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bioRxiv · 10.1101/2023.05.11.538780

AT7867 promotes pancreatic progenitor differentiation of human iPSCs and accelerates diabetes reversal

Cuesta-Gomez, N.·Verhoeff, K.·Dadheech, N.·Pawlick, R.·Marfil-Garza, B.·Razavy, H.·Shapiro, J. A.
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Abstract

Generation of pure pancreatic progenitor cells (PPs) is critical for clinical translation of stem cell derived islets. Herein, we performed PP differentiation with and without AKT/P70 inhibitor AT7867 and characterized the resulting cells at protein and transcript level in vitro and in vivo upon transplantation into diabetic mice. AT7867 treatment increased the percentage of PDX1+NKX6.1+ (-AT7867: 50.9% [IQR 48.9%-53.8%]; +AT7867: 90.8% [IQR 88.9%-93.7%]; p=0.0021) and PDX1+GP2+ PP cells (-AT7867: 39.22% [IQR 36.7%-44.1%; +AT7867: 90.0% [IQR 88.2%-93.6%]; p=0.0021). Transcriptionally, AT7867 treatment significantly upregulated PDX1 (p=0.0001), NKX6.1 (p=0.0005) and GP2 (p=0.002) expression compared to controls, while off-target markers PODXL (p<0.0001) and TBX2 (p <0.0001) were significantly downregulated. Transplantation of AT7867 treated PPs resulted in faster hyperglycemia reversal in diabetic mice compared to controls (time and group: p<0.0001). Overall, our data shows that AT7867 enhances PP cell differentiation leading to accelerated diabetes reversal.

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Cuesta-Gomez, N., Verhoeff, K., Dadheech, N., Pawlick, R., Marfil-Garza, B., Razavy, H., Shapiro, J. A.. 2023-05-12. AT7867 promotes pancreatic progenitor differentiation of human iPSCs and accelerates diabetes reversal. https://doi.org/10.1101/2023.05.11.538780

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