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

Luc Baeyens, Marie Lemper, Gunter Leuckx, Sofie De Groef, Paola Bonfanti, Geert Stangé, Ruth Shemer, Christoffer Nord, David W. Scheel, Fong C. Pan, Ulf Ahlgren, Guoqiang Gu, Doris A. Stoffers, Yuval Dor, Jorge Ferrer, Gerard Gradwohl, Christopher V.E. Wright, Mark Van De Casteele, Michael S. German, Luc BouwensHarry Heimberg*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

153 Scopus citations

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.

Original languageAmerican English
Pages (from-to)76-83
Number of pages8
JournalNature Biotechnology
Volume32
Issue number1
DOIs
StatePublished - Jan 2014

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