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Journal Article

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

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Mansouri,  A.
Research Group of Molecular Cell Differentiation, MPI for biophysical chemistry, Max Planck Society;

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Citation

Al-Hasani, K., Pfeifer, A., Courtney, M., Ben-Othman, N., Gjernes, E., Vieira, A., et al. (2013). Adult duct-lining cells can reprogram into β-like cells able to counter repeated cycles of toxin-induced diabetes. Developmental Cell, 26(1), 86-100. doi:10.1016/j.devcel.2013.05.018.


Cite as: http://hdl.handle.net/11858/00-001M-0000-0014-3C2F-6
Abstract
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.