Multiple sclerosis (MS) is a chronic autoimmune disorder that affects the central nervous system (CNS). It is characterized by inflammation, the breakdown of the protective myelin covering of nerve fibers, and progressive nerve damage. These processes contribute to a wide range of symptoms including fatigue, sensory changes, vision problems, and cognitive difficulties. MS primarily affects young adults, with women being more commonly affected than men. The disease is classified into three main types: relapsing-remitting MS (RRMS), secondary progressive MS (SPMS), and primary progressive MS (PPMS), each with distinct patterns of disease progression and neurological damage. The exact causes of MS are complex and involve interactions between genetics, environment, viral infections like Epstein-Barr virus, and epigenetic factors.
Despite advances in treatment, current therapies for MS largely focus on modulating the immune system to reduce inflammation and the frequency of relapses. Drugs such as interferon-beta, glatiramer acetate, natalizumab, and fingolimod can slow disease progression but do not consistently prevent long-term neurodegeneration or reverse existing damage. For patients with progressive forms of MS, treatment options are especially limited. This has led researchers to explore novel approaches, including stem cell-based therapies, as potential solutions to protect and repair the nervous system.
Sheikhi et al.’s review analyzes how mesenchymal stem cells (MSCs) work in multiple sclerosis (MS), including immune regulation, remyelination, and neuroregeneration. It evaluates preclinical and clinical studies on MSC efficacy, safety, and limitations, addressing challenges like delivery methods, dosing, and combining MSCs with standard therapies. The review also highlights MSCs’ potential to transform MS treatment through personalized and combination approaches.
Understanding Mesenchymal Stem Cells
MSCs are multipotent stromal cells capable of self-renewal and differentiation into various tissues, including bone, cartilage, and fat. They were first identified in bone marrow in the 1960s and later named MSCs in 1991. Beyond their regenerative properties, MSCs have significant immunomodulatory capabilities, allowing them to influence immune cell activity and reduce inflammation. These cells are naturally found in many tissues including bone marrow, adipose tissue, umbilical cord, dental pulp, and amniotic fluid. When cultured in the laboratory, they can be expanded to large populations suitable for therapeutic applications.
MSCs are particularly promising for MS because they can address multiple aspects of the disease. They help regulate immune responses, promote remyelination, support neuroprotection, and facilitate tissue repair. MSCs can modulate immune cell activity by promoting regulatory T cells, reducing pro-inflammatory cytokines, and inhibiting the proliferation of T cells, B cells, and natural killer cells. They can also differentiate into neural-like cells and release neurotrophic factors that support nerve survival and regeneration. These properties position MSCs as a potential multi-target therapy capable of both slowing disease progression and supporting repair mechanisms.
MS Pathophysiology and Immune Involvement
MS develops when the immune system mistakenly attacks the myelin sheath that insulates nerve fibers, leading to demyelination and neurodegeneration. This process is driven primarily by T helper 1 (Th1) and T helper 17 (Th17) cells, which release pro-inflammatory cytokines like interferon-gamma, interleukin-17, and tumor necrosis factor-alpha. Other immune cells, including CD8+ T cells and B cells, contribute to lesion formation by producing autoantibodies, presenting antigens, and promoting inflammation. Disruption of the blood-brain barrier allows these immune cells to infiltrate the CNS, exacerbating damage. Over time, repeated inflammatory attacks result in the formation of sclerotic plaques and permanent neurological deficits.
MS manifests in different patterns depending on disease type. RRMS is characterized by episodes of symptom flare-ups followed by partial or complete recovery. Over time, many RRMS patients transition to SPMS, which involves gradual worsening without remission. PPMS, affecting about 15% of patients, shows a steady decline from onset with minimal periods of symptom remission. Understanding these differences is important when considering therapeutic strategies, as immune-mediated inflammation dominates RRMS while neurodegeneration is more prominent in progressive forms of the disease.
Mechanisms of MSC Therapy
MSCs influence the immune system through multiple mechanisms. They can directly interact with T and B cells to promote regulatory cell populations and suppress inflammatory responses. They also release paracrine factors—signaling molecules that affect nearby cells—to reduce inflammation and protect nerve tissue. In laboratory models, MSCs inhibit the differentiation of pro-inflammatory Th1 and Th17 cells, reduce B cell activity, and support the survival of neural cells. They also produce growth factors such as hepatocyte growth factor, which enhances immune tolerance and reduces CNS inflammation.
In addition to immune modulation, MSCs support tissue repair and neuroregeneration. They provide structural support to neurons, promote oligodendrocyte development, reduce oxidative stress, and enhance angiogenesis. By secreting neurotrophic factors, they help preserve existing neurons and stimulate the formation of new neural and glial cells. This dual role of controlling inflammation and promoting regeneration makes MSC therapy particularly attractive for treating both inflammatory and progressive forms of MS.
Advanced MSC Approaches
Several strategies have been developed to enhance MSC therapy. Primed or preconditioned MSCs are treated with molecules like interferon-gamma or estradiol before administration, improving their survival, proliferation, and immunomodulatory effects. Genetically modified MSCs can express specific cytokines or adhesion molecules, further enhancing anti-inflammatory activity and neuroprotection. Additionally, MSCs release exosomes—small extracellular vesicles containing proteins, RNA, and signaling molecules—that can cross the blood-brain barrier, modulate immune cells, and promote remyelination. These cell-free approaches offer potential advantages in safety and biocompatibility while maintaining therapeutic efficacy.
Integration with Conventional Therapies
Current disease-modifying therapies (DMTs) for MS aim to control inflammation and limit structural damage to the CNS. While effective in reducing relapse rates, DMTs often have incomplete efficacy, especially in progressive MS, and can carry significant risks including infections, liver toxicity, and rare neurological complications. Combining MSC therapy with DMTs offers potential synergistic benefits. DMTs can reduce systemic inflammation, creating a favorable environment for MSC-mediated repair, while MSCs target neurodegeneration and promote remyelination. This combinatory approach could enhance overall efficacy and improve clinical outcomes compared to either treatment alone.
Challenges and Limitations
While MSC therapy shows considerable promise, several challenges remain. Optimal dosing, delivery routes, and infusion vehicles need further refinement to maximize CNS targeting and therapeutic outcomes. The source of MSCs, donor age, and cell quality also influence therapeutic potential, particularly in autologous transplants. Careful monitoring and long-term studies are essential to ensure patient safety and treatment efficacy.
Future Directions
Research continues to refine MSC therapies for MS, exploring novel delivery methods, preconditioning techniques, and combinatory approaches with existing DMTs. Personalized treatment strategies tailored to disease type, severity, and patient-specific immune profiles may maximize the benefits of MSC therapy. Advances in exosome-based therapies also offer potential for safe, effective, and minimally invasive interventions. As clinical evidence accumulates, MSCs may become a cornerstone of MS treatment, providing both neuroprotection and regeneration while complementing existing immune-modulating strategies.
Conclusion
Mesenchymal stem cells represent a transformative approach in the treatment of multiple sclerosis, offering a multi-faceted strategy that addresses both immune dysregulation and neurodegeneration. Preclinical and clinical studies demonstrate that MSC therapy can reduce inflammation, promote remyelination, support neural repair, and improve overall outcomes. Although challenges remain in optimizing delivery and dosing, ongoing research is rapidly advancing the field. With continued innovation and integration with conventional therapies, the authors conclude that MSCs hold the potential to revolutionize MS treatment, offering hope for improved quality of life and personalized care for patients living with this complex disease.
Source: Sheikhi, K., Ghaderi, S., Firouzi, H., Rahimibarghani, S., Shabani, E., Afkhami, H., & Yarahmadi, A. (2025). Recent advances in mesenchymal stem cell therapy for multiple sclerosis: Clinical applications and challenges. Frontiers in Cell and Developmental Biology, 13, 1517369.
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