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

Al-Hasani K, Pfeifer A, Courtney M, Ben-Othman N, Gjernes E, Vieira A, Druelle N, Avolio F, Ravassard P, Leuckx G, Lacas-Gervais S, Ambrosetti D, Benizri E, Hecksher-Sorensen J, Gounon P, Ferrer J, Gradwohl G, Heimberg H, Mansouri A, Collombat P
Dev Cell. 2013 26 (1): 86-100

PMID: 23810513 · DOI:10.1016/j.devcel.2013.05.018

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.

Copyright © 2013 Elsevier Inc. All rights reserved.

MeSH Terms (19)

Animals Basic Helix-Loop-Helix Transcription Factors Blood Glucose Cell Differentiation Cell Lineage Cell Movement Cellular Reprogramming Diabetes Mellitus, Experimental Epithelial-Mesenchymal Transition Gene Expression Regulation Glucagon-Secreting Cells Homeodomain Proteins Hypertrophy Insulin-Secreting Cells Mice Nerve Tissue Proteins Paired Box Transcription Factors Pancreatic Ducts Streptozocin

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