Department of Physiology and Department of Hepatobiliary and Pancreatic Surgery of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China.
Neuroscience Care Unit, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310009, China.
Nat Commun. 2024 May 10;15(1):3976. doi: 10.1038/s41467-024-48328-8.
Bleeding and thrombosis are known as common complications of polycythemia for a long time. However, the role of coagulation system in erythropoiesis is unclear. Here, we discover that an anticoagulant protein tissue factor pathway inhibitor (TFPI) plays an essential role in erythropoiesis via the control of heme biosynthesis in central macrophages. TFPI levels are elevated in erythroblasts of human erythroblastic islands with JAK2 mutation and hypoxia condition. Erythroid lineage-specific knockout TFPI results in impaired erythropoiesis through decreasing ferrochelatase expression and heme biosynthesis in central macrophages. Mechanistically, the TFPI interacts with thrombomodulin to promote the downstream ERK1/2-GATA1 signaling pathway to induce heme biosynthesis in central macrophages. Furthermore, TFPI blockade impairs human erythropoiesis in vitro, and normalizes the erythroid compartment in mice with polycythemia. These results show that erythroblast-derived TFPI plays an important role in the regulation of erythropoiesis and reveal an interplay between erythroblasts and central macrophages.
出血和血栓形成长期以来一直被认为是红细胞增多症的常见并发症。然而，凝血系统在红细胞生成中的作用尚不清楚。在这里，我们发现抗凝蛋白组织因子途径抑制剂（TFPI）通过控制中心巨噬细胞中的血红素生物合成，在红细胞生成中发挥着重要作用。在具有 JAK2 突变和缺氧条件的人类红系造血岛的成红细胞中，TFPI 水平升高。红细胞谱系特异性敲除 TFPI 通过降低中心巨噬细胞中的亚铁螯合酶表达和血红素生物合成，导致红细胞生成受损。在机制上，TFPI 与血栓调节蛋白相互作用，促进下游 ERK1/2-GATA1 信号通路，诱导中心巨噬细胞中的血红素生物合成。此外，TFPI 阻断在体外损害人类红细胞生成，并使红细胞增多症小鼠的红细胞区室正常化。这些结果表明，红细胞衍生的 TFPI 在红细胞生成的调节中起着重要作用，并揭示了红细胞和中心巨噬细胞之间的相互作用。
