HIF1α synergizes with glucocorticoids to promote BFU-E progenitor self-renewal
HIF1α synergizes with glucocorticoids to promote BFU-E progenitor self-renewal
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DOI：
10.1182/blood-2010-07-295550
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发表时间：
2011-03-24
期刊：
影响因子：
20.3
通讯作者：
Lodish, Harvey F.
中科院分区：
文献类型：
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作者：
Flygare, Johan;Estrada, Violeta Rayon;Lodish, Harvey F.
为了找到比促红细胞生成素更早刺激红细胞生成并增强红细胞集落形成单位（CFU-E）产生的小分子，我们研究了糖皮质激素增加CFU-E形成的机制。使用通过新技术纯化的红系爆发形成单位（BFU-E）和CFU-E祖细胞，我们证明糖皮质激素刺激最早的（BFU-E）祖细胞进行有限的自我更新，这使CFU-E细胞的形成增加> 20倍。有趣的是，糖皮质激素诱导BFU-E细胞中基因的表达，这些细胞含有高度富集缺氧诱导因子1 α（HIF 1 α）结合位点的启动子区域。这表明HIF 1 α的激活可能增强或取代糖皮质激素对BFU-E自我更新的作用。事实上，通过脯氨酰羟化酶抑制剂（PHI）的HIF 1 α活化与糖皮质激素协同作用，并使CFU-Es的产生增加170倍。由于PHI能够在非常低浓度的糖皮质激素下增加成红细胞产生，因此PHI诱导的BFU-E祖细胞的刺激代表了用于治疗红细胞生成素抗性贫血的概念上新的治疗窗口。（血。2011; 117（12）：3435-3444）
With the aim of finding small molecules that stimulate erythropoiesis earlier than erythropoietin and that enhance erythroid colony-forming unit (CFU-E) production, we studied the mechanism by which glucocorticoids increase CFU-E formation. Using erythroid burst-forming unit (BFU-E) and CFU-E progenitors purified by a new technique, we demonstrate that glucocorticoids stimulate the earliest (BFU-E) progenitors to undergo limited self-renewal, which increases formation of CFU-E cells > 20-fold. Interestingly, glucocorticoids induce expression of genes in BFU-E cells that contain promoter regions highly enriched for hypoxia-induced factor 1 alpha (HIF1 alpha) binding sites. This suggests activation of HIF1 alpha may enhance or replace the effect of glucocorticoids on BFU-E self-renewal. Indeed, HIF1 alpha activation by a prolyl hydroxylase inhibitor (PHI) synergizes with glucocorticoids and enhances production of CFU-Es 170-fold. Because PHIs are able to increase erythroblast production at very low concentrations of glucocorticoids, PHI-induced stimulation of BFU-E progenitors thus represents a conceptually new therapeutic window for treating erythropoietin-resistant anemia. (Blood. 2011; 117(12): 3435-3444)