Sheng Xiaolong, Zhao Jinyun, Li Miao, Xu Yan, Zhou Yi, Xu Jiaqi, He Rundong, Lu Hongbin, Wu Tianding, Duan Chunyue, Cao Yong, Hu Jianzhong
Department of Spine Surgery and Orthopaedics, Xiangya Hospital, Central South University, Changsha, China.
Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Changsha, China.
Front Cell Dev Biol. 2021 Nov 8;9:772205. doi: 10.3389/fcell.2021.772205. eCollection 2021.
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 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.
巨噬细胞吞噬作用主要有助于处理中枢神经系统（CNS）碎片，并进一步促进中枢神经系统损伤后神经功能的恢复。本研究的目的是评估骨髓间充质干细胞（BMSC）衍生的外泌体（BMSC-Exos）对巨噬细胞清除髓鞘碎片吞噬能力的影响，并研究脊髓损伤（SCI）过程中的潜在分子机制。这项工作表明，浸润到SCI部位的单核细胞衍生巨噬细胞（MDMs）可以有效地吞噬髓鞘碎片并处理吞噬物质。然而，SCI后巨噬细胞清除组织碎片的吞噬能力受损。将BMSC-Exos作为一种SCI治疗方法进行给药，可以通过提高髓鞘碎片内化的吞噬能力来挽救巨噬细胞的正常功能，这对SCI修复有益，在啮齿动物模型中，轴突再生更好和后肢运动功能恢复增加证明了这一点。用BMSC-Exos处理巨噬细胞的研究表明，BMSC-Exos可以促进巨噬细胞吞噬髓鞘碎片的能力，并可以为轴突再生创造一个再生微环境。此外，我们证实，BMSC-Exo处理通过促进巨噬细胞中具有胶原结构的巨噬细胞受体（MARCO）的表达，导致吞噬的髓鞘碎片的吞噬作用得到改善。用PolyG（一种MARCO拮抗剂）抑制MARCO会损害BMSC-Exos对巨噬细胞吞噬能力的影响，并导致损伤部位的髓鞘清除受损，导致SCI后进一步的组织损伤和功能愈合受损。总之，这些数据表明，针对巨噬细胞的吞噬能力可能对改善SCI后的功能愈合具有治疗潜力。将BMSC-Exos作为一种无细胞免疫治疗策略进行给药在SCI治疗中具有广泛的应用前景。
