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Proteomic and Transcriptional Profiles of Human Stem Cell-Derived beta Cells Following Enteroviral Challenge

  • Nyalwidhe, Julius O.
  • Jurczyk, Agata
  • Satish, Basanthi
  • Redick, Sambra D.
  • Qaisar, Natasha
  • Trombly, Melanie I.
  • Vangala, Pranitha
  • Racicot, Riccardo
  • Bortell, Rita
  • Harlan, David M.
  • Greiner, Dale L.
  • Brehm, Michael A.
  • Nadler, Jerry L.
  • Wang, Jennifer P.
Publication Date
Feb 20, 2020
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Enteroviral infections are implicated in islet autoimmunity and type 1 diabetes (T1D) pathogenesis. Significant beta-cell stress and damage occur with viral infection, leading to cells that are dysfunctional and vulnerable to destruction. Human stem cell-derived beta (SC-beta) cells are insulin-producing cell clusters that closely resemble native beta cells. To better understand the events precipitated by enteroviral infection of beta cells, we investigated transcriptional and proteomic changes in SC-beta cells challenged with coxsackie B virus (CVB). We confirmed infection by demonstrating that viral protein colocalized with insulin-positive SC-beta cells by immunostaining. Transcriptome analysis showed a decrease in insulin gene expression following infection, and combined transcriptional and proteomic analysis revealed activation of innate immune pathways, including type I interferon (IFN), IFN-stimulated genes, nuclear factor-kappa B (NF-kappaB) and downstream inflammatory cytokines, and major histocompatibility complex (MHC) class I. Finally, insulin release by CVB4-infected SC-beta cells was impaired. These transcriptional, proteomic, and functional findings are in agreement with responses in primary human islets infected with CVB ex vivo. Human SC-beta cells may serve as a surrogate for primary human islets in virus-induced diabetes models. Because human SC-beta cells are more genetically tractable and accessible than primary islets, they may provide a preferred platform for investigating T1D pathogenesis and developing new treatments.

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