Epo receptor signaling in macrophages alters the splenic niche to promote erythroid differentiation
Epo receptor signaling in macrophages alters the splenic niche to promote erythroid differentiation
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DOI：
10.1182/blood.2019003480
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发表时间：
2020-07-09
期刊：
影响因子：
20.3
通讯作者：
Paulson, Robert F.
中科院分区：
文献类型：
--
作者：
Chen, Yuanting;Xiang, Jie;Paulson, Robert F.
贫血应激诱导应激性红细胞生成，迅速生成新的红细胞，以恢复组织的氧合。应激性红细胞生成最好的理解是在小鼠的髓外，主要发生在脾。然而，人类和小鼠的应激性红细胞生成都使用了不同于稳态红细胞生成的信号和祖细胞。未成熟的应激性红系祖细胞(SEPs)来源于短期造血干细胞。尽管SEP具有自我更新的能力，但它们受到红系的限制。炎症和贫血应激可诱导SEP快速增殖，但直到血清促红细胞生成素(EPO)水平升高时，SEP才能分化。在这里，我们表明，EPO不是直接调节SEP，而是通过作用于脾细胞壁龛中的巨噬细胞来促进从增殖到分化的转变。在增殖期，巨噬细胞产生典型的Wnt配体，促进增殖和抑制分化。EPO/Stat5依赖的信号通路诱导巨噬细胞产生生物活性脂质介质。前列腺素J2(PGJ(2))的增加可激活依赖于PPARg(PPARg)的Wnt表达抑制，而前列腺素E2(PGE(2))的增加促进SEP的分化。
Anemic stress induces stress erythropoiesis, which rapidly generates new erythrocytes to restore tissue oxygenation. Stress erythropoiesis is best understood in mice where it is extramedullary and occurs primarily in the spleen. However, both human and mouse stress erythropoiesis use signals and progenitor cells that are distinct from steady-state eryth-ropoiesis. Immature stress erythroid progenitors (SEPs) are derived from short-term he-matopoietic stem cells. Although the SEPs are capable of self-renewal, they are erythroid restricted. Inflammation and anemic stress induce the rapid proliferation of SEPs, but they do not differentiate until serum erythropoietin (Epo) levels increase. Here we show that rather than directly regulating SEPs, Epo promotes this transition from proliferation to differentiation by acting on macrophages in the splenic niche. During the proliferative stage, macrophages produce canonical Wnt ligands that promote proliferation and inhibit differentiation. Epo/Stat5-dependent signaling induces the production of bioactive lipid mediators in macrophages. Increased production of prostaglandin J2 (PGJ(2)) activates peroxisome proliferator-activated receptor g (PPARg)-dependent repression of Wnt expression, whereas increased production of prosta-glandin E2 (PGE(2)) promotes the differentiation of SEPs.