Adult Duct-Lining Cells Can Reprogram into β-like Cells Able to Counter Repeated Cycles of Toxin-Induced Diabetes

It was recently demonstrated that embryonic glucagon-producing cells in the pancreas can regenerate and convert into insulin-producing β-like cells through the constitutive/ectopic expression of the Pax4 gene. However, whether α cells in adult mice display the same plasticity is unknown. Similarly, the mechanisms underlying such reprogramming remain unclear. We now demonstrate that the misexpression of Pax4 in glucagon+ cells age-independently induces their conversion into β-like cells and their glucagon shortage-mediated replacement, resulting in islet hypertrophy and in an unexpected islet neogenesis. Combining several lineage-tracing approaches, we show that, upon Pax4-mediated α-to-β-like cell conversion, pancreatic duct-lining precursor cells are continuously mobilized, re-express the developmental gene Ngn3, and successively adopt a glucagon+ and a β-like cell identity through a mechanism involving the reawakening of the epithelial-to-mesenchymal transition. Importantly, these processes can repeatedly regenerate the whole β cell mass and thereby reverse several rounds of toxin-induced diabetes, providing perspectives to design therapeutic regenerative strategies. [Display omitted] •Adult glucagon+ cells can be converted into β-like cells upon Pax4 misexpression•Duct cells can reprogram into β-like cells via epithelial-to-mesenchymal transition•Pax4 misexpression in glucagon+ cells induces cycles of β-like cell regeneration•Regenerated β-like cells are functional and can counter chemically induced diabetes Using the mouse as a model, Al-Hasani et al. show that adult pancreatic glucagon+ cells can be regenerated and converted into β-like cells by the expression of a single gene, Pax4. These processes can repeatedly regenerate the whole pancreatic β cell mass and thereby counter several rounds of chemically induced diabetes.