Functional, transcriptomic, and proteomic profiles of human primary and stem cell-derived beta cells in a state of high insulin production and increased fragility

Résumé fourni par la source

Abstract Insulin production is a cardinal feature of pancreatic β cells. Studies in rodents show that β cells can switch between low and high insulin gene activity states and that elevated insulin production makes β cells more vulnerable to stresses associated with diabetes. In people, genetically elevated insulin production increases the risk of type 1 diabetes. Via effects on obesity, hyperinsulinemia contributes to the pathogenesis of type 2 diabetes. Here, we characterize β cells in low and high INS gene activity states sorted from primary human islets transduced with INS -GFP adenovirus and differentiated INS -EGFP knock-in embryonic stem cells (SCβ cells). We profile β cell function, protein synthesis, resilience to diabetes associated stress, single β cell transcriptomes and their co-activity networks, and purified β cell proteomes. We show that human β cells transition between distinct states. High INS cells have elevated maturity marker mRNAs and proteins, increased protein translation, are larger, but also more susceptible to cell death when exposed to diabetes-relevant stresses. We also catalogue thousands of differences in proteins in high INS stem cell-derived β cells compared directly with high INS primary β cells. Our study improves our understanding of the delicate balance between insulin production and β cell resilience and guides the engineering of better β cells. Blurb: transcriptional, proteomic, and functional analyses of insulin gene expression states in human β cells from donor islets and stem cells Key findings Functional, transcriptomic, and proteomic analyses identify similarities and differences between high and low INS gene activity states in primary and stem cell-derived β cells. We characterize the relationship between insulin production and fragility, demonstrating that increased insulin production comes at a cost of reduced resilience to multiple stresses. We report a comprehensive side-by-side proteomic analysis of purified primary and stem cell-derived β cells in the high INS state and identify differences in protein production and secretion machinery, providing a roadmap for making better β cells. Proteomic analyses of unfolded protein response markers and cell death effectors reveal key differences in how primary and stem cell-derived β cells respond to the stress of high insulin production.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.