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  3. 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

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

  • Acta Pharmacol Sin. 2024 Jun 24. doi: 10.1038/s41401-024-01327-3.
Bian-Lei Yang # 1,  Yao-Ying Long # 2,  Qian Lei 3,  Fei Gao 4,  Wen-Xiang Ren 2,  Yu-Lin Cao 1,  Di Wu 2,  Liu-Yue Xu 1,  Jiao Qu 2,  He Li 2,  Ya-Li Yu 1,  An-Yuan Zhang 2,  Shan Wang 1,  Hong-Xiang Wang 4,  Zhi-Chao Chen 2,  Qiu-Bai Li 5 6
Affiliations

Affiliations

  • 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 Department of Rheumatology and Immunology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China. qiubaili@hust.edu.cn.
  • 6 Hubei Engineering Research Center for Application of Extracellular Vesicles, Hubei University of Science and Technology, Xianning, 437100, China. qiubaili@hust.edu.cn.
  • # Contributed equally.
PMID: 38914677 DOI: 10.1038/s41401-024-01327-3
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

coagulation; extracellular vesicles; heparin; mesenchymal stem cells; pulmonary thromboembolism; tissue factor.

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