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.
Highlights
Spinal cord injury (SCI) is a devastating event that may result in permanent damage to sensation and motor functions below the injured site of the spinal cord (Huang et al, 2020a; Li Y. et al, 2020; Zrzavy et al, 2021)
Several proteins have been previously identified as exosome markers by Western blotting analysis, and the results showed that CD9, TSG101, and CD63 were expressed in bone morrow mesenchymal stem cells (BMSCs)-Exos (Figure 1C)
We administered BMSCExos to rescue normal macrophage function, which resulted in a pro-regenerative environment that promoted axon regeneration and facilitated neurological functional restoration after SCI
Summary
Spinal cord injury (SCI) is a devastating event that may result in permanent damage to sensation and motor functions below the injured site of the spinal cord (Huang et al, 2020a; Li Y. et al, 2020; Zrzavy et al, 2021). SCI provokes an inflammatory response after primary injury consisting of activated resident and infiltrating immune cells (Sefiani and Geoffroy, 2021). A remarkable feature of the inflammatory processes in SCI is the infiltration of monocyte-derived macrophages (MDMs) from the circulation to the lesion site (David et al, 2018). The initial injury triggers inflammation, contributes to oligodendrocyte and neuronal cell death, and causes the accumulation of excessive myelin and cellular debris at the lesion site of the spinal cord (Gensel and Zhang, 2015). Damaged myelin debris is engulfed by MDMs if the blood–brain barrier is disrupted, which is essential for creating a pro-regenerative environment (Wang et al, 2015)
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