AbstractIntroductionExcessive 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.MethodsIn 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.ResultsOur 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.ConclusionFucoidan improves SCI repair by modulating the microenvironment and promoting remyelination.

of a highly organized myelin sheath. Considering these challenges, over the past several years, a number of cell-based strategies have been developed to optimize remyelination therapeutically. Outcomes of these basic and preclinical discoveries are promising and signify the importance of remyelination as a mechanism for improving functions in CNS injuries. In this review, we provide an overview on: (1) the precise organization of myelinated axons and the reciprocal axo-myelin interactions that warrant properly balanced physiological activities within the CNS; (2) underlying cause of demyelination and the structural and functional consequences of demyelination in axons following injury and disease; (3) the endogenous mechanisms of oligodendrocyte replacement; (4) the modulatory role of reactive astrocytes and inflammatory cells in remyelination; and (5) the current status of cell-based therapies for promoting remyelination. Careful elucidation of the cellular and molecular mechanisms of demyelination in the pathologic CNS is a key to better understanding the impact of remyelination for CNS repair. Keywords: demyelination, spinal cord injury, cell therapy, oligodendrocytes, remyelination, neural stem cells, oligodendrocyte precursor cells, astrocytes Introduction Myelin is a cholesterol rich extension of oligodendrocytes and Schwann cells (SCs) plasma membrane, which serves as a specialized insulation sheath for axons in the nervous system. Myelin facilitates axon signal conduction through enabling “saltatory conduction” (see review by Miron and Franklin, 2014 ). However, the importance of myelin in the central nervous system (CNS) is beyond its role in rapid signal conduction along axons as its disturbance also cause other severe functional and neurobehavioral disabilities (as reviewed by Love, 2006 ). Myelin is important for axon maintenance and function ( Nave and Trapp, 2008 ). Perturbations of myelin structure and function or “demyelination” is associated with a

Schwann cells (SCs), the predominant glial cell population in the peripheral nervous system (PNS), have undergone a paradigm shift from historically passive structural components of myelinated axons to active, multifunctional regulators of neural development, regeneration, and neuropathology. This review briefly outlines Schwann cell developmental origin as a biological backdrop, while centering on their inherent phenotypic plasticity and translational applications. Following peripheral nerve injury, SCs rapidly undergo context-dependent dedifferentiation and transcriptional reprogramming, acquiring a regenerative phenotype characterized by phagocytic activity, secretion of neurotrophic factors, and structural reorganization into Büngner bands. Notably, both endogenous and exogenously delivered SCs demonstrate capacity to migrate into lesioned central nervous system (CNS), including spinal cord injury sites, where they contribute to remyelination, modulation of glial scar formation, and partial restoration of electrophysiological connectivity and behavioral function. These attributes collectively establish SCs as phenotypically adaptable cellular mediators capable of facilitating neural repair across anatomically and functionally distinct compartments. To inform translational efforts, this review critically evaluates emerging strategies, including autologous cell transplantation and SC-derived exosomes, by appraising their mechanisms, limitations, and future perspectives. This review aims to deepen the mechanistic understanding of Schwann cell biology and provide a theoretical basis for the development of regenerative treatments for peripheral nerve injury and spinal cord injury.

sulation for your nerve cell, like the plastic insulation covering that encases the wires of an electrical cord. It allows the electrical impulses to travel quickly and efficiently between one nerve cell and the next. It maintains the strength of the impulse message as it travels down the axon. Myelin is made by oligodendrocytes in your brain and spinal cord (your central nervous system [CNS]) and by Schwann cells in your peripheral nervous system. Your peripheral nervous system is the network of nerves outside of your CNS. These nerves communicate between your CNS and the rest of your body. What are the gaps in the myelin sheath called? Your myelin sheath isn’t one solid covering. It’s a lineup of individual sections of myelin, each separated from the next by a tiny gap — like the small amount of space you see between individual box cars on one long train. Each section of myelin is called an internode. Each gap in the myelin sheath — between internodes — is called the nodes of Ranvier. The nodes of Ranvier are rich in positive sodium ions. As the electrical signal or impulse travels along the axon, it jumps from one node to the next. When passing over the gap, the sodium ions recharge the electrical signal so it can continue in its travel without losing its charge or lessening in signal strength. What happens when the myelin sheath is damaged? About 100 billion nerve cells are in constant activity, sending and receiving messages that control every aspect of your body’s functioning. When your myelin sheath on nerve cells is damaged, the electrical signal is slowed or stopped. Myelin can be damaged when your body’s immune cells think that myelin is a foreign substance. Your body’s immune system produces inflammatory substances that damage myelin and eventually kill the cells (the oligodendrocytes and Schwann cells) that make myelin. The location where the myelin is attacked determines your symptoms. The destruction of the myelin sheath is called demyelination. What d

Damage to myelin is a key feature of multiple sclerosis (MS) pathology. Magnetic resonance imaging (MRI) has revolutionized our ability to detect and monitor MS pathology in vivo. Proton density, T1 and T2 can provide qualitative contrast weightings that yield superb in vivo visualization of central nervous system tissue and have proved invaluable as diagnostic and patient management tools in MS. However, standard clinical MR methods are not specific to the types of tissue damage they visualize, and they cannot detect subtle abnormalities in tissue that appears otherwise normal on conventional MRIs. Myelin water imaging is an MR method that provides in vivo measurement of myelin. Histological validation work in both human brain and spinal cord tissue demonstrates a strong correlation between myelin water and staining for myelin, validating myelin water as a marker for myelin. Myelin water varies throughout the brain and spinal cord in healthy controls, and shows good intra- and inter-site reproducibility. MS plaques show variably decreased myelin water fraction, with older lesions demonstrating the greatest myelin loss. Longitudinal study of myelin water can provide insights into the dynamics of demyelination and remyelination in plaques. Normal appearing brain and spinal cord tissues show reduced myelin water, an abnormality which becomes progressively more evident over a timescale of years. Diffusely abnormal white matter, which is evident in 20%-25% of MS patients, also shows reduced myelin water both in vivo and postmortem, and appears to originate from a primary lipid abnormality with relative preservation of myelin proteins. Active research is ongoing in the quest to refine our ability to image myelin and its perturbations in MS and other disorders of the myelin sheath.

Demyelinating disorders such as multiple sclerosis and leukodystrophies are on the rise, posing substantial challenges due to their progressive nature and the current limitations of therapies that effectively restore lost myelin. Over the past decade, advancements in regenerative neuroscience, including cutting-edge stem cell therapies, advanced biomaterials and groundbreaking gene-editing technologies, offer promising avenues for remyelination, immunomodulation and neural repair. Yet, to successfully transition these innovations into clinical therapies, we need robust preclinical models that accurately reflect disease pathology and predict treatment efficacy. This Review offers a thorough overview of the preclinical models utilized in regenerative neurology for demyelinating diseases, highlighting the rapid progress in biomaterial and gene-editing research, which requires meticulous testing and validation in both in vitro and in vivo environments. We begin by explaining the pathophysiology of demyelination, then provide an exhaustive discussion on various preclinical models, including toxin-induced, autoimmune, genetic, viral-induced and large animal models. This is followed by an exploration of emerging regenerative strategies, from cell-based and pharmacological approaches to bioengineered techniques, and we conclude with an analysis of current challenges, translational barriers and future directions in the field. By synthesizing insights from multiple disciplines, this Review strives to engage a diverse audience eager to connect laboratory discoveries with clinical applications in regenerative neuroscience.