TFPI from erythroblasts drives heme production in central macrophages promoting erythropoiesis in polycythemia

作者：Junkai Ma, Li‐Da Su, Linlin Feng, Jinglin Li, Li Pan, Qupei Danzeng, Yanwei Li, Tongyao Shang, Xiaolin Zhan, Siying Chen, Shibo Ying, Jian-Rao Hu, Xue Qun Chen, Qi Zhang, Tingbo Liang, Xin‐Jiang Lu · 发表于：Nature Communications · 年份：2024 · DOI：10.1038/s41467-024-48328-8 · 被引用次数：10 · 研究领域：Hemoglobinopathies and Related Disorders、Erythrocyte Function and Pathophysiology、Myeloproliferative Neoplasms: Diagnosis and Treatment

Abstract 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 V617F 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.