The effect of WnT pathway modulators on human iPSC-derived pancreatic beta cell maturation
Vethe, Heidrun; Ghila, Luiza; Berle, Magnus; Hoareau, Laurence; Haaland, Øystein Ariansen; Scholz, Hanne; Paulo, Joao A.; Chera, Simona; Ræder, Helge
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2019-05-08Metadata
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Vethe H, Ghila L, Berle MF, Hoareau ML, Haaland ØA, Scholz HS, Paulo JA, Chera S, Ræder H. The effect of WnT pathway modulators on human iPSC-derived pancreatic beta cell maturation. Frontiers in Endocrinology. 2019;10:293 https://doi.org/10.3389/fendo.2019.00293Abstract
Current published protocols for targeted differentiation of human stem cells toward pancreatic β-cells fail to deliver sufficiently mature cells with functional properties comparable to human islet β-cells. We aimed to assess whether Wnt-modulation could promote the final protocol stages of β-cell maturation, building our hypothesis on our previous findings of Wnt activation in immature hiPSC-derived stage 7 (S7) cells compared to adult human islets and with recent data reporting a link between Wnt/PCP and in vitro β-cell maturation. In this study, we stimulated canonical and non-canonical Wnt signaling in hiPSC-derived S7 cells using syntetic proteins including WNT3A, WNT4, WNT5A and WNT5B, and we inhibited endogenous Wnt signaling with the Tankyrase inhibitor G007-LK (TKi). Whereas neither canonical nor non-canonical Wnt stimulation alone was able to mature hiPSC-derived S7 cells, WNT-inhibition with TKi increased the fraction of monohormonal cells and global proteomics of TKi-treated S7 cells showed a proteomic signature more similar to adult human islets, suggesting that inhibition of endogenous Wnt contributes toward final β-cell maturation.