BACKGROUND: Excessive neuroinflammation, apoptosis, glial scar, and demyelination triggered by spinal cord injury (SCI) are major obstacles to SCI repair. Fucoidan, a natural marine plant extract, possesses broad-spectrum anti-inflammatory and immunomodulatory effects and is regarded as a potential therapeutic for various diseases, including neurological disorders. However, its role in SCI has not been investigated.
METHODS: In this study, we established an SCI model in mice and intervened in injury repair by daily intraperitoneal injections of different doses of fucoidan (10 and 20 mg/kg). Concurrently, primary oligodendrocyte precursor cells (OPCs) were treated in vitro to validate the differentiation-promoting effect of fucoidan on OPCs. Basso Mouse Scale (BMS), Louisville Swim Scale (LSS), and Rotarod test were carried out to measure the functional recovery. Immunofluorescence staining, and transmission electron microscopy (TEM) were performed to assess the neuroinflammation, apoptosis, glial scar, and remyelination. Western blot analysis was conducted to clarify the underlying mechanism of remyelination.
RESULTS: Our results indicate that in the SCI model, fucoidan exhibits significant anti-inflammatory effects and promotes the transformation of pro-inflammatory M1-type microglia/macrophages into anti-inflammatory M2-type ones. Fucoidan enhances the survival of neurons and axons in the injury area and improves remyelination. Additionally, fucoidan promotes OPCs differentiation into mature oligodendrocytes by activating the PI3K/AKT/mTOR pathway.
CONCLUSIONS: Fucoidan improves SCI repair by modulating the microenvironment and promoting remyelination.

The research aims to study the therapeutic impact of HEK293-XPack-Olig2 cell-derived exosomes on remyelination of the corpus callosum in a cuprizone-induced demyelinating disease model. A lentiviral vector expressing Olig2 was constructed using XPack technology. The highly abundant Olig2 exosomes (ExoOs) were isolated by centrifugation for subsequent experiments. Western blot, nanoparticle tracking analysis (NTA), and electron microscopy showed no significant difference in particle size and morphology between Exos and ExoOs, and a high level of Olig2 expression could be detected in ExoOs, indicating that exosome modification by XPack technology was successful. The Black Gold/Fluromyelin staining analysis showed that the ExoOs group significantly reduced the demyelination area in the corpus callosum compared to the PBS and Exos groups. Additionally, the PDGFRα/APC staining of the demyelinating region revealed an increase in APC+ oligodendrocytes and a decrease in PDGFRα+ oligodendrocyte progenitor cells (OPCs) in the ExoOs group. Furthermore, there was evident myelin regeneration in the demyelinated areas after ExoOs treatment, with better g-ratio and a higher number of intact myelin compared to the other treatment groups. The level of Sox10 expression in the brain tissue of the ExoOs group were higher compared to those of the PBS and Exos groups. The demyelination process can be significantly slowed down by the XPack-modified exosomes, the differentiation of OPCs promoted, and myelin regeneration accelerated under pathological conditions. This process is presumed to be achieved by changing the expression level of intracellular differentiation-related genes after exosomes transport Olig2 enriched into oligodendrocyte progenitors.

The myelin sheath plays crucial roles in brain development and neuronal functions. In the central nervous system, myelin is generated by oligodendrocytes, that differentiate from oligodendrocyte progenitor cells (OPC). In demyelinating diseases, the differentiation capacity of OPC is impaired and remyelination is dampened. Boosting remyelination by promoting OPC differentiation is a novel strategy for the treatment of demyelinating diseases. The opioid system, which consists of four receptors and their ligands, has been implicated in OPC differentiation and myelin formation. However, the exact roles of each opioid receptor and the relevant pharmacological molecules in OPC differentiation and myelin formation remain elusive. In the present study, specific agonists and antagonists of each opioid receptor were used to explore the function of opioid receptors in OPC differentiation. Nociceptin/orphanin FQ receptor (NOPR) specific antagonist LY2940094 was found to stimulate OPC differentiation and myelination in both in vitro and in vivo models. Unexpectedly, other NOPR ligands did not affect OPC differentiation, and NOPR knockdown did not mimic or impede the effect of LY2940094. LY2940094 was found to modulate the expression of the oligodendrocytes differentiation-associated transcription factors ID4 and Myrf, although the exact mechanism remains unclear. Since LY2940094 has been tested clinically to treat depression and alcohol dependency and has displayed an acceptable safety profile, it may provide an alternative approach to treat demyelinating diseases.

Demyelination is characterized by disruption of myelin sheath and disorders in myelin formation. Currently, there are no effective therapeutic treatments available. Microglia, especially anti-inflammatory phenotype microglia are critical for remyelination. Galectin-3 (Gal-3), which is known to modulate microglia activation, is correlated with myelination. In this study, we aimed to elucidate the roles of Gal-3 during myelin formation and explore the efficiency and mechanism of rGal-3 administration in remyelination. We enrolled Gal-3 knockout (Lgals3 KO) mice and demonstrated Lgals3 KO causes demyelination during spontaneous myelinogenesis. We performed a cuprizone (CPZ) intoxication model and found Lgals3 KO aggravates demyelinated lesions and favors microglial pro-inflammatory phenotype polarization. Recombinant Gal-3 (rGal-3) administration alleviates CPZ intoxication and drives microglial towards anti-inflammatory phenotype. Additionally, RNA sequencing results reveal the correlation between Gal-3 and the PPARγ-CD36 axis. Thus, we performed SSO and GW9662 administration to inhibit the activation of the PPARγ-CD36 axis and found that rGal-3 administration modulates microglial phenotype polarization by regulating the PPARγ-CD36 axis. Together, our findings highlight the importance of Gal-3 in myelination and provide insights into rGal-3 administration for modulating microglial anti-inflammatory phenotype polarization through the PPARγ-CD36 axis.

Chronic cerebral hypoperfusion can cause progressive demyelination as well as ischemic vascular dementia, however no effective treatments are available. Here, based on magnetic resonance imaging studies of patients with white matter damage, we found that this damage is associated with disorganized cortical structure. In a mouse model, optogenetic activation of glutamatergic neurons in the somatosensory cortex significantly promoted oligodendrocyte progenitor cell (OPC) proliferation, remyelination in the corpus callosum, and recovery of cognitive ability after cerebral hypoperfusion. The therapeutic effect of such stimulation was restricted to the upper layers of the cortex, but also spanned a wide time window after ischemia. Mechanistically, enhancement of glutamatergic neuron-OPC functional synaptic connections is required to achieve the protection effect of activating cortical glutamatergic neurons. Additionally, skin stroking, an easier method to translate into clinical practice, activated the somatosensory cortex, thereby promoting OPC proliferation, remyelination and cognitive recovery following cerebral hypoperfusion. In summary, we demonstrated that activating glutamatergic neurons in the somatosensory cortex promotes the proliferation of OPCs and remyelination to recover cognitive function after chronic cerebral hypoperfusion. It should be noted that this activation may provide new approaches for treating ischemic vascular dementia via the precise regulation of glutamatergic neuron-OPC circuits.

Spinal cord injury (SCI) can result in severe motor and sensory deficits, for which currently no effective cure exists. The pathological process underlying this injury is extremely complex and involves many cell types in the central nervous system. In this study, we have uncovered a novel function for macrophage G protein-coupled receptor kinase-interactor 1 (GIT1) in promoting remyelination and functional repair after SCI. Using GIT1flox/flox Lyz2-Cre (GIT1 CKO) mice, we identified that GIT1 deficiency in macrophages led to an increased generation of tumor necrosis factor-alpha (TNFα), reduced proportion of mature oligodendrocytes (mOLs), impaired remyelination, and compromised functional recovery in vivo. These effects in GIT1 CKO mice were reversed with the administration of soluble TNF inhibitor. Moreover, bone marrow transplantation from GIT1 CWT mice reversed adverse outcomes in GIT1 CKO mice, further indicating the role of macrophage GIT1 in modulating spinal cord injury repair. Our in vitro experiments showed that macrophage GIT1 plays a critical role in secreting TNFα and influences the differentiation of oligodendrocyte precursor cells (OPCs) after stimulation with myelin debris. Collectively, our data uncovered a new role of macrophage GIT1 in regulating the transformation of OPCs into mOLs, essential for functional remyelination after SCI, suggesting that macrophage GIT1 could be a promising treatment target of SCI.

Oligodendrocytes (OLs) are differentiated from oligodendrocyte precursor cells (OPCs) in the central nervous system (CNS). Demyelination is a common feature of many neurological diseases such as multiple sclerosis (MS) and leukodystrophies. Although spontaneous remyelination can happen after myelin injury, nevertheless, it is often insufficient and may lead to aggravated neurodegeneration and neurological disabilities. Our previous study has discovered that MEK/ERK pathway negatively regulates OPC-to-OL differentiation and remyelination in mouse models. To facilitate possible clinical evaluation, here we investigate several MEK inhibitors which have been approved by FDA for cancer therapies in both mouse and human OPC-to-OL differentiation systems. Trametinib, the first FDA approved MEK inhibitor, displays the best effect in stimulating OL generation in vitro among the four MEK inhibitors examined. Trametinib also significantly enhances remyelination in both MOG-induced EAE model and LPC-induced focal demyelination model. More exciting, trametinib facilitates the generation of MBP+ OLs from human embryonic stem cells (ESCs)-derived OPCs. Mechanism study indicates that trametinib promotes OL generation by reducing E2F1 nuclear translocation and subsequent transcriptional activity. In summary, our studies indicate a similar inhibitory role of MEK/ERK in human and mouse OL generation. Targeting the MEK/ERK pathway might help to develop new therapies or repurpose existing drugs for demyelinating diseases.

Dietary administration of a copper chelator, cuprizone (CPZ), has long been reported to induce intense and reproducible demyelination of several brain structures such as the corpus callosum. Despite the widespread use of CPZ as an animal model for demyelinating diseases such as multiple sclerosis (MS), the mechanism by which it induces demyelination and then allows robust remyelination is still unclear. An intensive mapping of the cell dynamics of oligodendrocyte (OL) lineage during the de- and remyelination course would be particularly important for a deeper understanding of this model. Here, using a panel of OL lineage cell markers as in situ hybridization (ISH) probes, including Pdgfra, Plp, Mbp, Mog, Enpp6, combined with immunofluorescence staining of CC1, SOX10, we provide a detailed dynamic profile of OL lineage cells during the entire course of the model from 1, 2, 3.5 days, 1, 2, 3, 4,5 weeks of CPZ treatment, as well as after 1, 2, 3, 4 weeks of recovery from CPZ treatment. The result showed an unexpected early death of mature OLs and response of OL progenitor cells (OPCs) in vivo upon CPZ challenge, and a prolonged upregulation of myelin-forming OLs compared to the intact control even 4 weeks after CPZ withdrawal. These data may serve as a basic reference system for future studies of the effects of any intervention on de- and remyelination using the CPZ model, and imply the need to optimize the timing windows for the introduction of pro-remyelination therapies in demyelinating diseases such as MS.

As one of the top causes of blindness worldwide, glaucoma leads to diverse optic neuropathies such as degeneration of retinal ganglion cells (RGCs). It is widely accepted that the level of intraocular pressure (IOP) is a major risk factor in human glaucoma, and reduction of IOP level is the principally most well-known method to prevent cell death of RGCs. However, clinical studies show that lowering IOP fails to prevent RGC degeneration in the progression of glaucoma. Thus, a comprehensive understanding of glaucoma pathological process is required for developing new therapeutic strategies. In this study, we provide functional and histological evidence showing that optic nerve defects occurred before retina damage in an ocular hypertension glaucoma mouse model, in which oligodendroglial lineage cells were responsible for the subsequent neuropathology. By treatment with clemastine, an Food and Drug Administration (FDA)-approved first-generation antihistamine medicine, we demonstrate that the optic nerve and retina damages were attenuated via promoting oligodendrocyte precursor cell (OPC) differentiation and enhancing remyelination. Taken together, our results reveal the timeline of the optic neuropathies in glaucoma and highlight the potential role of oligodendroglial lineage cells playing in its treatment. Clemastine may be used in future clinical applications for demyelination-associated glaucoma.

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.