Combinatorial Transcription Factor Profiles Predict Mature And Functional Human Islet Alpha And Beta Cells

Islet-enriched transcription factors (TFs) exert broad control over cellular processes in pancreatic alpha and beta cells, and changes in their expression are associated with developmental state and diabetes. However, the implications of heterogeneity in TF expression across islet cell populations are not well understood. To define this TF heterogeneity and its consequences for cellular function, we profiled more than 40,000 cells from normal human islets by single-cell RNA-Seq and stratified alpha and beta cells based on combinatorial TF expression. Subpopulations of islet cells coexpressingARX/ MAFB (alpha cells) and MAFA/MAFB (beta cells) exhibited greater expression of key genes related to glucose sensing and hormone secretion relative to subpopulations expressing only one or neither TF. Moreover, all subpopulations were identified in native pancreatic tissue from multiple donors. By Patch-Seq, MAFA/MAFB-coexpressing beta cells showed enhanced electrophysiological activity. Thus, these results indicate that combinatorial TF expression in islet alpha and beta cells predicts highly functional, mature subpopulations.