Stage-Specific Transcriptomic Changes In Pancreatic Alpha-Cells After Massive Beta-Cell Loss

BackgroundLoss of pancreatic insulin-secreting beta -cells due to metabolic or autoimmune damage leads to the development of diabetes. The discovery that alpha -cells can be efficiently reprogrammed into insulin-secreting cells in mice and humans has opened promising avenues for innovative diabetes therapies. beta -cell loss triggers spontaneous reprogramming of only 1-2% of alpha -cells, limiting the extent of regeneration. Most alpha -cells are refractory to conversion and their global transcriptomic response to severe beta -cell loss as well as the mechanisms opposing their reprogramming into insulin producers are largely unknown. Here, we performed RNA-seq on FAC-sorted alpha -cells to characterize their global transcriptional responses at different time points after massive beta -cell ablation.ResultsOur results show that alpha -cells undergo stage-specific transcriptional changes 5- and 15-days post-diphtheria toxin (DT)-mediated beta -cell ablation. At 5days, alpha -cells transiently upregulate various genes associated with interferon signaling and proliferation, including Interferon Induced Protein with Tetratricopeptide Repeats 3 (Ifit3). Subsequently, at 15days post beta -cell ablation, alpha -cells undergo a transient downregulation of genes from several pathways including Insulin receptor, mTOR and MET signaling.ConclusionsThe results presented here pinpoint novel markers discriminating alpha -cells at different stages after acute beta -cell loss, and highlight additional signaling pathways that are modulated in alpha -cells in this context.