Targeted Delivery of RGD-CD146+CD271+ Human Umbilical Cord Mesenchymal Stem Cell-Derived Exosomes Promotes Blood-Spinal Cord Barrier Repair after Spinal Cord Injury

Yong Xie; Yi Sun; Yudong Liu; Jinyun Zhao; Quanbo Liu; Jiaqi Xu; Yiming Qin; Rundong He; Feifei Yuan; Tianding Wu; Chunyue Duan; Liyuan Jiang; Hongbin Lu; Jianzhong Hu

doi:10.1021/acsnano.3c04423

Targeted Delivery of RGD-CD146⁺CD271⁺ Human Umbilical Cord Mesenchymal Stem Cell-Derived Exosomes Promotes Blood-Spinal Cord Barrier Repair after Spinal Cord Injury

ACS Nano. 2023 Sep 26;17(18):18008-18024. doi: 10.1021/acsnano.3c04423. Epub 2023 Sep 11.

Authors

Yong Xie^{1

2

3

4}, Yi Sun^{1

2

3

4}, Yudong Liu^{1

2

3

4}, Jinyun Zhao^{1

2

3

4}, Quanbo Liu^{1

2

3

4}, Jiaqi Xu^{1

2

3

4}, Yiming Qin^{1

2

3

4}, Rundong He^{1

2

3

4}, Feifei Yuan^{1

2

3

4}, Tianding Wu^{1

2

3

4}, Chunyue Duan^{1

2

3

4}, Liyuan Jiang^{1

2

3

4}, Hongbin Lu^{5

2

3

4}, Jianzhong Hu^{1

2

3

4}

Affiliations

¹ Department of Spine Surgery and Orthopaedics, Xiangya Hospital, Central South University, Changsha 410005, China.
² Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Changsha 410005, China.
³ Hunan Engineering Research Center of Sports and Health, Changsha 410005, China.
⁴ National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410005, China.
⁵ Department of Sports Medicine, Xiangya Hospital, Central South University, Changsha 410005, China.

PMID: 37695238
DOI: 10.1021/acsnano.3c04423

Abstract

Spinal cord injury (SCI) disrupts the blood-spinal cord barrier (BSCB), potentially exacerbating nerve damage and emphasizing the criticality of preserving the BSCB integrity during SCI treatment. This study explores an alternative therapeutic approach for SCI by identifying a subpopulation of exosomes with stable BSCB function and achieving a specific targeted delivery. Specific subpopulations of CD146⁺CD271⁺ umbilical cord mesenchymal stem cells (UCMSCs) were isolated, from which engineered exosomes (RGD-CD146⁺CD271⁺ UCMSC-Exos) with targeted neovascularization function were obtained through gene transfection. In vivo and in vitro experiments were performed to explore the targeting and therapeutic effects of RGD-CD146⁺CD271⁺ UCMSC-Exos and the potential mechanisms underlying BSCB stabilization and neural function recovery. The results demonstrated that RGD-CD146⁺CD271⁺ UCMSC-Exos exhibited physical and chemical properties similar to those of regular exosomes. Notably, following intranasal administration, RGD-CD146⁺CD271⁺ UCMSC-Exos exhibited enhanced aggregation at the SCI center and demonstrated the specific targeting of neovascular endothelial cells. In the SCI model, intranasal administration of RGD-CD146⁺CD271⁺ UCMSC-Exos reduced Evans blue dye leakage, increased tight junction protein expression, and improved neurological function recovery. In vitro testing revealed that RGD-CD146⁺CD271⁺ UCMSC-Exos treatment significantly reduced the permeability of bEnd.3 cells subjected to oxygen-glucose deprivation, thereby restoring the integrity of tight junctions. Moreover, further exploration of the molecular mechanism underlying BSCB stabilization by CD146⁺CD271⁺ UCMSC-Exos identified the crucial role of the miR-501-5p/MLCK axis in this process. In conclusion, targeted delivery of RGD-CD146⁺CD271⁺ UCMSC-Exos presents a promising and effective treatment option for SCI.

Keywords: Blood−Spinal Cord Barrier; Exosome; Melanoma Cell Adhesion Molecule; Nerve Growth Factor Receptor; Spinal Cord Injury; Umbilical Cord Mesenchymal Stem Cell.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adapalene
Animals
CD146 Antigen
Endothelial Cells
Exosomes*
Humans
Immunologic Factors
Mesenchymal Stem Cells*
Mice
Oligopeptides / pharmacology
Spinal Cord Injuries* / therapy

Substances

CD146 Antigen
Adapalene
Immunologic Factors
Oligopeptides