Article

Lethal pulmonary thromboembolism in mice induced by intravenous human umbilical cord mesenchymal stem cell-derived large extracellular vesicles in a dose- and tissue factor-dependent manner

Bian-lei Yang1, Yao-ying Long2, Qian Lei3, Fei Gao4, Wen-xiang Ren2, Yu-lin Cao1, Di Wu2, Liu-yue Xu1, Jiao Qu2, He Li2, Ya-li Yu1, An-yuan Zhang2, Shan Wang1, Hong-xiang Wang4, Zhi-chao Chen2, Qiu-bai Li1,5
1 Department of Rheumatology and Immunology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
2 Department of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
3 West China Biomedical Big Data Center, West China Hospital, Sichuan University, Chengdu 610041, China
4 Department of Hematology, Key Laboratory for Molecular Diagnosis of Hubei Province, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430014, China
5 Hubei Engineering Research Center for Application of Extracellular Vesicles, Hubei University of Science and Technology, Xianning 437100, China
Correspondence to: Qiu-bai Li: qiubaili@hust.edu.cn,
DOI: 10.1038/s41401-024-01327-3
Received: 30 January 2024
Accepted: 27 May 2024
Advance online: 24 June 2024

Abstract

Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have obvious advantages over MSC therapy. But the strong procoagulant properties of MSC-EVs pose a potential risk of thromboembolism, an issue that remains insufficiently explored. In this study, we systematically investigated the procoagulant activity of large EVs derived from human umbilical cord MSCs (UC-EVs) both in vitro and in vivo. UC-EVs were isolated from cell culture supernatants. Mice were injected with UC-EVs (0.125, 0.25, 0.5, 1, 2, 4 μg/g body weight) in 100 μL PBS via the tail vein. Behavior and mortality were monitored for 30 min after injection. We showed that these UC-EVs activated coagulation in a dose- and tissue factor-dependent manner. UC-EVs-induced coagulation in vitro could be inhibited by addition of tissue factor pathway inhibitor. Notably, intravenous administration of high doses of the UC-EVs (1 μg/g body weight or higher) led to rapid mortality due to multiple thrombus formations in lung tissue, platelets, and fibrinogen depletion, and prolonged prothrombin and activated partial thromboplastin times. Importantly, we demonstrated that pulmonary thromboembolism induced by the UC-EVs could be prevented by either reducing the infusion rate or by pre-injection of heparin, a known anticoagulant. In conclusion, this study elucidates the procoagulant characteristics and mechanisms of large UC-EVs, details the associated coagulation risk during intravenous delivery, sets a safe upper limit for intravenous dose, and offers effective strategies to prevent such mortal risks when high doses of large UC-EVs are needed for optimal therapeutic effects, with implications for the development and application of large UC-EV-based as well as other MSC-EV-based therapies.
Keywords: mesenchymal stem cells; extracellular vesicles; tissue factor; coagulation; pulmonary thromboembolism; heparin

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