Transient cytokine treatment induces acinar cell reprogramming and regenerates functional beta cell mass in diabetic mice
Authors: Gerard Gradwohl
Geert Stangé
Luc Baeyens
Guoqiang Gu
Jorge Ferrer
Mark Van de Casteele
Luc Bouwens
Sofie De Groef
Doris A Stoffers
David W Scheel
Fong C Pan
Paola Bonfanti
Gunter Leuckx
Ruth Shemer
Christoffer Nord
Christopher V E Wright
Harry Heimberg
Ulf Ahlgren
Marie Lemper
Yuval Dor
Michael S German
Journal: Nature biotechnology (2014)
Discipline: BIOLOGY & BIOCHEMISTRY
Keywords: Pancreatic exocrine cells; beta cells; diabetes; epidermal growth factor; ciliary neurotrophic factor
Affiliations: 1] Diabetes Research Center, Vrije Universiteit Brussel, Brussels, Belgium. [2] Diabetes Center, California Institute for Regenerative Medicine (CIRM), University of California San Francisco, San Francisco, California, USA., Diabetes Research Center, Vrije Universiteit Brussel, Brussels, Belgium., The Institute for Medical Research Israel-Canada, The Hebrew University, Jerusalem, Israel., Umeå Center for Molecular Medicine, Umeå University, Umeå, Sweden., Diabetes Center, California Institute for Regenerative Medicine (CIRM), University of California San Francisco, San Francisco, California, USA., Department of Cell and Developmental Biology, Vanderbilt University Program in Developmental Biology, Vanderbilt University Medical Center, Nashville, Tennessee, USA., Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA., 1] Institut d'Investigacions Biomediques August Pi i Sunyer, Hospital Clinic de Barcelona, Barcelona, Spain. [2] Imperial College London, London, UK., Development and Stem Cells Program, Institute of Genetics and Molecular and Cellular Biology (IGBMC), Illkirch, France.

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. 

Retracted: Yes

PubPeer comments:
 2020 retraction. https: www.nature.com articles s41587-020-0426-2 The authors are retracting this paper owing to errors in the reported data. The paper claimed that treatment with a combination of epidermal growth factor and ciliary neurotrophic factor normalized glycemia and converted acinar cells to beta cells in 65% of hyperglycemic mice studied. However, these findings were not reproduced when the authors recently repeated the experiments. Reexamination by immunohistochemistry and genotyping of archived pancreas tissue samples from mice used in Baeyens et al. showed that the transgenic mice reported in Supplementary Figs. 3 and 6 and in Figs. 4 and 5 were misidentified, invalidating data central to the main claims of the paper. ,