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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


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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  1. 1.

    & Forcing cells to change lineages. Nature 462, 587–594 (2009).

  2. 2.

    , , , & In vivo reprogramming of adult pancreatic exocrine cells to beta-cells. Nature 455, 627–632 (2008).

  3. 3.

    et al. Direct conversion of fibroblasts to functional neurons by defined factors. Nature 463, 1035–1041 (2010).

  4. 4.

    et al. Direct reprogramming of fibroblasts into functional cardiomyocytes by defined factors. Cell 142, 375–386 (2010).

  5. 5.

    et al. Conversion of adult pancreatic alpha-cells to beta-cells after extreme beta-cell loss. Nature 464, 1149–1154 (2010).

  6. 6.

    et al. Efficient direct reprogramming of mature amniotic cells into endothelial cells by ETS factors and TGFβ suppression. Cell 151, 559–575 (2012).

  7. 7.

    et al. Adult duct-lining cells can reprogram into beta-like cells able to counter repeated cycles of toxin-induced diabetes. Dev. Cell 26, 86–100 (2013).

  8. 8.

    et al. In vivo direct reprogramming of reactive glial cells into functional neurons after brain injury and in an Alzheimer's disease model. Cell Stem Cell 14, 188–202 (2014).

  9. 9.

    et al. Transient cytokine treatment induces acinar cell reprogramming and regenerates functional beta cell mass in diabetic mice. Nat. Biotechnol. 32, 76–83 (2014).

  10. 10.

    et al. Expansion and conversion of human pancreatic ductal cells into insulin-secreting endocrine cells. eLife 2, e00940 (2013).

  11. 11.

    & Molecular roadblocks for cellular reprogramming. Mol. Cell 47, 827–838 (2012).

  12. 12.

    et al. Inefficient reprogramming of fibroblasts into cardiomyocytes using Gata4, Mef2c, and Tbx5. Circ. Res. 111, 50–55 (2012).

  13. 13.

    , & A guide to choosing fluorescent proteins. Nat. Methods 2, 905–909 (2005).

  14. 14.

    , , , & Very slow turnover of beta-cells in aged adult mice. Diabetes 54, 2557–2567 (2005).

  15. 15.

    , & All β cells contribute equally to islet growth and maintenance. PLoS Biol. 5, e163 (2007).

  16. 16.

    , & Transplanted beta cell response to increased metabolic demand. Changes in beta cell replication and mass. J. Clin. Invest. 93, 1577–1582 (1994).

  17. 17.

    Life and death of the pancreatic β cells. Trends Endocrinol. Metab. 11, 375–378 (2000).

  18. 18.

    , , & Beneficial influence of glycemic control upon the growth and function of transplanted islets. Diabetes 43, 1334–1339 (1994).

  19. 19.

    , & Beta cell mass and growth after syngeneic islet cell transplantation in normal and streptozocin diabetic C57BL/6 mice. J. Clin. Invest. 91, 780–787 (1993).

  20. 20.

    et al. Genome-scale DNA methylation maps of pluripotent and differentiated cells. Nature 454, 766–770 (2008).

  21. 21.

    et al. In vivo reprogramming of pancreatic acinar cells to three islet endocrine subtypes. eLife 3, e01846 (2014).

  22. 22.

    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).

  23. 23.

    , & Cadherins regulate aggregation of pancreatic beta-cells in vivo. Development 122, 2895–2902 (1996).

  24. 24.

    , & Structure-function relationships in pancreatic islets: support for intraislet modulation of insulin secretion. Endocrinology 117, 2073–2080 (1985).

  25. 25.

    et al. Rapid and reversible secretion changes during uncoupling of rat insulin-producing cells. J. Clin. Invest. 86, 759–768 (1990).

  26. 26.

    et al. Loss of connexin36 channels alters beta-cell coupling, islet synchronization of glucose-induced Ca2+ and insulin oscillations, and basal insulin release. Diabetes 54, 1798–1807 (2005).

  27. 27.

    et al. EphA-Ephrin-A-mediated beta cell communication regulates insulin secretion from pancreatic islets. Cell 129, 359–370 (2007).

  28. 28.

    , , , & Reprogramming of pancreatic exocrine cells towards a beta (β) cell character using Pdx1, Ngn3 and MafA. Biochem. J. 442, 539–550 (2012).

  29. 29.

    , , , & In vivo reprogramming of Sox9+ cells in the liver to insulin-secreting ducts. Proc. Natl. Acad. Sci. USA 109, 15336–15341 (2012).

  30. 30.

    et al. De novo formation of insulin-producing “neo-beta cell islets” from intestinal crypts. Cell Reports 6, 1046–1058 (2014).

  31. 31.

    et al. Reproducible high yield of rat islets by stationary in vitro digestion following pancreatic ductal or portal venous collagenase injection. Transplantation 43, 725–730 (1987).

  32. 32.

    , , & Direct lineage conversion of pancreatic exocrine to endocrine beta cells in vivo with defined factors. Methods Mol. Biol. 1150, 247–262 (2014).

  33. 33.

    et al. Preparation of reduced representation bisulfite sequencing libraries for genome-scale DNA methylation profiling. Nat. Protoc. 6, 468–481 (2011).

  34. 34.

    Linear models and empirical Bayes methods for assessing differential expression in microarray experiments. Stat. Appl. Genet. Molec. Biol. 3, 3 (2004).

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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.


  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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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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