Single-Cell Transcriptome Profiling Reveals β Cell Maturation in Stem Cell-Derived Islets after Transplantation

Human pluripotent stem cells differentiated to insulin-secreting beta cells (SC-beta cells) in islet organoids could provide an unlimited cell source for diabetes cell replacement therapy, However, current SC-beta cells generated in vitro are transcriptionally and functionally immature compared to native adult beta cells. Here, we use single-cell transcriptomic profiling to catalog changes that occur in transplanted SC-beta cells. We find that transplanted SC-beta cells exhibit drastic transcriptional changes and mature to more closely resemble adult beta cells. Insulin and IAPP protein secretions increase upon transplantation, along with expression of maturation genes lacking with differentiation in vitro, including INS, MAFA, CHGB, and G6PC2. Other differentiated cell types, such as SC-alpha and SC-enterochromaffin (SC-EC) cells, also exhibit large transcriptional changes. This study provides a comprehensive resource for understanding human islet cell maturation and provides important insights into maturation of SC-beta cells and other SC-islet cell types to enable future differentiation strategy improvements.