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
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