Table of Contents
- Key Points
- Background: Why This Research Matters
- What Are Mesenchymal Stem Cells?
- The Immune Imbalance in Multiple Sclerosis
- Current Treatments and Their Limitations
- How This Review Was Conducted
- Where the Researchers Searched for Studies
- How Study Quality Was Assessed
- How the Eight Studies Were Selected
- Key Findings: Immune and Clinical Effects
- What This Means for Patients
- Limitations: What the Review Could Not Prove
- Recommendations and Future Directions
- Frequently Asked Questions
- Source Information
Key Points
- In eight reviewed studies, MSC therapy expanded regulatory T cells and suppressed T helper 17 cells, rebalancing the immune system in multiple sclerosis.
- Improvements in EDSS disability scores and MRI lesion burden were seen in a significant subset of patients, not all.
- MSC therapy was generally safe, with mostly mild and self-limiting side effects, unlike some immunosuppressive treatments that carry higher infection and tumor risks.
- Studies differed widely in MSC source, delivery route, and outcome measures, and sample sizes were small, limiting comparability.
- MSC therapy is not yet a proven standard treatment; larger studies with standardized protocols and control groups are needed.
Background: Why This Research Matters
Multiple sclerosis (MS) is an inflammatory disease in which the immune system attacks the central nervous system (the brain and spinal cord). The disease damages myelin, the protective coating around nerve fibers, and this damage leads to nerve degeneration over time.
MS is the most common non-traumatic cause of disability in young adults. It affects more than 2.8 million people worldwide, and the number of new cases has risen notably in recent decades.
Earlier research showed that immune dysregulation in MS mainly comes from myelin-specific autoreactive CD4+ T cells. These are immune cells that mistakenly target the body's own myelin. This process is strongly linked to immune dysfunction, temporary activation of immune cells, and an imbalance in the ratios of different immune cell subpopulations.
Despite notable progress in recent decades, a proven cure for MS remains elusive. The available treatments have drawbacks that limit their use in clinical settings because of undesirable side effects.
What Are Mesenchymal Stem Cells?
Mesenchymal stem cells (MSCs) are a type of non-hematopoietic stem cell, meaning they are not the blood-forming stem cells found in bone marrow. MSCs are distinguished by their ability to self-renew.
Since their initial extraction from bone marrow, MSCs have been found in several other tissues. These tissues include the periendothelium (the tissue surrounding blood vessels), adipose tissue (fat tissue), the epidermis (outer skin layer), and umbilical cord blood.
When exposed to suitable stimuli, MSCs can differentiate into cells of diverse mesenchymal lineages. These include osteoblasts (bone-forming cells), chondrocytes (cartilage cells), fibroblasts (connective tissue cells), and adipocytes (fat cells).
MSCs can display diverse surface markers and cytokine profiles, and these characteristics are influenced by the tissue the cells come from. MSCs play a crucial role in preserving immunological and vascular balance, and they also assist the hematopoietic stem cells in bone marrow.
MSCs can migrate selectively to areas of tissue injury or inflammation. This process is known as "homing." MSCs are accessible as either autologous (from the patient) or allogeneic (from a donor) somatic stem cells. Therefore, MSCs have been the subject of extensive research across various disease models.
MSCs possess significant immunomodulatory properties and exhibit low immunogenicity (a low tendency to trigger an immune rejection response). For these reasons, researchers regard MSCs as a crucial resource for managing the progression of MS and re-establishing immune tolerance.
MSCs substantially enhance both innate and adaptive immune responses because of their anti-inflammatory, anti-apoptotic (cell-protecting), and immunomodulatory qualities. The immunomodulatory effects may result from direct interactions with immune cells or through paracrine signaling mechanisms, in which MSCs release signaling molecules that affect nearby cells.
The Immune Imbalance in Multiple Sclerosis
When naive CD4+ T cells become activated, they differentiate into several helper subsets. These subsets include T helper type 1 (Th1) cells, T helper type 2 (Th2) cells, T helper type 17 (Th17) cells, and regulatory T (Treg) cells.
Two changes are especially important in MS. First, Th17 cells show heightened pro-inflammatory effects. Second, Tregs show a reduced ability to suppress immune activity. Together, these changes are essential elements contributing to the breakdown of immune tolerance in MS.
This imbalance between Th17 cells and Treg cells is a central target of new treatment research. A deeper understanding of the possible mechanisms behind MSC-mediated Th17/Treg homeostasis is necessary to support the creation of novel MSC-based treatments.
Current Treatments and Their Limitations
At present, numerous immunotherapies are available, and they aim to restore the balance of Th17 and Treg cells in MS. These include a range of disease-modifying therapies (DMTs) and immunosuppressive agents.
- Interferon beta (IFN-β)
- Glatiramer acetate (GA)
- Teriflunomide
- Fingolimod
- Several monoclonal antibodies that employ cell depletion strategies
In MS patients, these DMTs and monoclonal antibodies have somewhat alleviated the Th17/Treg imbalance. However, these medication therapies are nonspecific and suppress the systemic immune system. They carry a higher risk of infection, tumors, and other negative effects.
The primary objectives of most currently available therapeutic approaches are to reduce symptoms, reduce the rate at which disability develops, avoid relapses, and limit disability accumulation. These approaches are based on the prescription of immunosuppressive and immune-modulating treatments.
Recent studies have shown that MSCs possess strong immunomodulatory potential, which makes them extremely promising options for the management of inflammatory autoimmune diseases. Novel treatments such as MSC therapy have demonstrated encouraging outcomes in addressing severe MS.
These advanced therapies provide renewed hope for patients who have not adequately responded to traditional treatment methods. They may work by repairing injured nerve cells and halting the progression of the disease.
Recent randomized controlled trials (RCTs) have demonstrated the neuroprotective and immunomodulatory effects of MSC therapy. These effects include an impact on cerebrospinal fluid (CSF) biomarkers, which in turn influence the progression of the disease.
Although MSCs are known to modulate immune responses, their exact mechanisms remain unclear. This is particularly true for how MSCs regulate the Th17/Treg axis in MS. Addressing these gaps is essential for advancing targeted therapies and improving clinical outcomes.
How This Review Was Conducted
The researchers conducted this systematic review by precisely following the 2020 guidelines for the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA).
The team selected studies according to the elements of Participants, Intervention, and Outcomes (PIO). The participants were MS patients. The intervention was stem cells, specifically MSCs. The outcome was immune response, measured as an immunomodulatory outcome measure.
The inclusion criteria encompassed English-language full-text articles disseminated within the preceding five years. The included study types were RCTs, systematic reviews, observational studies, meta-analyses, and reviews. The exclusion criteria comprised case reports, case studies, and editorials.
The researchers opted to include systematic reviews, meta-analyses, and narrative reviews because the number of such works in this field is limited.
Where the Researchers Searched for Studies
The team systematically searched PubMed, PubMed Central (PMC), the Cochrane Library, Google Scholar, and ClinicalTrials.gov. They looked for relevant studies published up to March 24, 2025.
The search strategy included combinations of Medical Subject Headings (MeSH) and free-text keywords. The key terms were "Multiple Sclerosis," "Mesenchymal Stem Cells," "Immunomodulation," and related terms. Boolean operators and database-specific filters were applied, including full text, English language, and the last five years.
The searches returned the following numbers of results:
- PubMed: 231 results, with filters of last five years and free full text
- Cochrane Library: 19 results, with a 2020-2025 filter
- Google Scholar: 122 results, with a 2020-2025 filter
- PMC: 55 results, with filters of open access and five years
- ClinicalTrials.gov: 5 results, with a 2020-2025 filter
All relevant articles were imported into EndNote (Clarivate, Philadelphia, PA, USA). The references were grouped and alphabetized using Microsoft Excel 2021 (Microsoft Corp., Redmond, WA, USA) for duplicate removal.
Each identified article underwent a preliminary screening process that involved examining titles and abstracts. After eligible articles were identified, the researchers evaluated the availability of their full texts. The most pertinent papers were assessed based on the predetermined inclusion and exclusion criteria.
Any disagreements between the reviewers during study selection or quality assessment were initially resolved through discussion. If consensus could not be reached, a third independent reviewer was consulted to reach a final decision.
How Study Quality Was Assessed
The researchers evaluated the remaining full articles for quality and risk of bias using specific tools tailored to each type of study. Each assessment tool had distinct criteria and scoring systems.
A score of one point was awarded for ratings of "LOW RISK," "YES," "PARTIAL YES," or "1." Two points were assigned for a score of "2." A minimum score of 70% was required for acceptance from each assessment tool. The researchers chose the >70% threshold to ensure inclusion of studies with acceptable methodological quality, consistent with practices in prior systematic reviews.
The tools used were:
- Cochrane Collaboration Risk of Bias Tool (CCRBT) for RCTs. This tool examines seven factors. The factors are random sequence generation and allocation concealment (selection bias). The factors are selective reporting of outcomes (reporting bias). The factors are other sources of bias. The factors are blinding of participants and personnel (performance bias). The factors are blinding of outcome assessment (detection bias). The factors are incomplete outcome data (attrition bias). Each type of bias is rated as LOW RISK, HIGH RISK, or UNCLEAR.
- Joanna Briggs Institute (JBI) Critical Appraisal Checklist for quasi-experimental studies. This checklist has nine key considerations. These include whether the study clearly defines cause and effect. These include whether participants were in comparable groups. These include whether a control group was present. These include whether outcomes were measured reliably. These include whether the statistical analysis was appropriate. Responses were categorized as YES, NO, UNCLEAR, or NOT ACCEPTABLE.
- Assessment of Multiple Systematic Reviews 2 (AMSTAR 2) for systematic reviews and meta-analyses. This tool has 16 segments. The segments cover whether the review question included the PICO components. The segments cover whether review methods were decided in advance. The segments cover the thoroughness of the literature search. The segments cover duplicate study selection and data extraction. The segments cover risk of bias assessment. The segments cover funding disclosure. The segments cover appropriateness of statistical methods. The segments cover handling of heterogeneity. The segments cover exploration of publication bias. The segments cover disclosure of conflicts of interest. Items were rated as YES or NO, and a partial "yes" was taken into account.
- Scale for the Assessment of Narrative Review Articles 2 (SANRA 2) for narrative reviews. This tool has six items. The items include description of the literature search, referencing, scientific logic, a statement of specific objectives or questions, justification of the article's relevance to the readership, and ideal data presentation. Items scored 0-1 or 2.
All RCTs assessed in the review used the CCRBT and exhibited a "LOW RISK" of bias concerning generating random sequences.
The JBI checklist was used to assess two quasi-experimental studies in the review. Item 4 was recorded as "NO" for both studies because there was no control or comparator group.
The two quasi-experimental studies were Cohen et al. (2023) and Jamali et al. (2024). Both studies met most of the nine JBI criteria:
- Both identified the "cause" and the "effect" (Yes for both)
- Cohen et al. had no comparable participant groups (N/A); Jamali et al. did (Yes)
- Cohen et al. did not have comparable care between groups (N/A); Jamali et al. did (Yes)
- Neither study used a control group (No for both)
- Both took repeated outcome measurements before and after the intervention (Yes for both)
- Both had thorough follow-up, with discrepancies justified and examined (Yes for both)
- Both measured participant results similarly in any comparisons (Yes for both)
- Both measured results accurately (Yes for both)
- Both applied proper statistical analysis (Yes for both)
Cohen et al. (2023) scored 7/9 (100%) and Jamali et al. (2024) scored 8/9 (100%). Both were included in the review.
How the Eight Studies Were Selected
The initial number of relevant studies identified across the five databases was 432. EndNote removed 14 duplicate articles, automated tools removed six records, and four records were removed for other reasons.
The researchers performed an extensive review of 408 articles. This included a thorough examination of titles and abstracts, as well as an evaluation of full-text accessibility.
As a result, 39 articles were chosen for retrieval, while 369 were eliminated from further consideration. After further assessment of the chosen studies, 11 reports were determined to be not retrievable. Ultimately, the team assessed 28 pertinent articles for eligibility and quality based on established appraisal criteria.
The researchers then excluded six studies with scores lower than 70%, 12 studies that were not open access, and two preclinical studies. As a result, eight pertinent articles were incorporated into the systematic review.
Articles with favorable and unfavorable outcomes were selected to mitigate the risk of bias. The final selection comprised:
- Two randomized controlled trials (RCTs)
- Two non-randomized experimental studies
- Three systematic reviews with meta-analyses
- One narrative review
The review describes these trials and reviews based on their outcomes, applicability, and limitations. The researchers used a narrative synthesis rather than performing a meta-analysis because of the inter-variability among studies. This variability included heterogeneity of participants, variety of interventions, and a range of outcome measures.
Data collected from each study included first author, year, study type, disease, inclusion and exclusion criteria, results, key findings, and funding sources. For clinical trials, the researchers also collected the sample size and demographics of research participants. The reviews addressed the total number of participants and the variety, quantity, and type of studies.
Key Findings: Immune and Clinical Effects
Following MSC therapy in MS patients, the researchers found significant alterations in neuroprotective biomarker levels in the cerebrospinal fluid (CSF). These results were positive.
On the immune side, MSC therapy facilitated the expansion of regulatory T cells (Tregs). At the same time, the therapy suppressed T helper type 17 (Th17) cell activity. Together, these two effects restored immune balance and diminished neuroinflammation.
Clinically, improvements in Expanded Disability Status Scale (EDSS) scores and MRI lesion burden were observed in a significant subset of patients. The EDSS is a standard scale used to measure disability in MS, and MRI lesion burden refers to the amount of visible damage on brain and spinal cord scans.
Across the included studies, MSC therapy was generally safe. The adverse effects reported were mild and self-limiting, meaning they resolved on their own.
However, the studies showed heterogeneity in several important areas. These areas included MSC sources, administration routes, and outcome measures. Along with small sample sizes, this heterogeneity limited comparability between studies.
What This Means for Patients
MSC-based therapies show promising potential as a personalized approach to MS management. The review found evidence that MSC therapy can shift the immune system toward a more balanced state.
Specifically, the expansion of Tregs and the suppression of Th17 cells address the exact immune imbalance that drives MS. This suggests that MSC therapy targets a root mechanism of the disease, not just its symptoms.
The improvements in EDSS scores and MRI lesion burden are encouraging for patients. However, these improvements were observed in a significant subset of patients, not in all patients. This means some patients benefited and others did not.
The safety profile is also encouraging. Most side effects were mild and resolved without intervention. This contrasts with some existing immunosuppressive treatments, which carry higher risks of infection and tumors because they suppress the entire immune system.
That said, patients should understand that this review synthesizes early-stage evidence. The small sample sizes and differences between studies mean the results cannot yet be used to predict how any individual patient would respond to MSC therapy.
Limitations: What the Review Could Not Prove
The review has several important limitations that patients and clinicians should keep in mind.
First, the included studies were heterogeneous. They used different sources of MSCs, different routes of administration, and different outcome measures. This made it difficult to compare results across studies.
Second, the sample sizes were small. Small studies are more likely to show chance findings and are less reliable for drawing firm conclusions.
Third, the two quasi-experimental studies had no control or comparator group. Without a control group, it is harder to know whether improvements were due to the treatment or to other factors.
Fourth, the researchers could not perform a meta-analysis, which is a statistical method for combining results from multiple studies. Instead, they used a narrative synthesis, which describes the studies without pooling their numbers.
Fifth, the exact mechanisms by which MSCs regulate the Th17/Treg axis in MS remain unclear. Several unanswered questions regarding their mechanistic role highlight the need for further research.
Recommendations and Future Directions
The review's authors conclude that MSC-based therapies show promising potential as a personalized approach to MS management. However, they emphasize that more research is needed before these therapies become standard care.
Key priorities for future research include:
- Larger studies with more participants to confirm the findings and improve reliability.
- Standardized protocols for MSC sources, administration routes, and outcome measures, so results can be compared across studies.
- Controlled study designs, including control groups, to distinguish treatment effects from other factors.
- Deeper investigation into the exact mechanisms by which MSCs regulate the Th17/Treg balance in MS.
- Development of novel MSC-based treatments targeted at more accurate immune-molecular interventions.
For patients, the practical takeaway is that MSC therapy is an active and promising area of research, but it is not yet a proven standard treatment. Patients who have not responded adequately to traditional treatments may wish to discuss clinical trial opportunities with their neurologist.
Frequently Asked Questions
What is mesenchymal stem cell therapy for multiple sclerosis?
Mesenchymal stem cells (MSCs) are non-blood-forming stem cells found in bone marrow, fat tissue, umbilical cord blood and other tissues. They can self-renew, migrate to areas of injury or inflammation, and have immunomodulatory properties. In multiple sclerosis, MSC therapy is being studied for its ability to rebalance the immune system by expanding regulatory T cells and suppressing T helper 17 cells.
Does MSC therapy actually improve disability or MRI lesions in MS?
Across eight included studies, improvements in Expanded Disability Status Scale (EDSS) scores and MRI lesion burden were observed in a significant subset of patients, not all. The review also found that MSC therapy expanded regulatory T cells and suppressed T helper 17 cells, restoring immune balance and reducing neuroinflammation. However, small sample sizes and differences between studies mean these results cannot predict how any individual patient would respond.
What are the side effects or risks of MSC therapy for MS?
In the eight studies reviewed, MSC therapy was generally safe. Reported adverse effects were mostly mild and self-limiting, meaning they resolved on their own without intervention. This contrasts with some existing immunosuppressive treatments, which carry higher risks of infection and tumors because they suppress the entire immune system. However, the review synthesizes early-stage evidence, so longer-term safety data are still limited.
Who might be eligible for MSC therapy, and is it available now?
MSC therapy is not yet a proven standard treatment for multiple sclerosis. The review included patients with MS who had not adequately responded to traditional treatments, but eligibility criteria varied across studies. Patients interested in MSC therapy may wish to discuss clinical trial opportunities with their neurologist. More research, including larger studies with standardized protocols and control groups, is needed before these therapies become standard care.
How is MSC therapy given, and how often?
The included studies used different sources of MSCs, different routes of administration, and different outcome measures. Because of this heterogeneity, the review could not determine a single standard approach for how MSC therapy is given or how often. The authors emphasize that standardized protocols for MSC sources, administration routes, and outcome measures are a key priority for future research so results can be compared across studies.
What does an EDSS score mean in the context of MSC therapy?
The Expanded Disability Status Scale (EDSS) is a standard scale used to measure disability in multiple sclerosis. In the eight studies reviewed, improvements in EDSS scores were observed in a significant subset of patients after MSC therapy. However, because the studies were small and heterogeneous, these improvements cannot be used to predict how any individual patient would respond to treatment.
Why can't the review prove MSC therapy works for MS?
The review could not prove MSC therapy works because the included studies were heterogeneous, using different MSC sources, administration routes, and outcome measures. Sample sizes were small, and two quasi-experimental studies had no control or comparator group. The researchers could not perform a meta-analysis and instead used a narrative synthesis. The exact mechanisms by which MSCs regulate the Th17/Treg axis also remain unclear.
If I have multiple sclerosis and my neurologist recommends disease-modifying therapy, when should I seek a second opinion about mesenchymal stem cell therapy?
MSC therapy is an active area of research, not a proven standard treatment for MS. The evidence comes from eight small, heterogeneous studies with differing cell sources, delivery routes, and outcome measures, and two studies lacked control groups. Improvements in disability scores and MRI lesion burden appeared in a subset of patients, not all. A second opinion can help clarify whether standard disease-modifying therapy or a clinical trial is appropriate for your situation. Diagnostic Detectives Network provides independent expert second opinions.
Source Information
Original article title: Immunomodulatory Role of Mesenchymal Stem Cell Therapy in Multiple Sclerosis: A Systematic Review.
Authors: Amin MN, Hashish R, Agha Tabari K, Swami SS, Kasagga A, Assefa AK, Yu AK.
Publication details: Cureus, published June 29, 2025, Volume 17, Issue 6, article e86988. DOI: 10.7759/cureus.86988. This is an open access article distributed under the terms of the Creative Commons Attribution License CC-BY 4.0.
Author affiliations: California Institute of Behavioral Neurosciences & Psychology (Fairfield, USA); Sherwood Forest Hospitals NHS Foundation Trust (Nottingham, UK); Queen Elizabeth University Hospital (Glasgow, UK); Peking University (Beijing, China); University Hospitals of Leicester NHS Trust (Leicester, UK).
Note: This patient-friendly article is based on peer-reviewed research. It restructures the findings of one systematic review for a general audience. It is not medical advice, and patients should consult their healthcare provider about any treatment decisions.
