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Long-term persistence and development of induced pancreatic beta cells generated by lineage conversion of acinar cells

Nature Biotechnology volume 32, pages 12231230 (2014) | Download Citation

  • A Corrigendum to this article was published on 07 August 2015

This article has been updated

Abstract

Direct lineage conversion is a promising approach to generate therapeutically important cell types for disease modeling and tissue repair. However, the survival and function of lineage-reprogrammed cells in vivo over the long term has not been examined. Here, using an improved method for in vivo conversion of adult mouse pancreatic acinar cells toward beta cells, we show that induced beta cells persist for up to 13 months (the length of the experiment), form pancreatic islet–like structures and support normoglycemia in diabetic mice. Detailed molecular analyses of induced beta cells over 7 months reveal that global DNA methylation changes occur within 10 d, whereas the transcriptional network evolves over 2 months to resemble that of endogenous beta cells and remains stable thereafter. Progressive gain of beta-cell function occurs over 7 months, as measured by glucose-regulated insulin release and suppression of hyperglycemia. These studies demonstrate that lineage-reprogrammed cells persist for >1 year and undergo epigenetic, transcriptional, anatomical and functional development toward a beta-cell phenotype.

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Change history

  • 14 May 2015

    In the version of this article initially published, Yingying Zhang's name was spelled Yinying Zhang. The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We thank M. Shear, J. Brown, J. Hollister-Lock, and R. Zhao for technical assistance; H.-H. Chen for assistance with gene profiling; D. Yu and T. Fabbro for statistical analysis; Boston Children's Hospital core facility for an Illumina array; Joslin Specialized Assay Core for insulin measurement; members of the Zhou laboratory for advice and feedback; and D. Melton and D. Breault for discussion and reading of the manuscript. Q.Z. was supported by awards from the US National Institutes of Health. W.L. is supported by a postdoctoral fellowship from the Juvenile Diabetes Research Foundation. C.C.-W. is supported by postdoctoral fellowships from the Swiss Science Foundation and the Swiss Foundation for Grants in Biology and Medicine.

Author information

Author notes

    • Weida Li
    • , Claudia Cavelti-Weder
    •  & Yingying Zhang

    These authors contributed equally to this work.

Affiliations

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

    • Weida Li
    • , Yingying Zhang
    • , Kendell Clement
    • , Scott Donovan
    • , Ke Xu
    • , Mio Nakanishi
    • , Yuemei Zhang
    • , Samuel Zeng
    • , Alexander Meissner
    •  & Qiao Zhou
  2. Section on Islet Cell and Regenerative Biology, Joslin Diabetes Center, Boston, Massachusetts, USA.

    • Claudia Cavelti-Weder
    • , Marianne Stemann
    • , Takatsugu Yamada
    •  & Gordon Weir
  3. Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.

    • Yingying Zhang
    • , Kendell Clement
    • , Scott Donovan
    • , Jiang Zhu
    •  & Alexander Meissner
  4. Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.

    • Kendell Clement
  5. Harvard Medical School, West Roxbury, Massachusetts, USA.

    • Gabriel Gonzalez
  6. Center for System Biology and Center for Cancer Research, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Jiang Zhu
  7. Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.

    • Tatsu Hashimoto
    •  & David Gifford

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Contributions

Experimental design: W.L., C.C.-W., G.W., A.M., D.G., Q.Z. Experimental execution: W.L., C.C.-W., Yinying Z., S.D., G.G., M.S., K.X., T.H., T.Y., M.N., Yuemei Z., S.Z. Data analyses: W.L., C.C.-W., K.C., J.Z., M.S., T.H., A.M., G.W., Q.Z. Figure preparation, manuscript writing and editing: W.L., C.C.-W., K.C., G.W., A.M., Q.Z.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Qiao Zhou.

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DOI

https://doi.org/10.1038/nbt.3082

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