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JCI Insight. 2018 Feb 8;3(3). pii: 97732. doi: 10.1172/jci.insight.97732. [Epub ahead of print]

Virus-like infection induces human β cell dedifferentiation.

Author information

1
INSERM U1016, Cochin Institute, Paris, France.
2
CNRS UMR 8104, Paris, France.
3
University of Paris Descartes, Sorbonne Paris Cité, Paris, France.
4
Paul Langerhans Institute Dresden of the Helmholtz Center Munich at University Hospital Carl Gustav Carus and Faculty of Medicine, Technische Universität Dresden, Dresden, Germany.
5
Molecular Diabetology, University Hospital Carl Gustav Carus and Faculty of Medicine, Technische Universität Dresden, Dresden, Germany.
6
German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany.
7
Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany.
8
Cell Therapy Unit Hospital Saint-Louis and University Paris-Diderot, Paris, France.
9
Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
10
Department of Diabetes, School of Life Course Sciences, Faculty of Life Sciences and Medicine, Denmark Hill, King's College London, London, United Kingdom.
11
Department of Medicine III, University Hospital Carl Gustav Carus, Dresden, Germany.

Abstract

Type 1 diabetes (T1D) is a chronic disease characterized by an autoimmune-mediated destruction of insulin-producing pancreatic β cells. Environmental factors such as viruses play an important role in the onset of T1D and interact with predisposing genes. Recent data suggest that viral infection of human islets leads to a decrease in insulin production rather than β cell death, suggesting loss of β cell identity. We undertook this study to examine whether viral infection could induce human β cell dedifferentiation. Using the functional human β cell line EndoC-βH1, we demonstrate that polyinosinic-polycytidylic acid (PolyI:C), a synthetic double-stranded RNA that mimics a byproduct of viral replication, induces a decrease in β cell-specific gene expression. In parallel with this loss, the expression of progenitor-like genes such as SOX9 was activated following PolyI:C treatment or enteroviral infection. SOX9 was induced by the NF-κB pathway and also in a paracrine non-cell-autonomous fashion through the secretion of IFN-α. Lastly, we identified SOX9 targets in human β cells as potentially new markers of dedifferentiation in T1D. These findings reveal that inflammatory signaling has clear implications in human β cell dedifferentiation.

KEYWORDS:

Beta cells; Diabetes; Inflammation; NF-kappaB; Virology

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