Pharmacological conversion of gut epithelial cells into insulin-producing cells lowers glycemia in diabetic animals

• Text
• PDF

Abstract

As a highly regenerative organ, the intestine is a promising source for cellular reprogramming for replacing lost pancreatic β cells in diabetes. Gut enterochromaffin cells can be converted to insulin-producing cells by forkhead box O1 (FoxO1) ablation, 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. Accordingly, lineage-tracing experiments show that, upon genetic or pharmacologic FoxO1 ablation, the Paneth/goblet lineage can also undergo conversion to the insulin lineage. We designed a screening platform in gut organoids to accurately quantitate β-like cell reprogramming and fine-tune a combination treatment to increase the efficiency of the conversion process in mice and human adult intestinal organoids. We identified a triple blockade of FOXO1, Notch, and TGF-β that, when tested in insulin-deficient streptozotocin (STZ) or NOD diabetic animals, resulted in near normalization of glucose levels, associated with the generation of intestinal insulin-producing cells. The findings illustrate a therapeutic approach for replacing insulin treatment in diabetes.

Authors

Wen Du, Junqiang Wang, Taiyi Kuo, Liheng Wang, Wendy M. McKimpson, Jinsook Son, Hitoshi Watanabe, Takumi Kitamoto, Yunkyoung Lee, Remi J. Creusot, Lloyd E. Ratner, Kasi McCune, Ya-Wen Chen, Brendan H. Grubbs, Matthew E. Thornton, Jason Fan, Nishat Sultana, Bryan S. Diaz, Iyshwarya Balasubramanian, Nan Gao, Sandro Belvedere, Domenico Accili