Schmidt, M. D.; Ishahak, M.; Augsornworawat, P.; Millman, J. R.

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