[PDF][PDF] Adult duct-lining cells can reprogram into β-like cells able to counter repeated cycles of toxin-induced diabetes

K Al-Hasani, A Pfeifer, M Courtney, N Ben-Othman… - Developmental cell, 2013 - cell.com
K Al-Hasani, A Pfeifer, M Courtney, N Ben-Othman, E Gjernes, A Vieira, N Druelle, F Avolio…
Developmental cell, 2013cell.com
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 …
Summary
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.
cell.com