Stage-specific transcriptomic changes in a-cells after massive ß-cell loss

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