IAPP Marks Mono-hormonal Stem-cell Derived β Cells that Maintain Stable Insulin Productionin vitroandin vivo

Abstract

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 functionin vitrowith current published differentiation protocols. We aimed to identify markers of mature subpopulations of SC-β cells by studying transcriptional changes associated within vivomaturation 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-cellsin 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.HighlightsIAPP expressionin vitromarks a mono-hormonal subpopulation of SC-β cells excluding endocrine hormones other than insulinOnly INS+IAPP+cells maintain stableINSexpressionin vitroup to 100 days after differentiationThe small molecule aconitine accelerates IAPP expression in SC-β cellsin vitro