Comprehensive alpha, beta, and delta cell transcriptomics reveal an association of cellular aging with MHC class I upregulation

This study aimed to evaluate the efficacy of a purification method developed for isolating alpha, beta, and delta cells from pancreatic islets of adult mice, extending its application to islets from newborn and aged mice. Furthermore, it sought to examine transcriptome dynamics in mouse pancreatic endocrine islet cells throughout postnatal development and to evaluate age-related alterations in intercellular communication within these cell populations. We leveraged the high surface expression of CD71 on beta cells and CD24 on delta cells to FACS-purify alpha, beta, and delta cells from newborn (1-week-old), adult (12-week-old), and old (18-month-old) mice. Bulk RNA sequencing was conducted on these purified cell populations, and subsequent bioinformatic analyses included differential gene expression, overrepresentation, intersection, and intercellular communication analysis. Alpha, beta, and delta cells from newborn and aged mice were successfully FACS-purified using the same method employed for adult mice. Our analysis of the age-related transcriptional changes in alpha, beta, and delta cell populations revealed a decrease in cell cycling and an increase in so-called “neurogenesis” processes during the transition from newborn to adult mice. Progressing from adult to old mice, we observed an increase in ß-2 microglobulin and major histocompatibility complex (MHC) Class I expression. Computational modeling of cell interactions suggested shifts in TGFß and BMP signaling underpinning these age-related changes. Our study demonstrates the effectiveness of our cell sorting technique in purifying endocrine subsets from mouse islets at different ages. We provide a valuable resource for better understanding endocrine pancreas aging and identified increased ß-2 microglobulin and MHC Class I expression as a common hallmark of old alpha, beta, and delta cells, with potential implications for immune response regulation. Overall design: To investigate transcriptomic changes in mouse pancreatic islets during aging, we leveraged data from RNA-seq experiments performed in three replicates of alpha, beta and delta cells at three different timepoints (1 week, 12 months and 18 months old).