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- Title
Oxygen tension regulates pancreatic beta-cell differentiation through hypoxia-inducible factor 1alpha.
- Authors
Heinis M; Simon MT; Ilc K; Mazure NM; Pouysségur J; Scharfmann R; Duvillié B; Heinis, Mylène; Simon, Marie-Thérèse; Ilc, Karine; Mazure, Nathalie M; Pouysségur, Jacques; Scharfmann, Raphael; Duvillié, Bertrand
- Abstract
<bold>Objective: </bold>Recent evidence indicates that low oxygen tension (pO2) or hypoxia controls the differentiation of several cell types during development. Variations of pO2 are mediated through the hypoxia-inducible factor (HIF), a crucial mediator of the adaptative response of cells to hypoxia. The aim of this study was to investigate the role of pO2 in beta-cell differentiation.<bold>Research Design and Methods: </bold>We analyzed the capacity of beta-cell differentiation in the rat embryonic pancreas using two in vitro assays. Pancreata were cultured either in collagen or on a filter at the air/liquid interface with various pO2. An inhibitor of the prolyl hydroxylases, dimethyloxaloylglycine (DMOG), was used to stabilize HIF1alpha protein in normoxia.<bold>Results: </bold>When cultured in collagen, embryonic pancreatic cells were hypoxic and expressed HIF1alpha and rare beta-cells differentiated. In pancreata cultured on filter (normoxia), HIF1alpha expression decreased and numerous beta-cells developed. During pancreas development, HIF1alpha levels were elevated at early stages and decreased with time. To determine the effect of pO2 on beta-cell differentiation, pancreata were cultured in collagen at increasing concentrations of O2. Such conditions repressed HIF1alpha expression, fostered development of Ngn3-positive endocrine progenitors, and induced beta-cell differentiation by O2 in a dose-dependent manner. By contrast, forced expression of HIF1alpha in normoxia using DMOG repressed Ngn3 expression and blocked beta-cell development. Finally, hypoxia requires hairy and enhancer of split (HES)1 expression to repress beta-cell differentiation.<bold>Conclusions: </bold>These data demonstrate that beta-cell differentiation is controlled by pO2 through HIF1alpha. Modifying pO2 should now be tested in protocols aiming to differentiate beta-cells from embryonic stem cells.
- Publication
Diabetes, 2010, Vol 59, Issue 3, p662
- ISSN
0012-1797
- Publication type
journal article
- DOI
10.2337/db09-0891