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

Abstract

SummaryGeneration 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 levelin vitroandin vivoupon 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 upregulatedPDX1(p=0.0001),NKX6.1(p=0.0005) andGP2(p=0.002) expression compared to controls, while off-target markersPODXL(p<0.0001) andTBX2(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.