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

Jun-Kai Ma, Li-Da Su, Lin-Lin Feng, Jing-Lin Li, Li Pan, Qupei Danzeng, Yanwei Li, Tongyao Shang, Xiao-Lin Zhan, Si-Ying Chen, Shibo Ying, Jian-Rao Hu, Xue Qun Chen, Qi Zhang (), Tingbo Liang () and Xin-Jiang Lu ()
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Jun-Kai Ma: Zhejiang University School of Medicine
Li-Da Su: Second Affiliated Hospital of Zhejiang University School of Medicine
Lin-Lin Feng: Zhejiang University School of Medicine
Jing-Lin Li: Zhejiang University School of Medicine
Li Pan: The General Hospital of Tibet Military Area Command
Qupei Danzeng: Department of Tibetan Medicine; University of Tibetan Medicine
Yanwei Li: Zhejiang University School of Medicine
Tongyao Shang: Zhejiang University School of Medicine
Xiao-Lin Zhan: Zhejiang University School of Medicine
Si-Ying Chen: Zhejiang University School of Medicine
Shibo Ying: Hangzhou Medical College
Jian-Rao Hu: Hangzhou Normal University
Xue Qun Chen: School of Brain Science and Brain Medicine
Qi Zhang: Zhejiang University School of Medicine
Tingbo Liang: Zhejiang University School of Medicine
Xin-Jiang Lu: Zhejiang University School of Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: 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 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 central macrophages.

Date: 2024
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DOI: 10.1038/s41467-024-48328-8

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