The therapeutic potential of microRNAs to ameliorate spinal cord injury by regulating oligodendrocyte progenitor cells and remyelination.

Spinal cord injury (SCI) can cause loss of sensory and motor function below the level of injury, posing a serious threat to human health and quality of life. One significant characteristic feature of pathological changes following injury in the nervous system is demyelination, which partially contributes to the long-term deficits in neural function after injury. The remyelination in the central nervous system (CNS) is mainly mediated by oligodendrocyte progenitor cells (OPCs). Numerous complex intracellular signaling and transcriptional factors regulate the differentiation process from OPCs to mature oligodendrocytes (OLs) and myelination. Studies have shown the importance of microRNA (miRNA) in regulating OPC functions. In this review, we focus on the demyelination and remyelination after SCI, and summarize the progress of miRNAs on OPC functions and remyelination, which might provide a potential therapeutic target for SCI treatments.

RNA sequencing of exosomes secreted by fibroblast and Schwann cells elucidates mechanisms underlying peripheral nerve regeneration.

JOURNAL/nrgr/04.03/01300535-202408000-00035/figure1/v/2023-12-16T180322Z/r/image-tiff Exosomes exhibit complex biological functions and mediate a variety of biological processes, such as promoting axonal regeneration and functional recovery after injury. Long non-coding RNAs (lncRNAs) have been reported to play a crucial role in axonal regeneration. However, the role of the lncRNA-microRNA-messenger RNA (mRNA)-competitive endogenous RNA (ceRNA) network in exosome-mediated axonal regeneration remains unclear. In this study, we performed RNA transcriptome sequencing analysis to assess mRNA expression patterns in exosomes produced by cultured fibroblasts (FC-EXOs) and Schwann cells (SC-EXOs). Differential gene expression analysis, Gene Ontology analysis, Kyoto Encyclopedia of Genes and Genomes analysis, and protein-protein interaction network analysis were used to explore the functions and related pathways of RNAs isolated from FC-EXOs and SC-EXOs. We found that the ribosome-related central gene Rps5 was enriched in FC-EXOs and SC-EXOs, which suggests that it may promote axonal regeneration. In addition, using the miRWalk and Starbase prediction databases, we constructed a regulatory network of ceRNAs targeting Rps5, including 27 microRNAs and five lncRNAs. The ceRNA regulatory network, which included Ftx and Miat, revealed that exsosome-derived Rps5 inhibits scar formation and promotes axonal regeneration and functional recovery after nerve injury. Our findings suggest that exosomes derived from fibroblast and Schwann cells could be used to treat injuries of peripheral nervous system.

Single-cell sequencing reveals microglia induced angiogenesis by specific subsets of endothelial cells following spinal cord injury.

Spinal cord injury (SCI) results in dynamic alterations of the microenvironment at the lesion site, which inevitably leads to neuronal degeneration and functional impairment. The destruction of the spinal vascular system leads to a significant deterioration of the milieu, which exacerbates inflammatory response and deprives cells of nutrient support in the lesion. Limited endogenous angiogenesis occurs after SCI, but the cellular events at the lesion site during this process are unclear so far. Here, we performed single-cell RNA sequencing (scRNA-seq) on spinal cord tissues of rats at different time points after SCI. After clustering and cell-type identification, we focused on vascular endothelial cells (ECs), which play a pivotal role in angiogenesis, and drew the cellular and molecular atlas for angiogenesis after SCI. We found that microglia and macrophages promote endogenous angiogenesis by regulating EC subsets through SPP1 and IGF signaling pathways. Our results indicate that immune cells promote angiogenesis by regulating specific subsets of vascular ECs, which provides new clues for exploring SCI intervention.

A comparative analysis of differentially expressed genes in rostral and caudal regions after spinal cord injury in rats.

The initial mechanical damage of a spinal cord injury (SCI) triggers a progressive secondary injury cascade, which is a complicated process integrating multiple systems and cells. It is crucial to explore the molecular and biological process alterations that occur after SCI for therapy development. The differences between the rostral and caudal regions around an SCI lesion have received little attention. Here, we analyzed the differentially expressed genes between rostral and caudal sites after injury to determine the biological processes in these two segments after SCI. We identified a set of differentially expressed genes, including Col3a1, Col1a1, Dcn, Fn1, Kcnk3, and Nrg1, between rostral and caudal regions at different time points following SCI. Functional enrichment analysis indicated that these genes were involved in response to mechanical stimulus, blood vessel development, and brain development. We then chose Col3a1, Col1a1, Dcn, Fn1, Kcnk3, and Nrg1 for quantitative real-time PCR and Fn1 for immunostaining validation. Our results indicate alterations in different biological events enriched in the rostral and caudal lesion areas, providing new insights into the pathology of SCI.

Changes in transcriptome profiling during the acute/subacute phases of contusional spinal cord injury in rats.

BACKGROUND: Spinal cord injuries (SCIs), along with subsequent secondary injuries, often result in irreversible damage to both sensory and motor functions. However, a thorough view of the underlying pathological mechanisms of SCIs, especially in a temporal-spatial manner, is still lacking. METHODS: To obtain a comprehensive, real-time view of multiple subsets of the cellular mechanisms involved in SCIs, we applied RNA-sequencing technology to characterize the temporal changes in gene expression around the lesion site of contusion SCI in rats. First, we identified the differentially expressed genes (DEGs) in contrast to sham controls at 1, 4, and 7 days post SCI. Through bioinformatics analysis, including Pathway analysis, Gene-act-net, and Pathway-act-net, we screened and verified potential key pathways and genes associated with either the acute or subacute stages of SCI pathology. RESULTS: The top three overrepresented pathways were associated with cytokine-cytokine receptor interaction, TNF signaling pathway, and cell cycle at day 1; lysosome, cytokine-cytokine receptor interaction, phagosome at day 4; and phagosome, lysosome, cytokine-cytokine receptor interaction at day 7 post injury. Further, we identified uniquely enriched genes at each time point, such as Ccr1 and Nos2 at day 1; as well as Mgst2, and Pla2g3 at 4 and 7 days post-injury. CONCLUSIONS: Our pathway analysis suggested a transition from inflammatory responses to multiple forms of cell death processes from the acute to subacute stages of SCI. Further, our results revealed a continuous transformation from a more inflammatory to an apoptotic/self-repairing transcriptome following the time-course of SCIs. Our research provides novel insights into the molecular mechanisms of SCI pathophysiology and identifies potential targets for therapeutic intervention after SCI.