Delineating mouse β-cell identity during lifetime and in diabetes with a single cell atlas

Multiple pancreatic islet single-cell RNA sequencing (scRNA-seq) datasets have been generated to study development, homeostasis, and diabetes. However, there is no consensus on cell states and pathways across conditions as well as the value of preclinical mouse models. Since these challenges can only be resolved by jointly analyzing multiple datasets, we present a scRNA-seq cross-condition mouse islet atlas (MIA). We integrated over 300,000 cells from nine datasets with 56 samples, varying in age, sex, and diabetes models, including an autoimmune type 1 diabetes (T1D) model (NOD), a gluco-/lipotoxicity T2D model (db/db), and a chemical streptozotocin (STZ) β-cell ablation model. MIA is a curated resource for interactive exploration and computational querying, providing new insights inaccessible from individual datasets. The β-cell landscape of MIA revealed new disease progression cell states and cross-publication differences between previously suggested marker genes. We show that in the STZ model β-cells transcriptionally correlate to human T2D and mouse db/db, but are less similar to human T1D and mouse NOD. We observe different pathways shared between immature, aged, and diabetes model β-cells. In conclusion, our work presents the first comprehensive analysis of β-cell responses to different stressors, providing a roadmap for the understanding of β-cell plasticity, compensation, and demise.