HIF1α and pancreatic β-cell development.

During early embryogenesis, the pancreas shows a paucity of blood flow, and oxygen tension, the partial pressure of oxygen (pO(2)), is low. Later, the blood flow increases as β-cell differentiation occurs. We have previously reported that pO(2) controls β-cell development in rats. Here, we checked that hypoxia inducible factor 1α (HIF1α) is essential for this control. First, we demonstrated that the effect of pO(2) on β-cell differentiation in vitro was independent of epitheliomesenchymal interactions and that neither oxidative nor energetic stress occurred. Second, the effect of pO(2) on pancreas development was shown to be conserved among species, since increasing pO(2) to 21 vs. 3% also induced β-cell differentiation in mouse (7-fold, P<0.001) and human fetal pancreas. Third, the effect of hypoxia was mediated by HIF1α, since the addition of an HIF1α inhibitor at 3% O(2) increased the number of NGN3-expressing progenitors as compared to nontreated controls (9.2-fold, P<0.001). In contrast, when we stabilized HIF1α by deleting ex vivo the gene encoding pVHL in E13.5 pancreas from Vhl floxed mice, Ngn3 expression and β-cell development decreased in such Vhl-deleted pancreas compared to controls (2.5 fold, P<0.05, and 6.6-fold, P<0.001, respectively). Taken together, these data demonstrate that HIF1α exerts a negative control over β-cell differentiation.