Comparative and integrative single cell analysis reveals new insights into the transcriptional immaturity of stem cell-derived β cells

Abstract

Diabetes cell replacement therapy has the potential to be transformed by human pluripotent stem cell-derived β cells (SC-β cells). However, the precise identity of SC-β cells in relationship to primary fetal and adult β-cells remains unclear. Here, we used single-cell sequencing datasets to characterize the transcriptional identity of islets from in vitro differentiation, fetal islets, and adult islets. Our analysis revealed that SC-β cells share a core β-cell transcriptional identity with human adult and fetal β-cells, however SC-β cells possess a unique transcriptional profile characterized by the persistent expression and activation of progenitor and neural-biased gene networks. These networks are present in SC-β cells, irrespective of the derivation protocol used. Notably, fetal β-cells also exhibit this neural signature at the transcriptional level. Our findings offer insights into the transcriptional identity of SC-β cells and underscore the need for further investigation of the role of neural transcriptional networks in their development.

Identification of unique cell type responses in pancreatic islets to stress

“…Another way to study islet health would be to generate SC-islets from patient cells by utilizing genetic engineering to introduce or correct disease-associated genetic variants 20 , 76 , 109 – 114 . Additionally, sequencing datasets from multiple sources could be combined into a more comprehensive atlas to reveal insights 115 to improve SC-islets for modeling, such as including endothelial cells 116 – 119 . Our robust scRNAseq of stressed primary islets provides a resource for future rigorous studies into identifying targets to improve diabetes treatments.…”