AT7867 promotes pancreatic progenitor differentiation of human iPSCs

Abstract

Generation of pure pancreatic progenitor (PP) cells 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 invitro and invivo 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 with 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 with controls (time and group: p<0.0001). Overall, our data show that AT7867 enhances PP cell differentiation leading to accelerated diabetes reversal.