Institute of Biochemistry I, Goethe-University Frankfurt, Frankfurt, Germany.
Blood. 2012 Oct 11;120(15):3001-6. doi: 10.1182/blood-2012-03-417022. Epub 2012 Aug 30.
Hypoxia-inducible factors (HIFs) regulate hematopoiesis in the embryo and maintain hematopoietic stem cell function in the adult. How hypoxia and HIFs contribute to hematopoietic lineage differentiation in the adult is ill defined. Here we provide evidence that HIF-1 limits differentiation of precursors into plasmacytoid dendritic cells (pDCs). Low oxygen up-regulated inhibitor of DNA binding 2 (ID2) and suppressed Flt3-L-induced differentiation of bone marrow cells to pDCs in wild-type but not HIF-1α(fl/fl) LysM-Cre bone marrow cells. Moreover, pDC differentiated normally in hypoxic ID2(-/-) bone marrow cultures. Finally, we observed elevated pDC frequencies in bone marrow, blood, and spleen of HIF-1α(fl/fl) LysM-Cre and ID2(-/-), but not HIF-2α(fl/fl) LysM-Cre mice. Our data indicate that the low oxygen content in the bone marrow might limit pDC development. This might be an environmental mechanism to restrict the numbers of these potentially autoreactive cells.
缺氧诱导因子 (HIFs) 调节胚胎中的造血作用，并维持成体中的造血干细胞功能。然而，低氧和 HIFs 如何促进成体造血谱系分化仍不清楚。本研究提供的证据表明，HIF-1 限制了前体细胞向浆细胞样树突状细胞 (pDC) 的分化。低氧上调 DNA 结合抑制因子 2 (ID2)，并抑制野生型而非 HIF-1α(fl/fl)LysM-Cre 骨髓细胞中 Flt3-L 诱导的 pDC 分化。此外，pDC 在缺氧 ID2(-/-)骨髓培养物中正常分化。最后，我们观察到 HIF-1α(fl/fl)LysM-Cre 和 ID2(-/-)，但不是 HIF-2α(fl/fl)LysM-Cre 小鼠的骨髓、血液和脾脏中 pDC 频率升高。我们的数据表明，骨髓中的低氧含量可能限制了 pDC 的发育。这可能是一种环境机制，限制了这些潜在自身反应性细胞的数量。
