IFNα and bleomycin-induced DNA damage activate distinct stress responses in human islets and induced pluripotent stem cell-derived islet cells.

Pancreatic β-cells undergo different stress responses during the development of type 1 diabetes (T1D), such as the type I interferon (IFN) response and senescence. Although the IFN response leads to endoplasmic reticulum (ER) stress and has been linked to senescence in other cell types, the extent to which senescence and the type I IFN response are related pathways in human β-cells are unclear. To address this question, we compared the transcriptional and protein secretory responses of human donor islets and induced pluripotent stem cell-derived islet cells (SC-islet cells) to IFNα and chemically-induced DNA damage using bleomycin. While IFNα induced a classical IFN response involving HLA Class I genes, ER stress genes, and reversible chemokine secretion, it did not lead to stable induction of senescence-related genes or a senescence-associated secretory phenotype (SASP) in human islets. Similarly, in SC-islet cell models derived from two donors with different HLA haplotypes, IFNα treatment led to the upregulation of IFN genes and HLA Class I genes without an effect on senescence genes or SASP. Conversely, bleomycin-induced DNA damage in SC-islet cells led to signatures of senescence without an effect on IFN genes, ER stress genes, or HLA Class I. Taken together, these data suggest that IFNα exposure and DNA damage elicit distinct stress responses in human donor islets and SC-islet cells. These findings have implications for our understanding of heterogeneity in β-cell stress in T1D.