Bone Marrow Mesenchymal Stem Cell-Derived Exosomes Accelerate Functional Recovery After Spinal Cord Injury by Promoting the Phagocytosis of Macrophages to Clean Myelin Debris

Xiaolong Sheng; Jinyun Zhao; Miao Li; Yan Xu; Yi Zhou; Jiaqi Xu; Rundong He; Hongbin Lu; Tianding Wu; Chunyue Duan; Yong Cao; Jianzhong Hu

doi:10.3389/fcell.2021.772205

Bone Marrow Mesenchymal Stem Cell-Derived Exosomes Accelerate Functional Recovery After Spinal Cord Injury by Promoting the Phagocytosis of Macrophages to Clean Myelin Debris

Front Cell Dev Biol. 2021 Nov 8:9:772205. doi: 10.3389/fcell.2021.772205. eCollection 2021.

Authors

Xiaolong Sheng^{1

2

3

4}, Jinyun Zhao^{1

2

3

4}, Miao Li^{1

2

3

4

5}, Yan Xu^{2

3

4

6}, Yi Zhou^{1

2

3

4

7}, Jiaqi Xu^{1

2

3

4}, Rundong He^{1

2

3

4}, Hongbin Lu^{2

3

4

6}, Tianding Wu^{1

2

3

4}, Chunyue Duan^{1

2

3

4}, Yong Cao^{1

2

3

4}, Jianzhong Hu^{1

2

3

4}

Affiliations

¹ Department of Spine Surgery and Orthopaedics, Xiangya Hospital, Central South University, Changsha, China.
² Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Changsha, China.
³ Hunan Engineering Research Center of Sports and Health, Changsha, China.
⁴ National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China.
⁵ Department of Orthopedics, Hunan Children's Hospital, Changsha, China.
⁶ Department of Sports Medicine, Xiangya Hospital, Central South University, Changsha, China.
⁷ Department of Pain, Institute of Pain Medicine, Third Xiangya Hospital of Central South University, Changsha, China.

Abstract

Macrophage phagocytosis contributes predominantly to processing central nervous system (CNS) debris and further facilitates neurological function restoration after CNS injury. The aims of this study were to evaluate the effect of bone marrow mesenchymal stem cells (BMSC)-derived exosomes (BMSC-Exos) on the phagocytic capability of macrophages to clear myelin debris and to investigate the underlying molecular mechanism during the spinal cord injury (SCI) process. This work reveals that monocyte-derived macrophages (MDMs) infiltrating into the SCI site could efficiently engulf myelin debris and process phagocytic material. However, the phagocytic ability of macrophages to clear tissue debris is compromised after SCI. The administration of BMSC-Exos as an approach for SCI treatment could rescue macrophage normal function by improving the phagocytic capability of myelin debris internalization, which is beneficial for SCI repair, as evidenced by better axon regrowth and increased hindlimb locomotor functional recovery in a rodent model. Examination of macrophage treatment with BMSC-Exos revealed that BMSC-Exos could promote the capacity of macrophages to phagocytose myelin debris in vitro and could create a regenerative microenvironment for axon regrowth. In addition, we confirmed that BMSC-Exo treatment resulted in improved phagocytosis of engulfed myelin debris by promoting the expression of macrophage receptor with collagenous structure (MARCO) in macrophages. The inhibition of MARCO with PolyG (a MARCO antagonist) impaired the effect of BMSC-Exos on the phagocytic capacity of macrophages and resulted in compromised myelin clearance at the lesion site, leading to further tissue damage and impaired functional healing after SCI. In conclusion, these data indicated that targeting the phagocytic ability of macrophages may have therapeutic potential for the improvement in functional healing after SCI. The administration of BMSC-Exos as a cell-free immune therapy strategy has wide application prospects for SCI treatment.

Keywords: BMSC derived exosomes; macrophage; myelin debris; phagocytosis; spinal cord injury.