Mesenchymal stem cells: applications

Mesenchymal stromal cells are plastically adherent cells that, under standard culture conditions, form fibroblast-like colonies, express the surface markers CD105, CD73, and CD90, do not express CD45, CD34, CD14, or CD11b, CD79a, or CD19, and HLA-DR, and are capable of osteogenic, adipogenic, and chondrogenic differentiation in vitro. These minimal criteria are proposed by the International Society for Cellular Therapy and remain the basic guideline for the description of such cells. [1]

Terminology has evolved. The International Society for Cell and Gene Therapy recommends using the term "mesenchymal stromal cells" with mandatory specification of the tissue source, as the properties of the cells significantly depend on the tissue from which they are derived. The term "stem cells" is only applicable when there is rigorous evidence of stemness both in vitro and in vivo. [2]

A number of researchers propose considering these cells primarily as "medicinal signaling cells," emphasizing that the primary therapeutic effect is not associated with transformation into the desired tissue, but with the release of a wide range of biologically active molecules that modulate local inflammation and recovery. This reflects modern understanding that paracrine mechanisms and immune regulation play a key role. [3]

The clinical value of mesenchymal stromal cells depends on standardized characteristics, quality of production, appropriate patient selection, and a transparent evidence base. This explains the heterogeneity of results: some approaches have already reached approved indications, others remain in active research, and some applications have been deemed insufficiently effective and are no longer supported by regulators. [4]

Table 1. Terms and definitions

Concept	The essence	Source of recommendations
Mesenchymal stromal cells	Cells that meet minimal criteria for adhesion, phenotype, and trilineage differentiation	International Society for Cellular Therapy
Indication of tissue source	Mandatory clarification: bone marrow, adipose tissue, umbilical cord tissue, etc.	International Society for Cell and Gene Therapy
"Medicinal signaling cells"	The concept of focusing on the secretome and immune regulation rather than on tissue transformation	Scientific comments by A. Kaplan
[5]

Where do cells come from and how do sources differ?

Cells are most commonly derived from bone marrow, adipose tissue, umbilical cord tissue, placenta, and dental pulp. Each niche yields cells with a different initial phenotype, secretome, level of coagulation factor expression, and potential immunogenicity. These differences impact the safety and clinical profile of a particular product and require clear labeling of origin. [6]

The origin also determines technological considerations. For example, adipose tissue is conveniently accessible, but cell isolation often requires enzymatic processing, which is often legally interpreted as "more than minimal manipulation" and requires full drug registration. For umbilical cord tissue and placenta products, the supply chain, donor selection, and complex banking requirements are important. [7]

Evaluation of procoagulant activity, particularly tissue factor CD142 expression, is critically important. High tissue factor levels in some cultures correlate with the risk of coagulation activation upon contact with blood, especially when administered intravascularly without adequate antithrombotic protection. This explains some of the reports of thrombotic complications and encourages manufacturers to standardize safety panels. [8]

Diversity of sources is both an advantage and a challenge. It expands the possibilities for product selection, but increases variability. Therefore, clinical protocols focus on specific, registered products with proven critical quality attributes, rather than on "average" mesenchymal stromal cells. [9]

Table 2. Comparison of the main cell sources

Source	Advantages	Limitations and risks	Typical areas of research
Bone marrow	Historically the most studied source, developed technological chains	Invasive sampling, variable procoagulability	Immunoregulation, cardiology, musculoskeletal system
Adipose tissue	High availability, large volumes of material	Often categorized as more than minimal manipulation, regulatory issues	Orthopedics, dermatology, tissue regeneration
Umbilical cord tissue and placenta	Young donors, theoretically low immunogenicity	Strict collection and banking requirements	Immunomodulation, healing, pediatrics
Dental pulp	Unique neurotropic properties in preclinical models	Limited clinical data	Nerve tissue, tooth regeneration
[10]

How do mesenchymal stromal cells work?

A modern concept: cells act as a "signal biofactory." They secrete cytokines, chemokines, lipids, enzymes, and extracellular vesicles that alter the behavior of local immune cells, reduce excessive inflammation, stimulate angiogenesis, and support reparative processes. The effect depends on the microenvironmental context and the delivery system. [11]

Extracellular vesicles, including exosomes, play an important role. They carry proteins and microRNAs capable of delivering anti-inflammatory signals without the need for the cells themselves. However, clinical development of vesicles is still in its infancy, and numerous studies have noted methodological gaps and the need for strict manufacturing and dosing standards. The use of exosomes outside of clinical trials has not been approved by regulators. [12]

In parallel, targeted delivery and "training" of cells prior to infusion are being explored. Engineering approaches aim to enhance specific functions, such as immune regulation or angiogenesis, but these solutions require even more stringent quality control and additional safety studies. [13]

Finally, the route of administration is important: intravascular administration exposes the drug to blood and the coagulation system, while local injections act primarily through local paracrine effects. The choice of route is incorporated into the protocol based on the balance of benefit and risk for a specific indication. [14]

Table 3. Main mechanisms of action

Mechanism	Key effects	Potential targets
Immune regulation	Decreased pro-inflammatory signals, enhanced anti-inflammatory pathways	Graft-versus-host disease, autoimmune processes
Paracrine trophism	Support of tissue survival, angiogenesis	Ischemic injuries, wound healing
Extracellular vesicles	Transport of proteins and microRNAs	The same indications with an emphasis on the safety of the product without living cells
Modulation of fibrosis	Matrix remodeling, reduction of scarring	Organ fibrosis, orthopedics
[15]

Manufacturing, Critical Quality Attributes and Safety

Cellular products are high-tech medicinal products and require good manufacturing practices. Key parameters include tissue source, culture conditions, marker profile, functional testing, microbiological purity, and hemocompatibility parameters, including tissue factor CD142 expression and coagulation-activating ability. These parameters are directly related to safety during intravascular infusion. [16]

Recent publications highlight that cells with high tissue factor expression can trigger thrombinogenesis and thrombosis. To reduce this risk, screening of cell lots for tissue factor, careful anticoagulant support, and avoiding intravascular administration of products with an unfavorable profile are used. Several studies have shown that low tissue factor and appropriate antithrombotic prophylaxis are associated with greater safety. [17]

Observed adverse events include infusion reactions with fever and hypotension, thromboembolic complications, and, rarely, infections due to contamination. Long-term oncological risks, according to current data, are low but require monitoring and registries. In controlled studies, the safety profile is generally favorable if quality standards and indications are met. [18]

It is critical to distinguish legitimate medicinal products from commercial clinics offering "stem cells" without regulatory approval. Such offerings are not only illegal in most jurisdictions but also unsafe. Regulators regularly issue warnings and letters regarding violations. [19]

Table 4. Critical quality attributes of cell product

Attribute	Why is it important?	How is it assessed?
Phenotype and functional tests	Compliance with minimum criteria and expected mechanism of action	Flow cytometry, differentiation, functional assays
Hemocompatibility and tissue factor CD142	Risk of activated coagulation upon contact with blood	Flow cytometry, thrombogenesis tests
Microbial and viral safety	Prevention of infections	Sterility, screening of donors and raw materials
Traceability and stability	Batch and storage conditions control	Documentation, stress tests, logistics control
[20]

Where the evidence is already mature enough, and where it is not

In December 2024, the US Food and Drug Administration approved remestemcel-L for the treatment of steroid-refractory acute graft-versus-host disease in children 2 months and older. This is the first approved indication for mesenchymal stromal cells in the US with a detailed efficacy and safety profile. In 2025, reviews of the approval process and regulatory aspects were published. A similar approach has long been implemented in Japan: TEMCELL HS Injection has been used for the same problem since 2015. [21]

Darvadstrocel was previously approved in Europe for the treatment of complex perianal fistulas in Crohn's disease, but on December 13, 2024, the European Commission revoked the marketing authorization following the failure of a confirmatory efficacy study. The drug is no longer being used in new patients. This is an important example of how updated studies can change regulatory decisions. [22]

In orthopaedics, particularly in knee osteoarthritis, randomized trials and meta-analyses show pain reduction and improved function over 6-12 months, but the impact on hard endpoints and structural cartilage repair remains limited, the quality of evidence is often moderate, and methods vary. Use should remain within the context of clinical trials or registered programs. [23]

In cardiology, the evidence is mixed: meta-analyses document small improvements in ejection fraction and symptoms, but no convincing effect on major cardiovascular outcomes. Hence, the recommendation to focus on well-designed trials with clinical endpoints before expanding practice. [24]

Table 5. Summary of key indications

Indication	Status for today	Comment
Acute graft-versus-host disease in children	Approved drug in the US, experience in Japan	Remestemcel-L and TEMCELL HS Injection in compliance with standards
Perianal fistulas in Crohn's disease	European registration revoked	An example of reconsidering decisions based on new data
Osteoarthritis of the knee joint	Improvement of pain and function, structural effects inconclusive	Participation in clinical trials is recommended
Heart failure	Signals of improvement in parameters without a lasting impact on “hard” outcomes	Large studies with clinical endpoints are needed
[25]

Legal and regulatory framework: what patients and physicians should consider

In the European Union, cellular therapies are classified as advanced medical technologies. This is a special legal framework with strict requirements for quality, preclinical data, and clinical trials. For complex cases, a classification procedure is in place to help developers understand in advance whether a product falls into this category and what rules apply. [26]

In the United States, human cell and tissue products are subject to criteria of minimal manipulation and homologous use. If a product does not meet these criteria, it is considered a biologic drug and requires full registration with evidence of safety and efficacy. Examples include adipose tissue-derived products, where cell isolation is often considered "more than minimal manipulation." [27]

Regulators regularly remind that any offers of "stem cell treatment" outside of approved indications and licensed products are illegal and dangerous. Consumer warnings are issued, and violation letters are issued to companies promoting unapproved products. It is important for patients to check the registration status of a specific drug and center. [28]

Even for approved indications, strict safety monitoring is applied after marketing. This allows for the prompt identification of rare adverse events and, if necessary, adjustments to recommendations or restrictions on use. [29]

Table 6. Regulatory guidelines

Jurisdiction	What is considered the "gold standard"	What to look out for
European Union	Classification as an advanced medical technology drug, opinion of the Advanced Medical Technology Committee	Availability of a registration certificate and valid conditions of use
United States of America	Compliance with the criteria of minimal manipulation and homologous use or full registration as a biologic product	Checking the regulator's database and consumer warnings
Japan	A separate framework for regenerative products, an approved drug for graft-versus-host disease	Availability and terms of reimbursement
[30]

How to distinguish proven therapies from dubious proposals

The first thing to ask is whether the product is registered and has a clearly defined indication. In the field of mesenchymal stromal cells, there are many examples of "generic" private proposals without an evidence base, and these are the ones that are associated with patient complaints and regulatory interventions. A licensed drug always has a public description of the indications, risks, and monitoring. [31]

The second filter is high-quality publications. Meta-analyses of randomized trials with clinical endpoints and consensus statements from professional societies significantly increase the likelihood that a therapy is justified. In orthopedics and cardiology, the evidence base for cells is still inconsistent, and this should be taken into account when making decisions. [32]

The third block is manufacturing standards and hemocompatibility testing. Ask the clinic or developer for information on testing for tissue factor CD142 and other parameters that influence the risk of thrombosis, especially if intravascular administration is being considered. This is not a formality, but a real safety factor. [33]

Finally, focus on centers with experience specifically in the indication you're interested in. Team experience and adherence to protocols influence outcomes just as much as the "average efficacy" reported in publications. [34]

Table 7. Checklist before consenting to therapy

Question	Why is it important?	What is considered a good answer?
Is there registration of the drug and indication?	Protection from illegal and dangerous interference	Name of registered product, approval number
Are there any data from randomized trials?	Evaluation of real clinical benefit	Publications and meta-analyses with clinical endpoints
How are hemocompatibility and tissue factor tested?	Reducing the risk of thrombosis and infusion complications	Systematic CD142 screening and a well-designed anticoagulant protocol
How security surveillance works	Early detection of rare risks	Monitoring plan, registries, reporting to regulatory authorities
[35]

Brief conclusions for practice

1. Mesenchymal stromal cells are not a "magic tissue replacement," but rather a source of regulatory signals. Minimal criteria and specification of the tissue source are mandatory. [36]
2. Approved uses are limited. Currently, the drug is registered in the United States for pediatric steroid-refractory graft-versus-host disease, and a similar approach is in place in Japan. A number of previous approvals have been reviewed, such as darvadstrocel in the European Union. [37]
3. Safety is closely linked to manufacturing quality and hemocompatibility. Screening for tissue factor CD142 and well-designed administration protocols are an integral part of therapy. [38]
4. In orthopedics and cardiology, there are signals of efficacy based on symptoms and functional indicators, but "hard" outcomes are insufficiently confirmed. Decisions should be made within the framework of studies or programs with a transparent regulatory framework. [39]
5. Avoid offering "stem cell treatments" outside of approved indications and without product registration - this is contrary to safety and legal requirements. [40]