Human pancreatic islets consist of multiple endocrine cell types. To facilitate the detection of rare cellular states and uncover population heterogeneity, UPENN School of Medicine researchers performed single-cell RNA-sequencing on islets from multiple deceased organ donors, including children, healthy adults, and individuals with type 1 or type 2 diabetes. The researchers developed a robust computational biology framework for cell-type annotation. Using this framework, they show that α- and β-cells from children exhibit less well-defined gene signatures than those in adults. Remarkably, α- and β-cells from donors with type 2 diabetes have expression profiles with features seen in children, indicating a partial dedifferentiation process. The researchers also examined a naturally proliferating α-cell from a healthy adult, for which pathway analysis indicated activation of cell-cycle and repression of checkpoint control pathways. Importantly, this replicating α-cell exhibited activated Sonic hedgehog signaling, a pathway not previously known to contribute to human α-cell proliferation. This study highlights the power of single-cell RNA-seq and provides a stepping-stone for future explorations of cellular heterogeneity in pancreatic endocrine cells.
Principle component analysis reveals distinct clusters of pure cells and ambiguous cells. The number of transcripts detected along with the first four principal components is shown. Analysis using genes more than 3.2-fold differentially expressed between α- and β-cells. Both PC1 and PC2 correlate with the number of transcripts.