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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 Pharmacologica Sinica volume 45, pages 2300–2312 (2024)Cite this article

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.

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Fig. 1: Validation of UC-EVs and detection of their surface TF/CD142 antigens.
Fig. 2: Procoagulant properties of UC-EVs.
Fig. 3: TF/CD142-dependent procoagulant activity of UC-EVs.
Fig. 4: Lethal PE induced by intravenous infusion of UC-EVs in mice.
Fig. 5: UC-EVs infusion induced coagulation reaction in vivo.
Fig. 6: Prevention of PE by slower infusion of UC-EVs or pre-injection of heparin.
Fig. 7: Schematic illustrations for the risk and mechanism of PE-induced acute death with the preventive strategies.

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Acknowledgements

This research was supported by grants from the National Key Research and Development Program of China (2021YFA1101500), the National Natural Science Foundation of China (81974221, 81974009, and 92049119), the Hubei Innovation Group Foundation (2022CFA019) and the General Program of Health Commission of Hubei Province (WJ2023M126). We would like to thank Shao-hua Zhang, Si-si Li, Na Li, Fan Hu, and Wen-long Huang from the Medical Sub-center, Analytical & Testing Center, Huazhong University of Science & Technology for their technical assistance.

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  1. These authors contributed equally: Bian-lei Yang, Yao-ying Long

Authors and Affiliations

  1. Department of Rheumatology and Immunology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China

    Bian-lei Yang, Yu-lin Cao, Liu-yue Xu, Ya-li Yu, Shan Wang & Qiu-bai Li

  2. Department of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China

    Yao-ying Long, Wen-xiang Ren, Di Wu, Jiao Qu, He Li, An-yuan Zhang & Zhi-chao Chen

  3. West China Biomedical Big Data Center, West China Hospital, Sichuan University, Chengdu, 610041, China

    Qian Lei

  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

    Fei Gao & Hong-xiang Wang

  5. Hubei Engineering Research Center for Application of Extracellular Vesicles, Hubei University of Science and Technology, Xianning, 437100, China

    Qiu-bai Li

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Contributions

ZCC and QBL conceived the idea and directed the entire study. BLY and YYL performed most of the experiments. BLY and YYL drafted the paper, and QBL revised it. QL, FG, WXR, YLC, DW, LYX, JQ, HL, YLY, AYZ, SW, and HXW contributed to conducting research, refining ideas, and finalizing the manuscript. All authors have approved the submitted version of the manuscript.

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Correspondence to Qiu-bai Li.

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Yang, Bl., Long, Yy., Lei, Q. et al. 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 45, 2300–2312 (2024). https://doi.org/10.1038/s41401-024-01327-3

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