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Transient cytokine treatment induces acinar cell reprogramming and regenerates functional beta cell mass in diabetic mice

Nature Biotechnology volume 32, pages 7683 (2014) | Download Citation

Abstract

Reprogramming of pancreatic exocrine cells into cells resembling beta cells may provide a strategy for treating diabetes. Here we show that transient administration of epidermal growth factor and ciliary neurotrophic factor to adult mice with chronic hyperglycemia efficiently stimulates the conversion of terminally differentiated acinar cells to beta-like cells. Newly generated beta-like cells are epigenetically reprogrammed, functional and glucose responsive, and they reinstate normal glycemic control for up to 248 d. The regenerative process depends on Stat3 signaling and requires a threshold number of Neurogenin 3 (Ngn3)-expressing acinar cells. In contrast to previous work demonstrating in vivo conversion of acinar cells to beta-like cells by viral delivery of exogenous transcription factors, our approach achieves acinar-to-beta-cell reprogramming through transient cytokine exposure rather than genetic modification.

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Acknowledgements

Special thanks to V. Laurysens, A. Demarré, E. Quartier, J. De Jonge for technical advice and assistance, D. Pipeleers for logistic support and G. Bin for the Stat3lox/lox mouse strain. We thank J. Kornak for support on biostatistics. L.Ba. is a postdoctoral fellow of the Research Foundation – Flanders (FWO). Financial support was obtained from the Research Foundation – Flanders (FWO) (H.H., L.Ba. and L.Bo.), the Juvenile Diabetes Research Foundation (H.H. and L.Bo.), DON Foundation (www.sdon.nl) (H.H.), the European Foundation for the Study of Diabetes (EFSD) (L.Ba., P.B. and L.Bo.), the European Union Sixth (#LSHB-CT-2005-512145), Seventh (HEALTH-F5-2009-241883) Framework Program (H.H. and L.Bo.), Diabetesfonds Nederland (H.H.), NIH U19 DK 042502 and U01 DK 089570 (C.V.E.W. and F.C.P.), P30 DK063720 and U01 DK089541 (M.S.G.).

Author information

Affiliations

  1. Diabetes Research Center, Vrije Universiteit Brussel, Brussels, Belgium.

    • Luc Baeyens
    • , Marie Lemper
    • , Gunter Leuckx
    • , Sofie De Groef
    • , Paola Bonfanti
    • , Geert Stangé
    • , Mark Van de Casteele
    • , Luc Bouwens
    •  & Harry Heimberg
  2. Diabetes Center, California Institute for Regenerative Medicine (CIRM), University of California San Francisco, San Francisco, California, USA.

    • Luc Baeyens
    • , David W Scheel
    •  & Michael S German
  3. The Institute for Medical Research Israel-Canada, The Hebrew University, Jerusalem, Israel.

    • Ruth Shemer
    •  & Yuval Dor
  4. Umeå Center for Molecular Medicine, Umeå University, Umeå, Sweden.

    • Christoffer Nord
    •  & Ulf Ahlgren
  5. Department of Cell and Developmental Biology, Vanderbilt University Program in Developmental Biology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

    • Fong C Pan
    • , Guoqiang Gu
    •  & Christopher V E Wright
  6. Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.

    • Doris A Stoffers
  7. Institut d'Investigacions Biomediques August Pi i Sunyer, Hospital Clinic de Barcelona, Barcelona, Spain.

    • Jorge Ferrer
  8. Imperial College London, London, UK.

    • Jorge Ferrer
  9. Development and Stem Cells Program, Institute of Genetics and Molecular and Cellular Biology (IGBMC), Illkirch, France.

    • Gerard Gradwohl

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Contributions

Design: L.Ba., H.H.; execution of experiments: L.Ba., M.L., G.L., S.D.G., R.S., C.N., D.W.S.; analyses: L.Ba., M.L.; transgenic mouse strain generation: F.C.P., C.V.E.W., Y.D., D.A.S., G.G., J.F., G.G.; cell sorting: L.Ba., G.S.; interpretation of results: L.Ba., M.L., P.B., U.A., M.S.G., M.V.d.C., H.H.; writing: L.Ba., M.S.G., H.H.; critical reading: L.Ba., P.B., C.V.E.W., Y.D., J.F., G.G., L.Bo., M.V.d.C., M.S.G., H.H.; project management: M.S.G., L.Bo., H.H.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Luc Bouwens or Harry Heimberg.

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DOI

https://doi.org/10.1038/nbt.2747