AT7867 promotes pancreatic progenitor differentiation of human iPSCs

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 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 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.

 

Comments:

It seems like you're discussing a scientific study related to generating pancreatic progenitor (PP) cells and their transplantation for treating diabetes. The study appears to have investigated the effects of the AKT/P70 inhibitor AT7867 on the differentiation of these cells and their subsequent transplantation into diabetic mice. The findings suggest that AT7867 treatment increased the percentage of specific markers associated with PP cells, such as PDX1+NKX6.1+ and PDX1+GP2+, both in vitro and in vivo.

The transcriptional analysis indicated that AT7867 treatment upregulated the expression of key markers (PDX1, NKX6.1, and GP2) relevant to pancreatic progenitor cells, while reducing the expression of off-target markers like PODXL and TBX2.

Moreover, the transplantation of AT7867-treated PP cells into diabetic mice resulted in a faster reversal of hyperglycemia compared to the control group.

These findings collectively suggest that AT7867 treatment enhances the differentiation of PP cells, leading to improved characteristics and quicker reversal of diabetes upon transplantation.

Is there anything specific you'd like to know or explore further about this study?

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S1558	AT7867	AT7867 is a potent ATP-competitive inhibitor of Akt1/2/3 and p70S6K/PKA with IC50 of 32 nM/17 nM/47 nM and 85 nM/20 nM in cell-free assays, respectively; little activity outside the AGC kinase family.

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