Multiple sclerosis (MS) is a long-term, immune-mediated disease in which the body’s immune system mistakenly attacks the central nervous system, including the brain, spinal cord, and optic nerves. Over time, this immune attack damages myelin—the protective insulation around nerve fibers—as well as the nerve fibers themselves. The resulting combination of inflammation, demyelination, and neurodegeneration disrupts nerve signaling and leads to symptoms such as numbness, weakness, balance problems, vision changes, fatigue, and cognitive impairment.
Current disease-modifying therapies (DMTs) can reduce relapses and slow progression for many individuals, but they do not reliably restore damaged myelin or rebuild lost neural tissue. This gap between slowing damage and repairing damage has driven growing interest in stem cell therapies. The goal is not only to suppress harmful immune activity but also to protect, repair, and potentially regenerate nervous system tissue.
This article reviews the application of stem cells in MS, encompassing various stem cell types, therapeutic potential mechanisms, preclinical explorations, clinical research advancements, the safety profiles of clinical applications, as well as limitations and challenges, aiming to provide new insights into MS treatment research.
Current Treatment Landscape: Immune Control Without True Repair
Most approved MS medications focus on immune modulation. DMTs are delivered by injection, orally, or by intravenous infusion and aim to reduce inflammatory activity in the nervous system. Steroids such as methylprednisolone are used during acute relapses to rapidly reduce inflammation, though long-term steroid use carries significant risks.
Despite therapeutic advances, MS remains highly variable. Some patients experience long periods of stability, while others accumulate disability even with treatment. Side effects, cost, and inconsistent response remain challenges. Most importantly, standard therapies have limited capacity to promote remyelination or replace damaged neural cells after injury. This limitation underscores the need for strategies that address both immune dysfunction and tissue repair.
Why Stem Cells Are Being Studied in MS
Stem cells are defined by their ability to self-renew and differentiate into specialized cell types. In MS research, they are being studied for three primary reasons. First, certain stem cell approaches may help reset or rebalance the immune system, reducing autoimmune activity. Second, stem cells release protective molecules, often called trophic factors, that support neural survival and function. Third, some stem cell types can be guided toward neural lineages, potentially supporting remyelination by generating cells related to oligodendrocytes, the myelin-producing cells of the central nervous system.
Major Stem Cell Platforms Under Investigation
Several stem cell categories are being evaluated in MS, each with distinct biological characteristics and clinical considerations.
Hematopoietic stem cells (HSCs), which form blood and immune cells, are primarily studied through hematopoietic stem cell transplantation (HSCT), particularly autologous HSCT using a patient’s own cells.
Mesenchymal stem cells (MSCs) can be derived from bone marrow, adipose tissue, placenta, or umbilical cord. They are widely studied for their strong immunomodulatory properties and their secretion of repair-supportive factors.
Neural stem cells (NSCs) can differentiate into neurons, astrocytes, and oligodendrocytes, making them biologically appealing for remyelination strategies, though sourcing and scalability remain challenges.
Embryonic stem cells (ESCs) are highly pluripotent and capable of generating neural cells, but ethical considerations and control over differentiation remain barriers.
Induced pluripotent stem cells (iPSCs) are adult cells reprogrammed into a pluripotent state, offering potential for personalized therapy while raising concerns regarding genetic stability and tumor risk.
Core Mechanisms of Stem Cell Action in MS
Stem cell approaches generally target three overlapping mechanisms.
Differentiation and cell replacement aim to generate neural-supportive cells, particularly oligodendrocytes or their precursors, to promote remyelination. While full cell replacement in the human central nervous system remains difficult, controlled neural differentiation is a major area of research.
Paracrine signaling refers to the release of bioactive molecules that influence surrounding tissue. Stem cells secrete growth factors and signaling proteins that reduce oxidative stress, support neuron survival, and promote repair. Extracellular vesicles (EVs), including exosomes, carry microRNAs and proteins that modify immune responses and cellular behavior. EV-based therapy is being explored as a cell-free alternative.
Immunomodulation is currently the most clinically established mechanism. Several stem cell approaches, especially HSCT and MSC therapy, aim to reduce inflammatory immune activity and shift immune balance toward regulation rather than attack.
Hematopoietic Stem Cell Transplantation: Immune Reset Strategy
Autologous HSCT (aHSCT) is among the most clinically advanced stem cell strategies for aggressive or treatment-resistant MS. The procedure involves collecting a patient’s HSCs, suppressing or ablating the immune system with intensive therapy, and reinfusing the stored stem cells to rebuild immune function.
The leading explanation for its benefit is immune “reset.” Autoreactive immune cells are removed, and a reconstituted immune system may develop improved tolerance. Clinical cohorts have reported high survival rates and meaningful reductions in relapses and disease activity in carefully selected patients.
However, risks are significant. Conditioning regimens can cause profound short-term immune suppression, increasing infection risk. Blood count complications, secondary autoimmune conditions such as thyroid disease, and fertility-related effects have been reported. The intensity of conditioning directly influences safety outcomes, and ongoing refinements aim to reduce toxicity while preserving benefit.
Mesenchymal Stem Cells and MSC-Derived EVs
MSCs are among the most widely studied stem cell types in MS due to accessibility and immunomodulatory capacity. In preclinical MS models, MSC therapy has reduced disease severity, shifted T cell populations away from pro-inflammatory Th1 and Th17 profiles, and increased regulatory T cell activity. MSCs also influence microglia and macrophages toward repair-supportive states.
The MSC secretome—the collection of bioactive factors released by MSCs—has become a major focus. MSC-derived EVs may deliver immunomodulatory and neuroprotective signals without requiring live cell transplantation. Animal studies suggest MSC-EVs improve symptoms and delay disease progression, though optimal dosing, timing, and delivery routes remain under investigation.
Clinically, MSC therapy has generally demonstrated a favorable safety profile, with mild side effects, such as transient fever or headache, most commonly reported. Some trials have shown improvements in imaging markers, relapse rates, or biomarkers such as neurofilament light chain, though findings are not uniform. Questions remain regarding optimal patient selection and the administration route, with some evidence suggesting that intrathecal delivery may offer advantages.
Neural Stem Cells, ESCs, and iPSC-Based Strategies
NSCs are biologically attractive because they can generate oligodendrocytes and migrate toward inflamed or demyelinated regions in preclinical models. Their effects appear to involve both cell replacement potential and strong immunomodulatory activity. Early clinical work, including neural progenitor approaches, has shown encouraging safety data, but scalability and sourcing limitations remain barriers.
ESC-based strategies offer robust differentiation potential but face ethical and regulatory challenges. Clinical evidence remains limited and requires further study.
iPSC-derived approaches offer a potential personalized strategy. Preclinical data indicate iPSC-derived oligodendrocyte precursor cells and neural progenitors can reduce inflammation, support oligodendrocyte survival, and, in some cases, promote remyelination.
Barriers to Clinical Integration
Several challenges limit routine clinical adoption of stem cell therapies in MS. Disease heterogeneity requires precise patient selection. Safety risks vary by platform, from infection risk in HSCT to potential tumorigenicity in pluripotent-derived therapies. Standardization of cell sourcing, manufacturing, dosing, and administration is still evolving, making comparisons across studies difficult.
Even when inflammation is controlled, achieving consistent, durable remyelination and neurorestoration in humans remains scientifically complex. The authors point out that future progress will likely require improved biomarkers, optimized timing of intervention, and potentially combination therapies.
Moving Beyond Suppression Toward Repair
Stem cell therapy represents a spectrum of strategies aimed at achieving two goals that traditional MS care struggles to accomplish: durable immune control and meaningful neural repair. Autologous HSCT has the strongest clinical foundation for immune reset in selected patients but can vary. MSCs and MSC-derived EVs offer favorable safety profiles and strong immunomodulatory biology, with early clinical signals supporting further study. NSCs, ESCs, and iPSC-based approaches are more directly repair-focused but can face translational challenges.
The field is transitioning from early proof-of-concept toward refinement—identifying optimal cell types, delivery methods, and patient profiles most likely to benefit. For individuals living with MS, this evolving research reflects a broader shift in therapeutic ambition: moving beyond slowing disease toward supporting repair and, ultimately, restoring neurological function.
Source: Wu L, Lu J, Lan T, Zhang D, Xu H, Kang Z, Peng F, Wang J. Stem cell therapies: a new era in the treatment of multiple sclerosis. Front Neurol. 2024 May 9;15:1389697. doi: 10.3389/fneur.2024.1389697. PMID: 38784908; PMCID: PMC11111935.