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

ABSTRACT

Diabetes cell replacement therapy has the potential to be transformed by human pluripotent stem cell-derived ß cells (SC-ß cells). However, the precise identity of SC-ß cells in relationship to primary fetal and adult ß-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-ß cells share a core ß-cell transcriptional identity with human adult and fetal ß-cells, however SC-ß 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-ß cells, irrespective of the derivation protocol used. Notably, fetal ß-cells also exhibit this neural signature at the transcriptional level. Our findings offer insights into the transcriptional identity of SC-ß cells and underscore the need for further investigation of the role of neural transcriptional networks in their development.