TFPI from Erythroblasts Drives Heme Production in Central Macrophages Promoting Erythropoiesis in Polycythemia

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 JAK2V617F 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 macrophages.

长期以来，出血与血栓形成被公认为红细胞增多症的常见并发症。然而，凝血系统在红细胞生成过程中的具体作用仍不明确。本研究发现，抗凝蛋白组织因子途径抑制物（tissue factor pathway inhibitor, TFPI）可通过调控成红细胞岛中中央巨噬细胞的血红素生物合成，在红细胞生成过程中发挥关键调控作用。在携带JAK2V617F突变且处于缺氧条件下的人类成红细胞岛中，成红细胞内的TFPI水平显著升高。红细胞系特异性敲除TFPI可通过降低中央巨噬细胞内亚铁螯合酶的表达水平与血红素生物合成能力，损害红细胞生成过程。机制研究表明，TFPI可与血栓调节蛋白相互结合，激活下游ERK1/2-GATA1信号通路，从而诱导中央巨噬细胞的血红素生物合成。进一步实验显示，阻断TFPI可在体外抑制人类红细胞生成，并使红细胞增多症模型小鼠的红系细胞群体恢复至正常水平。上述研究结果证实，成红细胞来源的TFPI在红细胞生成调控中具有重要作用，并揭示了成红细胞与巨噬细胞之间的相互调控关系。