Islet transplantation for treatment of diabetes is limited by availability of donor islets and requirements for immunosuppression. Stem cell-derived islets might circumvent these issues. SC-islets effectively control glucose metabolism post transplantation, but do not yet achieve full function in vitro with current published differentiation protocols. We aimed to identify markers of mature subpopulations of SC-β cells by studying transcriptional changes associated with in vivo maturation of SC-β cells using RNA-seq and co-expression network analysis. The β cell-specific hormone islet amyloid polypeptide (IAPP) emerged as the top candidate to be such a marker. IAPP + cells had more mature β cell gene expression and higher cellular insulin content than IAPP - cells in vitro . IAPP + INS + cells were more stable in long-term culture than IAPP - INS + cells and retained insulin expression after transplantation into mice. Finally, we conducted a small molecule screen to identify compounds that enhance IAPP expression. Aconitine up-regulated IAPP and could help to optimize differentiation protocols.

Highlights

IAPP expression in vitro marks a mono-hormonal subpopulation of SC-β cells excluding endocrine hormones other than insulin Only INS + IAPP + cells maintain stable INS expression in vitro up to 100 days after differentiation The small molecule aconitine accelerates IAPP expression in SC-β cells in vitro