Stage-specific transcriptomic changes in α-cells after massive β-cell loss

Conversion of α-cells into insulin-producers upon β-cell loss is modulated by constitutive signals ensuring α-cell identity maintenance. Here, we characterized the plasticity of mouse α-cells by profiling their transcriptome at different time-points after massive β-cell ablation. Our results show that α-cells undergo stage-specific transcriptional changes 5- and 15-days post-diphtheria toxin (DT)-mediated β-cell ablation. At 5 days, α-cells transiently upregulate various genes associated with interferon signaling and proliferation, including Interferon Induced Protein with Tetratricopeptide Repeats 3 (Ifit3). Subsequently, at 15 days post β-cell ablation, α-cells undergo a transient downregulation of genes from several pathways including Insulin receptor, mTOR and MET signaling. These results pinpoint novel markers discriminating α-cells at different stages after acute β-cell loss, and highlight additional signaling pathways that could be involved in reprogramming the functional identity of α-cells. α-cell transcriptional profile upon β-cell loss.