4.1 Multiple Sclerosis

MS is the most common inflammatory disease of the central nervous system (CNS), which is characterized by demyelination, neuronal damage and loss, and ultimately neurological dysfunction (80). Experimental autoimmune encephalomyelitis (EAE) is the commonly used animal model of MS (81). As the primary immune cells of the central nervous system, microglia can maintain tissue homeostasis and contribute to central nervous system development under normal physiological conditions (82). Following pathogen invasion, activated microglia with an M1 phenotype as the first line of defense secrete pro-inflammatory cytokines to eliminate invading pathogens. However, when tissue homeostasis is restored, microglia exhibiting an M2 phenotype need to be activated, otherwise the excessive release of pro-inflammatory cytokines can lead to neuronal damage (83). Microglia have both neurodestructive and neuroprotective functions. An imbalance of the M1/M2 phenotype inhibits the nerve protection function and promotes the occurrence of MS (84). Therefore, M1 to M2 polarization of microglia may be beneficial to the neuroprotective function of microglia, thereby preventing disease progression. The study by Zijian et al. demonstrated that BM-MSC-EXOs therapy inhibits microglia from developing into an M1 phenotype, promotes M2 phenotype polarization, and secretes anti-inflammatory cytokines (e.g., TNF-α, IL-10, and TGF-β). Moreover, BM-MSC-EXOs treatment significantly improved the neurobehavioral symptoms of EAE rats and relieved the inflammation and demyelination of CNS (85). Human periodontal ligament stem cells (hPDLSCs)-EVs from MS patients has been shown to inhibit NALP3 inflammasome activation in an EAE model (86). Although substantial progress has been made in the treatment of MS, the appropriate treatment for MS remains controversial. The currently available drugs may have potentially harmful side effects and cannot meet future needs (87). MSC-EXOs is a natural non-toxic vesicle that can deliver mRNA, miRNA, and proteins, as well as alleviate the condition of EAE by regulating microglia polarization (88). As the carrier of MSC-specific tolerance molecules (e.g., PD-L1, Galecin-1 [GAL-1], and TGF-β), MSC-EVs can effectively inhibit the activation and proliferation of self-responding lymphocytes and promote the secretion of anti-inflammatory cytokines derived from lymphocytes, thereby alleviating EAE disease progression (76). In another study, it was also shown that the infiltration of microglia in spinal cord sections treated with MSC-EXOs was significantly reduced, and MSC-EXOs induced the formation of Tregs and alleviated the development of EAE (89). Therefore, MSC-EXOs may hold great potential for the treatment of MS.