Triple Notch/Tgfβ/FoxO1 blockade converts multiple intestinal sub-lineages into β-like cells and lowers glycemia in diabetic animals

Du, W.; Wang, J.; Kuo, T.; Wang, L.; McKimpson, W.; Son, J.; Watanabe, H.; Kitamoto, T.; Yunkyoung, L.; Ratner, L.; McCune, K.; Chen, Y.-W.; Grubbs, B.; Thornton, M.; Fan, J.; Sultana, N.; Diaz, B.; Balasubramanian, I.; Gao, N.; Belvedere, S.; Accili, D.

doi:10.1101/2022.03.21.484748

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bioRxiv · 10.1101/2022.03.21.484748

Triple Notch/Tgfβ/FoxO1 blockade converts multiple intestinal sub-lineages into β-like cells and lowers glycemia in diabetic animals

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Abstract

Insulin is the essential treatment of Type 1 (T1D) and is often used in Type 2 Diabetes. For nearly five decades, efforts have been focused on replenishing {beta}-cells in T1D patients as a more durable treatment. Gut endocrine cells can be converted into insulin-producing cells, but their numbers are limited. In this study we report that insulin-immunoreactive cells with Paneth/goblet cell features are present in human fetal intestine, in addition to enteroendocrine cells. Accordingly, lineage tracing experiments show that, besides enterochromaffin cells, the Paneth/goblet lineage can undergo conversion to the insulin lineage upon genetic or pharmacologic Foxo1 ablation in mice. We leveraged these data to design a screening platform in organoids to accurately quantitate {beta}-like cell reprogramming and fine-tune a combination treatment to increase the efficiency of the conversion process by expanding the intestinal secretory lineage. We identified a triple blockade of FoxO1, Notch, and Tgf{beta} that, when tested in insulin-deficient diabetic animals resulted in a near-normalization of glucose levels, associated with the appearance of gut insulin-producing cells. The findings illustrate a therapeutic approach to replace insulin treatment in diabetes.

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Du, W., Wang, J., Kuo, T., Wang, L., McKimpson, W., Son, J., Watanabe, H., Kitamoto, T., Yunkyoung, L., Ratner, L., McCune, K., Chen, Y.-W., Grubbs, B., Thornton, M., Fan, J., Sultana, N., Diaz, B., Balasubramanian, I., Gao, N., Belvedere, S., Accili, D.. 2022-03-21. Triple Notch/Tgfβ/FoxO1 blockade converts multiple intestinal sub-lineages into β-like cells and lowers glycemia in diabetic animals. https://doi.org/10.1101/2022.03.21.484748

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