Transient cytokine treatment induces acinar cell reprogramming and regenerates functional beta cell mass in diabetic mice.
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.
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.
Luc
L
Baeyens
Diabetes Research Center, Vrije Universiteit Brussel, Brussels, Belgium.
Marie
M
Lemper
Diabetes Research Center, Vrije Universiteit Brussel, Brussels, Belgium.
Gunter
G
Leuckx
Diabetes Research Center, Vrije Universiteit Brussel, Brussels, Belgium.
Sofie
S
De Groef
Diabetes Research Center, Vrije Universiteit Brussel, Brussels, Belgium.
Paola
P
Bonfanti
Diabetes Research Center, Vrije Universiteit Brussel, Brussels, Belgium.
Geert
G
Stangé
The Institute for Medical Research Israel-Canada, The Hebrew University, Jerusalem, Israel.
Ruth
R
Shemer
Umeå Center for Molecular Medicine, Umeå University, Umeå, Sweden.
Christoffer
C
Nord
Diabetes Center, California Institute for Regenerative Medicine (CIRM), University of California San Francisco, San Francisco, California, USA.
David W
DW
Scheel
Department of Cell and Developmental Biology, Vanderbilt University Program in Developmental Biology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Fong C
FC
Pan
Umeå Center for Molecular Medicine, Umeå University, Umeå, Sweden.
Ulf
U
Ahlgren
Department of Cell and Developmental Biology, Vanderbilt University Program in Developmental Biology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Guoqiang
G
Gu
Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Doris A
DA
Stoffers
The Institute for Medical Research Israel-Canada, The Hebrew University, Jerusalem, Israel.
Yuval
Y
Dor
1] Institut d'Investigacions Biomediques August Pi i Sunyer, Hospital Clinic de Barcelona, Barcelona, Spain. [2] Imperial College London, London, UK.
Jorge
J
Ferrer
Development and Stem Cells Program, Institute of Genetics and Molecular and Cellular Biology (IGBMC), Illkirch, France.
Gerard
G
Gradwohl
Department of Cell and Developmental Biology, Vanderbilt University Program in Developmental Biology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Christopher V E
CV
Wright
Diabetes Research Center, Vrije Universiteit Brussel, Brussels, Belgium.
Mark
M
Van de Casteele
Diabetes Center, California Institute for Regenerative Medicine (CIRM), University of California San Francisco, San Francisco, California, USA.
Michael S
MS
German
Diabetes Research Center, Vrije Universiteit Brussel, Brussels, Belgium.
Luc
L
Bouwens
Diabetes Research Center, Vrije Universiteit Brussel, Brussels, Belgium.
Harry
H
Heimberg
D061354:Acinar Cells / Q000187:drug effects / Q000473:pathology; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D020934:Ciliary Neurotrophic Factor / Q000008:administration & dosage* / Q000235:genetics; D003920:Diabetes Mellitus / Q000188:drug therapy* / Q000235:genetics; D004815:Epidermal Growth Factor / Q000008:administration & dosage* / Q000235:genetics; D006943:Hyperglycemia / Q000188:drug therapy; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD / Q000235:genetics; D015398:Signal Transduction
D020934:Ciliary Neurotrophic Factor; D004815:Epidermal Growth Factor