IAPP Marks Mono-hormonal Stem-cell Derived β Cells that Maintain Stable Insulin Production in vitro and in vivo.
IAPP Marks Mono-hormonal Stem-cell Derived β Cells that Maintain Stable Insulin Production in vitro and in vivo.
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IAPP 标记单激素干细胞衍生的 β 细胞，可在体外和体内维持稳定的胰岛素生产。
DOI：
10.1101/2024.04.10.587726
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发表时间：
2024
期刊：
影响因子：
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通讯作者：
Melton,DouglasA
中科院分区：
文献类型：
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作者：
Davis,JeffreyC;Ryaboshapkina,Maria;Kenty,JenniferH;Eser,PinarÖ;Menon,Suraj;Tyrberg,Björn;Melton,DouglasA
胰岛移植治疗糖尿病受到供体胰岛可用性和免疫抑制要求的限制。干细胞衍生的胰岛可能会规避这些问题。sc -胰岛可有效控制移植后的葡萄糖代谢，但目前已发表的分化方案尚未在体外实现完全功能。我们旨在通过RNA-seq和共表达网络分析，研究SC-β细胞在体内成熟过程中相关的转录变化，从而鉴定SC-β细胞成熟亚群的标志物。β细胞特异性激素胰岛淀粉样蛋白多肽（IAPP）成为此类标记物的首选候选物。IAPP+细胞比IAPP−细胞具有更成熟的β细胞基因表达和更高的细胞胰岛素含量。IAPP+ INS+细胞在长期培养中比IAPP−INS+细胞更稳定，移植到小鼠体内后仍能保持胰岛素的表达。最后，我们进行了小分子筛选，以确定增强IAPP表达的化合物。乌头碱上调IAPP，有助于优化分化方案。
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.