Virus-like infection induces human β cell dedifferentiation

JCI Insight. 2018 Feb 8;3(3):e97732. doi: 10.1172/jci.insight.97732.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Dedifferentiation / drug effects
  • Cell Dedifferentiation / immunology*
  • Cell Line
  • Diabetes Mellitus, Type 1 / immunology*
  • Diabetes Mellitus, Type 1 / virology
  • Enterovirus / immunology
  • Enterovirus Infections / immunology*
  • Enterovirus Infections / virology
  • Gene Expression Profiling
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / immunology
  • Humans
  • Insulin-Secreting Cells / physiology*
  • Interferon Inducers / pharmacology
  • Interferon-alpha / immunology
  • Interferon-alpha / metabolism
  • NF-kappa B / metabolism
  • Poly I-C / pharmacology
  • Primary Cell Culture
  • SOX9 Transcription Factor / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / immunology


  • Interferon Inducers
  • Interferon-alpha
  • NF-kappa B
  • SOX9 Transcription Factor
  • SOX9 protein, human
  • Poly I-C