Exosome-specific loading Sox10 for the treatment of Cuprizone-induced demyelinating model.

Demyelination is a pathological feature commonly observed in various central nervous system diseases. It is characterized by the aggregation of oligodendrocyte progenitor cells (OPCs) in the lesion area, which face difficulties in differentiating into mature oligodendrocytes (OLGs). The differentiation of OPCs requires the presence of Sox10, but its expression decreases under pathological conditions. Therefore, we propose a therapeutic strategy to regulate OPCs differentiation and achieve myelin repair by endogenously loading Sox10 into exosomes. To accomplish this, we generated a lentivirus-armed Sox10 that could anchor to the inner surface of the exosome membrane. We then infected HEK293 cells to obtain exosomes with high expression of Sox10 (exosomes-Sox10, ExoSs). In vitro, experiments confirmed that both Exos and ExoSs can be uptaken by OPCs, but only ExoSs exhibit a pro-differentiation effect on OPCs. In vivo, we administered PBS, Exos, and ExoSs to cuprizone-induced demyelinating mice. The results demonstrated that ExoSs can regulate the differentiation of PDGFRα+ OPCs into APC+ OLGs and reduce myelin damage in the corpus callosum region of the mouse brain compared to other groups. Further testing suggests that Sox10 may have a reparative effect on the myelin sheath by enhancing the expression of MBP, possibly facilitated by the exosome delivery of the protein into the lesion. This endogenously loaded technology holds promise as a strategy for protein-based drugs in the treatment of demyelinating diseases.

Microglia-derived exosomes modulate myelin regeneration via miR-615-5p/MYRF axis.

Demyelination and failure of remyelination in the central nervous system (CNS) characterize a number of neurological disorders. Spontaneous remyelination in demyelinating diseases is limited, as oligodendrocyte precursor cells (OPCs), which are often present in demyelinated lesions in abundance, mostly fail to differentiate into oligodendrocytes, the myelinating cells in the CNS. In addition to OPCs, the lesions are assembled numbers of activated resident microglia/infiltrated macrophages; however, the mechanisms and potential role of interactions between the microglia/macrophages and OPCs are poorly understood. Here, we generated a transcriptional profile of exosomes from activated microglia, and found that miR-615-5p was elevated. miR-615-5p bound to 3'UTR of myelin regulator factor (MYRF), a crucial myelination transcription factor expressed in oligodendrocyte lineage cells. Mechanistically, exosomes from activated microglia transferred miR-615-5p to OPCs, which directly bound to MYRF and inhibited OPC maturation. Furthermore, an effect of AAV expressing miR-615-5p sponge in microglia was tested in experimental autoimmune encephalomyelitis (EAE) and cuprizone (CPZ)-induced demyelination model, the classical mouse models of multiple sclerosis. miR-615-5p sponge effectively alleviated disease progression and promoted remyelination. This study identifies miR-615-5p/MYRF as a new target for the therapy of demyelinating diseases.

Single-Cell RNA-Sequencing in Astrocyte Development, Heterogeneity, and Disease.

Astrocytes are the most plentiful cell type in the central nervous system (CNS) and perform complicated functions in health and disease. It is obvious that different astrocyte subpopulations, or activation states, are relevant with specific genomic programs and functions. In recent years, the emergence of new technologies such as single-cell RNA sequencing (scRNA-seq) has made substantial advance in the characterization of astrocyte heterogeneity, astrocyte developmental trajectory, and its role in CNS diseases which has had a significant impact on neuroscience. In this review, we present an overview of astrocyte development, heterogeneity, and its essential role in the physiological and pathological environments of the CNS. We focused on the critical role of single-cell sequencing in revealing astrocyte development, heterogeneity, and its role in different CNS diseases.

Oligodendrocyte lineage cells: Advances in development, disease, and heterogeneity.

Oligodendrocyte progenitor cells (OPCs) originate in the ventricular zone (VZ) of the brain and spinal cord, and their primary function is to differentiate into oligodendrocytes (OLs). Studies have shown that OPCs and OLs are pathologically and physiologically heterogeneous. Previous transcriptome analyses used Bulk RNA-seq, which compares average gene expression in cells and does not allow for heterogeneity. In recent years, the development of single-cell sequencing (scRNA-seq) and single-cell nuclear sequencing (snRNA-seq) has allowed us to study an individual cell. In this review, sc/snRNA-seq was used to study the different subpopulations of OL lineage cells, their developmental trajectories, and their applications in related diseases. These techniques can distinguish different subpopulations of cells, and identify differentially expressed genes in particular cell types under certain conditions, such as treatment or disease. It is of great significance to the study of the occurrence, prevention, and treatment of various diseases.

Treatment with anacardic acid modulates dendritic cell activation and alleviates the disease development of autoimmune neuroinflammation in mice.

Anacardic acid (AA) is a phenolic acid extract found in a number of plants, crops, and fruits. It exhibits a wide range of biological activities. This study displayed that AA effectively alleviated EAE, a classical mouse model of multiple sclerosis. AA administered to the EAE greatly decreased inflammatory cell infiltration to the CNS and protected the myelin integrity in the white matter of the spinal cord. AA could block lipopolysaccharide-induced DC activation. inhibited the polarization of 2D2 mice-derived T cells by inhibiting the DCs activity. Immunoblot results indicated that the phosphorylation of NF-κB is significantly suppressed in AA-treated DCs. This work displayed that AA possessed a potential anti-inflammatory therapeutic effect for the treatment of autoimmune disease.