Understanding the Safety of Mesenchymal Stromal Cell Therapy

by admin | Sep 2, 2025 | Mesenchymal Stem Cells, Regenerative Medicine, Stem Cell Research, Stem Cell Therapy, Studies

Mesenchymal stromal cell therapy, often called MSC therapy, has become one of the most widely studied approaches in regenerative and cellular medicine. Over the past two decades, researchers have explored its potential to treat a wide range of inflammatory and immune-related conditions, including heart disease, lung injury, autoimmune disorders, and complications following cancer treatment.

As interest grows and more patients are invited to participate in clinical trials, one question becomes increasingly important: Is MSC therapy safe? This large, updated scientific review provides reassuring answers, demonstrating that MSC therapy continues to show a strong, favorable safety profile across thousands of patients and dozens of high-quality clinical trials.

As part of this review, Thompson et al. explain what MSC therapy is, why safety is such a critical concern, how researchers evaluated safety across many studies, and what the findings mean for patients, families, clinicians, and regulators.

Mesenchymal Stromal Cells and Their Therapeutic Role

Mesenchymal stromal cells are multipotent cells that can be collected from adult tissues such as bone marrow, adipose tissue, and other sources. They were first described in the 1970s and have since gained attention for their ability to interact with the immune system and respond to inflammation.

Unlike embryonic stem cells, MSCs have a limited ability to turn into different cell types. Instead, their primary therapeutic value appears to lie in their ability to communicate with surrounding tissues. MSCs release bioactive molecules that help regulate immune responses, reduce excessive inflammation, and promote healing. They also migrate toward areas of injury or inflammation, making them attractive candidates for conditions where inflammation plays a central role.

Preclinical research, including animal studies, has shown promising results in conditions such as acute lung injury, sepsis, and heart attack. These findings have led to a growing number of human clinical trials evaluating both safety and potential benefits.

Safety Considerations for Mesenchymal Stromal Cell Therapy

Any therapy that involves living cells raises important safety questions. MSCs can divide, interact with the immune system, and circulate through the bloodstream. Because of these properties, scientists carefully monitor potential risks that could limit clinical use.

Early clinical trials suggested MSCs were generally safe, but these studies were small. As more trials were completed and patient numbers increased, researchers recognized the need to systematically review the evidence to identify any consistent safety signals that might not be obvious in individual studies.

Methods Used to Evaluate MSC Safety

To answer this question, researchers conducted a comprehensive systematic review and meta-analysis of randomized controlled trials. These trials compared patients who received MSC therapy via the bloodstream with those who received standard care or a placebo.

The review included studies published between 2012 and 2019 and built on an earlier 2012 review. The authors searched major medical databases and screened nearly 7,500 scientific papers. After careful evaluation, 55 randomized controlled trials involving 2,696 adult patients met the inclusion criteria.

By pooling data from multiple trials and using rigorous statistical methods, the researchers were able to estimate whether MSC therapy increased the risk of any negative events compared to control treatments.

Incidence of Fever Following MSC Therapy

Across all included trials, fever was the only adverse event that occurred more frequently in patients receiving MSC therapy compared to controls. Patients treated with MSCs were about 2.5 times more likely to develop a fever.

Notably, most of these fevers were mild and temporary. Although some fevers were reported as serious adverse events, they were rare overall. Fever typically occurred shortly after infusion and resolved without long-term consequences.

This finding is consistent with earlier reviews and is thought to reflect the body’s immune response to the infused cells rather than a sign of lasting harm. Recognizing fever as a known and manageable side effect helps clinicians monitor patients appropriately during and after treatment.

No Increased Risk of Infection, Thrombosis, or Malignancy

Beyond fever, the review found no significant increase in other major safety concerns. Patients receiving MSC therapy did not experience higher infection rates than controls, despite the cells’ immune-modulating effects. This suggests that MSCs do not meaningfully weaken immune defenses in clinical settings.

The analysis also found no association between MSC therapy and thrombotic or embolic events. Blood clots were rare overall and occurred at similar rates in both MSC-treated patients and control groups. This is particularly reassuring given ongoing research into how MSCs may interact with clotting pathways.

Perhaps most importantly, the review found no increased risk of malignancy. MSC-treated patients did not develop cancer more frequently than those in control groups. This finding addresses a longstanding concern related to the cells’ ability to proliferate and supports their continued investigation in clinical medicine.

Observed Reduction in Mortality

One of the more notable findings from this review was a reduced risk of death in patients receiving MSC therapy compared to controls. While this review was focused on safety rather than effectiveness, this observation suggests that MSC therapy does not increase mortality risk and may even offer protective benefits in specific patient populations.

It is important to interpret this finding cautiously, as the trials involved varied conditions and were not designed to measure survival as a primary outcome. Still, the absence of increased mortality provides further reassurance regarding safety.

Improved Safety Monitoring in Recent Trials

Compared to earlier studies, recent MSC clinical trials demonstrated improved attention to safety monitoring. More than three-quarters of the included trials reported having a predefined plan to track adverse events, a substantial improvement over earlier research.

Notably, none of the trials were stopped early due to safety concerns. Serious adverse events that were judged to be related or possibly related to treatment were extremely rare, occurring in only a small fraction of patients across all studies.

This progress reflects a maturing field that recognizes the importance of transparency, standardized reporting, and rigorous trial design.

Challenges in Trial Design and Reporting

Despite these encouraging findings, the authors highlighted areas that still need improvement. Only a small number of trials met all criteria for low risk of bias, indicating that study design quality varies widely across the field.

Reporting of MSC characteristics was another area of concern. Only a minority of trials fully described how MSCs were defined, tested for viability, or assessed for biological potency. These details are critical for understanding why some trials succeed while others do not.

Without consistent reporting standards, it becomes harder to compare results across studies or identify factors that influence outcomes. Improving transparency in cell characterization will be essential as newer, second-generation MSC products move into clinical trials.

Implications for Patients and Families

For patients considering participation in MSC clinical trials or learning about regenerative medicine options, this large body of evidence offers important reassurance. Across thousands of patients and dozens of trials, MSC therapy has consistently shown a strong safety record.

The most common side effect, fever, is generally temporary and manageable. Serious concerns such as infection, blood clots, cancer, and death have not been linked to MSC therapy when compared to standard treatments.

As with any investigational therapy, participation in clinical trials should involve careful discussion with healthcare providers, but concerns about safety alone should not be a barrier, given the current evidence.

Future Directions in MSC Research

MSC research continues to evolve as researchers learn more about how these cells work, how they interact with the immune and clotting systems, and how manufacturing methods influence their behavior. Future trials will explore new indications, refined dosing strategies, and enhanced cell products designed to improve consistency and effectiveness.

Ongoing safety monitoring remains essential, particularly as therapies move into larger and more diverse patient populations. Continued adherence to rigorous trial design and transparent reporting will help ensure that advances in regenerative medicine are both effective and safe.

Overall Conclusions on MSC Safety

Thompson et al.’s updated review provides the most comprehensive evaluation to date of the safety of mesenchymal stromal cell therapy in adult clinical trials. Aside from an increased likelihood of fever, no meaningful safety signals were identified across thousands of patients.

The findings reinforce the conclusion that MSC therapy continues to demonstrate a favorable safety profile. For researchers, clinicians, regulators, and patients alike, this growing body of evidence supports the responsible, ongoing development of MSC-based therapies as part of the evolving field of regenerative medicine.

As research progresses, maintaining high standards for study design, cell characterization, and adverse event reporting will be key to translating this promising therapy into broader clinical practice.



Source: Thompson M, Mei SHJ, Wolfe D, Champagne J, Fergusson D, Stewart DJ, Sullivan KJ, Doxtator E, Lalu M, English SW, Granton J, Hutton B, Marshall J, Maybee A, Walley KR, Santos CD, Winston B, McIntyre L. Cell therapy with intravascular administration of mesenchymal stromal cells continues to appear safe: An updated systematic review and meta-analysis. EClinicalMedicine. 2020 Jan 17;19:100249. doi: 10.1016/j.eclinm.2019.100249. PMID: 31989101; PMCID: PMC6970160.

Mesenchymal Stromal Cell Therapy: Current Evidence, Challenges, and Future Directions

by admin | Aug 28, 2025 | Mesenchymal Stem Cells, Regenerative Medicine, Stem Cell Research, Stem Cell Therapy, Studies

Mesenchymal stromal stem cells, commonly called MSCs, have been among the most-studied cell types in regenerative medicine over the past two decades. They have been tested in hundreds of clinical trials for conditions ranging from joint degeneration to heart disease, autoimmune disorders, lung injury, and complications after transplantation.

MSCs have consistently been shown to be safe, but their effectiveness has been mixed. Many trials have not met their main efficacy goals, and only a small number of MSC-based products have received regulatory approval worldwide. 

This review by Lu and Allickson examines what has been discovered about MSC therapy and what remains to be done before these therapies can be widely adopted in routine clinical practice.

From Bone Marrow Cells to Powerful Immune Modulators

MSCs were first identified in mouse bone marrow as cells that could support blood-forming stem cells and form bone, cartilage, and fat. Human MSCs were later isolated in the 1990s. Early on, much of the excitement around MSCs focused on their ability to turn into different mesodermal tissues and directly replace damaged cells.

However, over time, it became clear that this “replacement” model did not fully explain what was happening in living organisms. In patients, MSCs do not routinely transform into large amounts of new tissue. Instead, their main therapeutic effects appear to come from the signals they send out rather than the cells they become.

Today, most researchers view MSCs as “medicinal signaling cells.” They can self-renew and still form bone, cartilage, and muscle, but their real power lies in their paracrine effects. MSCs sense damage and inflammation in their environment and respond by releasing a complex mix of biologically active molecules. This includes cytokines, chemokines, growth factors, extracellular matrix components, and extracellular vesicles that carry proteins, lipids, and genetic material, such as microRNAs. These signals help guide other cells to repair tissue, grow new blood vessels, calm harmful immune responses, and limit scarring.

How MSCs Influence Repair and Immunity

MSCs have been shown in laboratory and animal studies to home to sites of injury and support tissue repair in the heart, lungs, joints, nervous system, and other organs. They create a local microenvironment that encourages healing, reduces cell death, and can improve organ function after injury.

Equally important is their role in immune modulation. MSC-derived factors can shift the immune system away from a highly inflammatory state and toward a more balanced, regulatory profile. They interact with many types of immune cells, including T cells, B cells, macrophages, dendritic cells, and natural killer cells, and can either dampen or support immune activity depending on the context. This flexible, environment-dependent behavior is one of the reasons MSCs are being studied for such a wide range of inflammatory and immune-mediated conditions.

Extracellular vesicles released by MSCs, also known as MSC-derived EVs, are a significant contributor to their effectiveness. These tiny membrane-bound packages carry proteins, RNAs, and other molecules that can travel to distant cells and influence their behavior. EVs from MSCs have shown the ability to reduce fibrosis, promote tissue regeneration, and calm inflammation in preclinical models, raising interest in EVs as a possible “cell-free” therapy that might someday complement or even replace live cell treatments.

Defining an MSC: Why Standards Matter

One ongoing challenge in MSC research is that not all MSCs are the same. They can be derived from many different tissues, including bone marrow, adipose tissue, and perinatal tissues such as the placenta and the umbilical cord. Each source can produce cells with different characteristics, and even cells from the same source can vary based on how they are collected, cultured, and stored.

To create consistency in the field, the International Society for Cellular Therapy established basic criteria in 2006 to define human MSCs. According to these guidelines, MSCs must adhere to plastic in standard lab cultures, express specific surface markers, and differentiate into bone, cartilage, and fat cells under appropriate laboratory conditions.

Even with these guidelines, the authors note that there remains considerable variability across MSC products. Differences in cell source, donor characteristics, manufacturing methods, dosing strategies, and delivery routes all contribute to the wide range of outcomes seen in clinical trials. This variability is one of the main reasons it has been difficult to draw simple conclusions about “MSC therapy” as a single, uniform treatment.

Regulatory Approvals: A Few Successes Among Many Trials

Despite the large number of registered MSC trials worldwide, only a limited number of MSC-based products have received regulatory approval so far. Different countries regulate cell therapies through agencies similar to the U.S. Food and Drug Administration, such as Health Canada, the European Medicines Agency, and others in Asia.

One important milestone highlighted in this review is the recent approval in the United States of an MSC therapy for pediatric graft-versus-host disease, a serious complication of stem cell transplantation. This marks the first MSC therapy approved by the FDA and demonstrates that, under the right conditions, MSCs can meet the rigorous safety, quality, and benefit standards required by regulators.

Outside the U.S., several other MSC-based products have been approved for conditions such as cartilage defects and graft-versus-host disease. However, when viewed against the backdrop of hundreds of trials, the number of approvals remains small, emphasizing how challenging it has been to translate the promise of MSCs into consistent, reproducible clinical benefit.

What the Clinical Trial Landscape Looks Like

A recent search of the ClinicalTrials.gov database found hundreds of registered studies involving mesenchymal stromal or mesenchymal stem cells, covering early-phase safety trials through more advanced phase 3 and 4 studies. These trials span a wide range of indications, from orthopedic and cardiovascular disorders to autoimmune diseases, neurological conditions, and complications of cancer treatment.

Yet, a key concern is that the vast majority of these trials have not reported their results publicly. This lack of accessible outcome data makes it difficult for clinicians and researchers to fully understand where MSCs are working well, where they are not, and what factors may explain the differences. It also slows progress in refining protocols and designing better future studies.

Safety: A Clear Strength of MSC Therapy

One consistent and reassuring theme across the MSC literature is safety. Clinical trials over more than two decades have shown that MSC therapy is generally very well tolerated. Reports of serious infusion reactions, organ damage, severe infections, cancers, or treatment-related deaths directly attributable to MSCs have been extremely rare.

Safety data is especially strong for bone marrow–derived and adipose-derived MSCs, which have the longest track record in human studies. Newer sources, including perinatal tissues, also appear promising but may benefit from longer follow-up and more comprehensive monitoring as experience grows.

The Efficacy Challenge and Future Directions

While safety has been firmly established, efficacy has been much less consistent. Many MSC trials have failed to meet their primary endpoints, and in some cases, the benefits have been modest or difficult to distinguish from placebo or standard care. This is not unique to MSCs—many new therapies face similar hurdles—but it does mean that expectations must be realistic.

Lu and Allickson emphasize that the next chapter for MSC therapy will depend on solving several key problems. These include better defining which patients and diseases are most likely to respond, standardizing and optimizing cell manufacturing, clarifying dose and timing, and understanding how factors like age, comorbidities, and prior treatments influence outcomes. It will also be important to determine when MSCs should be used alone and when they may be most effective in combination with other therapies.

What This Means for Patients Today

The data shows that MSCs are safe with clear potential for tissue repair and immune modulation. At the same time, the field is still working to consistently translate these biological effects into strong, repeatable clinical benefits across many diseases.

As research continues, mesenchymal stromal cell therapy remains one of the most carefully studied and promising avenues in regenerative medicine. The progress to date provides a strong foundation, and the future outlook will depend on rigorous science, thoughtful trial design, and continued collaboration between researchers, clinicians, regulators, and patients.

Source:  Lu, W., & Allickson, J. Mesenchymal stromal cell therapy: Progress to date and future outlook. Molecular Therapy (2025). https://doi.org/10.1016/j.ymthe.2025.02.003