Single cell transcriptomics of human islet ontogeny defines the molecular basis of beta cell dedifferentiation in T2D

Dedifferentiation of pancreatic beta cells may reduce islet function in type 2 diabetes (T2D). However, the prevalence, plasticity and functional consequences of this cellular state remain unknown. We employed single-cell RNAseq to detail the maturation program of alpha and beta cells during human ontogeny. We show that although both alpha and beta cells mature in part by repressing non-endocrine genes, alpha-cells retain hallmarks of an immature state, while beta-cells attain a full beta-cell specific gene expression program. In islets from T2D donors, both alpha- and beta-cells return to a less mature expression profile, de-repressing the juvenile genetic program and exocrine genes while increasing expression of exocytosis, inflammation and stress response signaling pathways. These changes support the increased proportion of beta-cells displaying suboptimal function observed in T2D islets. These findings provide new insights into the molecular program underlying islet cell maturation during human ontogeny and the loss of transcriptomic maturity that occurs in islets of type 2 diabetics. More that 619 cells from islets of one newborn (84), five toddlers (27, 17, 15, 12, 23), two adolescents (14, 22), four adult (22, 22, 37, 54) controls, and ten T2D donors (24, 13, 11, 30, 15, 23, 11, 19, 34, 24) were sequenced using Fluidigm C1 single-cell RNA-Seq. Numbers in parathesis indicates number of cells sequenced that were assigned a cell type following rigorous evalution.