Abstract

A human pancreatic β-cell line that is functionally equivalent to primary β-cells has not been available. We established a reversibly immortalized human β-cell clone (NAKT-15) by transfection of primary human β-cells with a retroviral vector containing simian virus 40 large T-antigen (SV40T) and human telomerase reverse transcriptase (hTERT) cDNAs flanked by paired loxP recombination targets, which allow deletion of SV40T and TERT by Cre recombinase. Reverted NAKT-15 cells expressed β-cell transcription factors (Isl-1, Pax 6, Nkx 6.1, Pdx-1), prohormone convertases 1/3 and 2, and secretory granule proteins, and secreted insulin in response to glucose, similar to normal human islets. Transplantation of NAKT-15 cells into streptozotocin- induced diabetic severe combined immunodeficiency mice resulted in perfect control of blood glucose within 2 weeks; mice remained normoglycemic for longer than 30 weeks. The establishment of this cell line is one step toward a potential cure of diabetes by transplantation.

Original language	English
Pages (from-to)	1274-1282
Number of pages	9
Journal	Nature Biotechnology
Volume	23
Issue number	10
DOIs	https://doi.org/10.1038/nbt1145
Publication status	Published - Oct 2005

ASJC Scopus subject areas

Biotechnology
Bioengineering
Applied Microbiology and Biotechnology
Molecular Medicine
Biomedical Engineering

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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Narushima, M., Kobayashi, N., Okitsu, T., Tanaka, Y., Li, S. A., Chen, Y., Miki, A., Tanaka, K., Nakaji, S., Takei, K., Gutierrez, A. S., Rivas-Carrillo, J. D., Navarro-Álvarez, N., Jun, H. S., Westerman, K. A., Noguchi, H., Lakey, J. R. T., Leboulch, P., Tanaka, N., & Yoon, J. W. (2005). A human β-cell line for transplantation therapy to control type 1 diabetes. Nature Biotechnology, 23(10), 1274-1282. https://doi.org/10.1038/nbt1145

Narushima, M, Kobayashi, N, Okitsu, T, Tanaka, Y, Li, SA, Chen, Y, Miki, A, Tanaka, K, Nakaji, S, Takei, K, Gutierrez, AS, Rivas-Carrillo, JD, Navarro-Álvarez, N, Jun, HS, Westerman, KA, Noguchi, H, Lakey, JRT, Leboulch, P, Tanaka, N & Yoon, JW 2005, 'A human β-cell line for transplantation therapy to control type 1 diabetes', Nature Biotechnology, vol. 23, no. 10, pp. 1274-1282. https://doi.org/10.1038/nbt1145

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title = "A human β-cell line for transplantation therapy to control type 1 diabetes",

abstract = "A human pancreatic β-cell line that is functionally equivalent to primary β-cells has not been available. We established a reversibly immortalized human β-cell clone (NAKT-15) by transfection of primary human β-cells with a retroviral vector containing simian virus 40 large T-antigen (SV40T) and human telomerase reverse transcriptase (hTERT) cDNAs flanked by paired loxP recombination targets, which allow deletion of SV40T and TERT by Cre recombinase. Reverted NAKT-15 cells expressed β-cell transcription factors (Isl-1, Pax 6, Nkx 6.1, Pdx-1), prohormone convertases 1/3 and 2, and secretory granule proteins, and secreted insulin in response to glucose, similar to normal human islets. Transplantation of NAKT-15 cells into streptozotocin- induced diabetic severe combined immunodeficiency mice resulted in perfect control of blood glucose within 2 weeks; mice remained normoglycemic for longer than 30 weeks. The establishment of this cell line is one step toward a potential cure of diabetes by transplantation.",

author = "Michiki Narushima and Naoya Kobayashi and Teru Okitsu and Yoshihito Tanaka and Li, {Shun Ai} and Yong Chen and Atsushi Miki and Kimiaki Tanaka and Shuhei Nakaji and Kohji Takei and Gutierrez, {Alejandro Soto} and Rivas-Carrillo, {Jorge David} and Nalu Navarro-{\'A}lvarez and Jun, {Hee Sook} and Westerman, {Karen A.} and Hirofumi Noguchi and Lakey, {Jonathan R.T.} and Philippe Leboulch and Noriaki Tanaka and Yoon, {Ji Won}",

note = "Funding Information: The work presented in this paper was supported in part by a Grant-in-Aid for Scientific Research (B) of the Japan Society for the Promotion of Science to N.K., Life Science Project of 21st Century, Japan, to N.T., and the American Diabetes Association (1-04-ISLET-31) and National Institutes of Health grant 1R21DK60192 to J.W.Y. and H.S.J. We thank Ann Kyle for editorial assistance.",

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doi = "10.1038/nbt1145",

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AU - Kobayashi, Naoya

AU - Okitsu, Teru

AU - Tanaka, Yoshihito

AU - Li, Shun Ai

AU - Chen, Yong

AU - Miki, Atsushi

AU - Tanaka, Kimiaki

AU - Nakaji, Shuhei

AU - Takei, Kohji

AU - Gutierrez, Alejandro Soto

AU - Rivas-Carrillo, Jorge David

AU - Navarro-Álvarez, Nalu

AU - Jun, Hee Sook

AU - Westerman, Karen A.

AU - Noguchi, Hirofumi

AU - Lakey, Jonathan R.T.

AU - Leboulch, Philippe

AU - Tanaka, Noriaki

AU - Yoon, Ji Won

N1 - Funding Information: The work presented in this paper was supported in part by a Grant-in-Aid for Scientific Research (B) of the Japan Society for the Promotion of Science to N.K., Life Science Project of 21st Century, Japan, to N.T., and the American Diabetes Association (1-04-ISLET-31) and National Institutes of Health grant 1R21DK60192 to J.W.Y. and H.S.J. We thank Ann Kyle for editorial assistance.

PY - 2005/10

Y1 - 2005/10

N2 - A human pancreatic β-cell line that is functionally equivalent to primary β-cells has not been available. We established a reversibly immortalized human β-cell clone (NAKT-15) by transfection of primary human β-cells with a retroviral vector containing simian virus 40 large T-antigen (SV40T) and human telomerase reverse transcriptase (hTERT) cDNAs flanked by paired loxP recombination targets, which allow deletion of SV40T and TERT by Cre recombinase. Reverted NAKT-15 cells expressed β-cell transcription factors (Isl-1, Pax 6, Nkx 6.1, Pdx-1), prohormone convertases 1/3 and 2, and secretory granule proteins, and secreted insulin in response to glucose, similar to normal human islets. Transplantation of NAKT-15 cells into streptozotocin- induced diabetic severe combined immunodeficiency mice resulted in perfect control of blood glucose within 2 weeks; mice remained normoglycemic for longer than 30 weeks. The establishment of this cell line is one step toward a potential cure of diabetes by transplantation.

AB - A human pancreatic β-cell line that is functionally equivalent to primary β-cells has not been available. We established a reversibly immortalized human β-cell clone (NAKT-15) by transfection of primary human β-cells with a retroviral vector containing simian virus 40 large T-antigen (SV40T) and human telomerase reverse transcriptase (hTERT) cDNAs flanked by paired loxP recombination targets, which allow deletion of SV40T and TERT by Cre recombinase. Reverted NAKT-15 cells expressed β-cell transcription factors (Isl-1, Pax 6, Nkx 6.1, Pdx-1), prohormone convertases 1/3 and 2, and secretory granule proteins, and secreted insulin in response to glucose, similar to normal human islets. Transplantation of NAKT-15 cells into streptozotocin- induced diabetic severe combined immunodeficiency mice resulted in perfect control of blood glucose within 2 weeks; mice remained normoglycemic for longer than 30 weeks. The establishment of this cell line is one step toward a potential cure of diabetes by transplantation.

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A human β-cell line for transplantation therapy to control type 1 diabetes

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