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Functional beta-cell maturation is marked by an increased glucose threshold and by expression of urocortin 3

Nature Biotechnology volume 30, pages261–264(2012)Cite this article

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Abstract

Insulin-expressing cells that have been differentiated from human pluripotent stem cells in vitro lack the glucose responsiveness characteristic of mature beta cells. Beta-cell maturation in mice was studied to find genetic markers that enable screens for factors that induce bona fide beta cells in vitro. We find that functional beta-cell maturation is marked by an increase in the glucose threshold for insulin secretion and by expression of the gene urocortin 3.

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Figure 1: Beta-cell maturation is defined by a decrease in GSIS sensitivity to low glucose levels and by the expression of Ucn3.
Figure 2: Ucn3 expression gradually increases during the course of mouse beta-cell maturation in vivo and is expressed in hESC-derived beta-like cells after differentiation and maturation in vivo, but not after differentiation in vitro.

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  • 07 May 2012

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Acknowledgements

We thank W. Vale (Salk Institute) for providing anti-human Ucn3 antibody, K. Blum for writing the MATLAB BioGUI for analysis of GSIS, A. Kweudjeu for help with transcriptional arrays, C. Honore for help with FACS analyses, A. Roose, A. Cheng and F. Deng for excellent technical assistance, and D. Cohen, Y. Mayshar and F. Pagliuca for critical reading of the manuscript. We are grateful to all members of the Melton laboratory and the Harvard Medical School Critical Discussion Group for helpful discussions and experimental advice. B.B. was supported by European Molecular Biology Organization and Juvenile Diabetes Research Foundation post-doctoral fellowships. D.A.M. is an Investigator of the Howard Hughes Medical Institute.

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Affiliations

  1. Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts, USA

    Barak Blum, Siniša Hrvatin, Christian Schuetz, Claire Bonal & Douglas A Melton

  2. BetaLogics Venture, Janssen Research and Development, LLC, Raritan, New Jersey, USA

    Alireza Rezania

Authors
  1. Barak Blum
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  2. Siniša Hrvatin
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  3. Christian Schuetz
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  4. Claire Bonal
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  5. Alireza Rezania
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  6. Douglas A Melton
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Contributions

B.B. and D.A.M. conceived and designed the research. B.B., S.H., C.S., C.B. and A.R. performed the experiments. B.B. and D.A.M. analyzed the data and wrote the manuscript.

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Correspondence to Douglas A Melton.

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Competing interests

A.Z. is an employee of BetaLogics, a division of Janssen Research & Development, LLC, one of the Johnson & Johnson Family of Companies, Raritan, NJ, USA.

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Supplementary Table 1, Supplementary Methods and Supplementary Figs. 1–5 (PDF 2191 kb)

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Blum, B., Hrvatin, S., Schuetz, C. et al. Functional beta-cell maturation is marked by an increased glucose threshold and by expression of urocortin 3. Nat Biotechnol 30, 261–264 (2012). https://doi.org/10.1038/nbt.2141

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