Intranasal delivery of small extracellular vesicles from specific subpopulation of mesenchymal stem cells mitigates traumatic spinal cord injury

Yi Sun; Jinyun Zhao; Quanbo Liu; Yan Xu; Yiming Qin; Rundong He; Lifu Zheng; Yong Xie; Chengjun Li; Tianding Wu; Yong Cao; Chunyue Duan; Hongbin Lu; Jianzhong Hu

doi:10.1016/j.jconrel.2024.03.037

Intranasal delivery of small extracellular vesicles from specific subpopulation of mesenchymal stem cells mitigates traumatic spinal cord injury

J Control Release. 2024 Apr 3:369:335-350. doi: 10.1016/j.jconrel.2024.03.037. Online ahead of print.

Authors

Yi Sun¹, Jinyun Zhao¹, Quanbo Liu¹, Yan Xu², Yiming Qin¹, Rundong He¹, Lifu Zheng¹, Yong Xie¹, Chengjun Li¹, Tianding Wu¹, Yong Cao¹, Chunyue Duan¹, Hongbin Lu³, Jianzhong Hu⁴

Affiliations

¹ Department of Spine Surgery and Orthopaedics, Xiangya Hospital, Central South University, Xiangya Road 87, Changsha 410008, China; Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Xiangya Road 87, Changsha 410008, China; Hunan Engineering Research Center of Sports and Health, Changsha 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Xiangya Road 87, Changsha 410008, China.
² Department of Sports Medicine, Xiangya Hospital, Central South University, Xiangya Road 87, Changsha 410008, China; Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Xiangya Road 87, Changsha 410008, China; Hunan Engineering Research Center of Sports and Health, Changsha 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Xiangya Road 87, Changsha 410008, China.
³ Department of Sports Medicine, Xiangya Hospital, Central South University, Xiangya Road 87, Changsha 410008, China; Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Xiangya Road 87, Changsha 410008, China; Hunan Engineering Research Center of Sports and Health, Changsha 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Xiangya Road 87, Changsha 410008, China. Electronic address: hongbinlu@csu.edu.cn.
⁴ Department of Spine Surgery and Orthopaedics, Xiangya Hospital, Central South University, Xiangya Road 87, Changsha 410008, China; Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Xiangya Road 87, Changsha 410008, China; Hunan Engineering Research Center of Sports and Health, Changsha 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Xiangya Road 87, Changsha 410008, China. Electronic address: jianzhonghu@csu.edu.cn.

PMID: 38519036
DOI: 10.1016/j.jconrel.2024.03.037

Abstract

Vascular injury following spinal cord injury (SCI) can significantly exacerbate secondary SCI and result in neurological dysfunction. Strategies targeting angiogenesis have demonstrated potential in enhancing functional recovery post-SCI. In the context of angiogenesis, the CD146⁺ and CD271⁺ subpopulations of mesenchymal stem cells (MSCs) have been recognized for their angiogenic capabilities in tissue repair. Small extracellular vesicles (sEVs) derived from MSCs are nanoscale vesicles containing rich bioactive components that play a crucial role in tissue regeneration. However, the precise role of sEVs derived from CD146⁺CD271⁺ UCMSCs (CD146⁺CD271⁺ UCMSC-sEVs) in SCI remain unclear. In this study, CD146⁺CD271⁺ UCMSC-sEVs were non-invasively administered via intranasal delivery, demonstrating a significant capacity to stimulate angiogenesis and improve functional recovery in mice following SCI. Furthermore, in vitro assessments revealed the effective enhancement of migration and tube formation capabilities of the murine brain microvascular endothelial cell line (bEnd.3) by CD146⁺CD271⁺UCMSC-sEVs. MicroRNA array analysis confirmed significant enrichment of multiple microRNAs within CD146⁺CD271⁺ UCMSC-sEVs. Subsequent in vivo and in vitro experiments demonstrated that CD146⁺CD271⁺ UCMSC-sEVs promote enhanced angiogenesis and improved functional recovery mediated by miR-27a-3p. Further mechanistic studies revealed that miR-27a-3p sourced from CD146⁺CD271⁺ UCMSC-sEVs enhances migration and tube formation of bEnd.3 cells in vitro by suppressing the expression of Delta Like Canonical Notch Ligand 4 (DLL4), thereby promoting angiogenesis in vivo. Collectively, our results demonstrate that a crucial role of CD146⁺CD271⁺ UCMSC-sEVs in inhibiting DLL4 through the transfer of miR-27a-3p, which leads to the promotion of angiogenesis and improved functional recovery after SCI.

Keywords: Angiogenesis; Melanoma cell adhesion molecule; Small extracellular vesicles; Spinal cord injury; Umbilical cord mesenchymal stem cell.