Mesenchymal stem cells (MSCs) are at the forefront of regenerative medicine, offering significant therapeutic potential due to their self-renewal, multipotency, and immunomodulatory properties. These nonhematopoietic adult stem cells can differentiate into various mesodermal lineages, including bone, cartilage, and adipose cells, while influencing immune and inflammatory pathways.
As part of this review, Han et al. explore the molecular mechanisms, signaling pathways, and regulatory factors that underpin the therapeutic effects of MSCs. The authors also examine the clinical applications and challenges associated with MSC-based therapies, emphasizing strategies to enhance their safety and efficacy.
The goal of this review was to provide a comprehensive understanding of how MSCs function and to guide future research aimed at optimizing their therapeutic potential in regenerative medicine and immune-mediated inflammatory diseases.
Biological Characteristics and Identification of MSCs
MSCs were first identified in bone marrow but are now known to exist in several tissues, including adipose tissue, umbilical cord, placental tissue, and dental pulp. They are defined by the International Society for Cellular Therapy (ISCT) through three key criteria: adherence to plastic in culture, expression of specific surface markers (CD73, CD90, CD105), and the ability to differentiate into osteoblasts, chondrocytes, and adipocytes. MSCs lack hematopoietic markers such as CD34, CD45, and HLA-DR, further distinguishing them from other stem cell types.
Their immunophenotype contributes directly to their clinical utility. For instance, CD105 is involved in angiogenesis and migration, CD90 mediates cell adhesion and signaling, and CD73 regulates adenosine production, which influences immune modulation. The absence of major histocompatibility complex (MHC-II) expression confers low immunogenicity, making MSCs suitable for allogeneic transplantation.
Sources and Comparative Properties
Bone marrow–derived MSCs (BM-MSCs) remain the most studied and exhibit robust immunomodulatory effects. Adipose-derived MSCs (AD-MSCs) offer easier harvest and higher yield, while umbilical cord–derived MSCs (UC-MSCs) demonstrate enhanced proliferation and reduced immune rejection risk. Placenta- and dental pulp–derived MSCs (P-MSCs and DP-MSCs) provide unique regenerative properties suited to obstetric and dental applications.
These differences underscore that MSCs are not a uniform population. Their biological behavior is influenced by the tissue of origin, donor age, and culture environment, each factor shaping proliferation rate, differentiation potential, and cytokine secretion profiles.
Mechanisms of Action: Beyond Differentiation
Although MSCs can differentiate into multiple tissue types, most therapeutic effects appear to result from paracrine activity rather than direct engraftment. MSCs release a diverse set of bioactive molecules—growth factors, cytokines, and extracellular vesicles (EVs)—that orchestrate local cellular responses. These mediators suppress inflammation, enhance angiogenesis, prevent apoptosis, and stimulate endogenous repair mechanisms.
Immunomodulation is another critical feature. MSCs interact with immune cell populations, including T cells, B cells, macrophages, and dendritic cells, to downregulate inflammatory cytokines and promote regulatory T cell (Treg) development. This ability to modulate immune responses underpins ongoing trials in autoimmune and inflammatory diseases such as rheumatoid arthritis, graft-versus-host disease (GVHD), and Crohn’s disease.
Clinical Research Progress
By 2025, more than ten MSC-based therapeutics have received market approval globally. Clinical trials span diverse indications, including orthopedic repair, cardiovascular disease, pulmonary injury, and neurodegenerative disorders. Preclinical evidence and early-phase trials support MSC safety and short-term efficacy, though variability in outcomes highlights the need for improved standardization.
For orthopedic conditions such as osteoarthritis, intra-articular MSC injections have shown cartilage repair and symptom relief. In cardiovascular applications, MSCs enhance cardiac function following myocardial infarction by promoting angiogenesis and limiting fibrosis. In neurological disorders—including Alzheimer’s and Parkinson’s disease—MSC-secreted neurotrophic factors like BDNF and VEGF contribute to neuroprotection and synaptic maintenance. MSCs are also being studied for their role in mitigating cytokine storms and repairing pulmonary damage in respiratory diseases such as ARDS and COVID-19.
Administration Routes, Dosage, and Frequency
Therapeutic outcomes depend significantly on the administration route. Intravenous injection is widely used for systemic conditions, although pulmonary trapping can reduce effective delivery to target sites. Localized injections (e.g., intra-articular, intrathecal, or intracerebral) improve precision but increase procedural complexity and risk.
Optimal dosing remains unresolved, with clinical studies using cell counts ranging from 2×10⁵ to 1×10⁹ cells per treatment. Overdosing raises concerns of microvascular obstruction or immune activation, while insufficient dosing may limit efficacy. Similarly, treatment frequency varies between single and multiple administrations, reflecting the transient persistence of MSCs in vivo and uncertainty regarding optimal therapeutic duration.
Safety and Quality Considerations
MSCs are considered safe, with minimal tumorigenic potential and low immunogenicity. However, key issues persist around sustainability, variability, and quality control. According to the authors, most evidence indicates that MSCs exert effects transiently via secreted factors rather than long-term engraftment, necessitating possible repeat dosing.
Heterogeneity among MSC preparations is a central challenge. Donor age, health status, and tissue source influence potency. Furthermore, extended in vitro culture can lead to senescence, loss of differentiation capacity, and altered surface marker expression. Rigorous potency assays—such as inhibition of T-cell proliferation—are used to gauge immunoregulatory function but remain imperfect surrogates for in vivo efficacy.
Cryopreservation can also reduce MSC viability and function. Standardizing thawing and delivery protocols is critical to maintain product consistency across clinical sites. Addressing these manufacturing and handling issues is essential for regulatory approval and broad clinical adoption.
In Vivo Tracking and Mechanistic Insights
Understanding MSC behavior after transplantation is essential to improving therapy design. Imaging approaches such as magnetic resonance imaging (MRI) using iron oxide nanoparticle labeling, positron emission tomography (PET) with radiolabels, and bioluminescence or fluorescence imaging in preclinical models have advanced this understanding. However, each technique carries trade-offs in sensitivity, resolution, and safety. Future development of multimodal imaging systems that combine MRI and PET could provide more comprehensive tracking and improve insight into MSC biodistribution, survival, and activity.
Challenges in Standardization and Regulation
Despite significant progress, translating MSC research into clinical practice faces technical and regulatory barriers. The inherent heterogeneity of MSC populations introduces batch-to-batch variation, complicating reproducibility. Standardization efforts include using bioreactor-based culture systems for scalable production and gene-editing tools like CRISPR-Cas9 to stabilize expression of therapeutic genes.
From a regulatory standpoint, agencies such as the FDA and EMA are establishing clearer frameworks for MSC product characterization, emphasizing genomic stability, potency testing, and long-term safety monitoring. These frameworks must balance innovation with patient safety and cost-effectiveness to enable equitable access to cell-based therapies.
Emerging Innovations
Recent developments aim to enhance MSC therapeutic durability and precision. Preconditioning strategies—such as hypoxia exposure or cytokine “licensing”—can increase cell survival and immunosuppressive potency. Genetic engineering to overexpress anti-apoptotic or angiogenic factors may further extend MSC viability and efficacy.
MSC-derived extracellular vesicles (EVs) represent a major innovation. EVs carry proteins, RNA, and lipids that mimic the parent cells’ paracrine activity without the risks associated with live-cell administration. Their stability and scalability make them promising candidates for next-generation acellular regenerative therapies.
Integration of artificial intelligence (AI) and single-cell transcriptomics allows researchers to map MSC subpopulations and predict therapeutic outcomes. These technologies will enable personalized MSC therapies tailored to individual disease mechanisms and patient profiles.
Conclusion and Future Perspective
Mesenchymal stem cells have transformed regenerative medicine, bridging cell biology and clinical therapy. Their multifunctional role—spanning tissue repair, immunoregulation, and anti-inflammatory signaling—positions them as pivotal tools for treating complex, chronic diseases. Despite substantial clinical advances, their full therapeutic potential will only be realized through greater mechanistic understanding, standardized manufacturing, and long-term outcome data.
Han et al. conclude that the future of MSC therapy lies in interdisciplinary innovation that combines stem cell science, bioengineering, and computational modeling. Rationally designed, mechanism-based, and digitally monitored MSC interventions may soon replace empirical approaches, ushering in an era of personalized cellular medicine. If ongoing challenges in scalability, reproducibility, and regulatory compliance are met, MSCs could transition from experimental therapies to front-line treatments across multiple disease domains—redefining the future of regenerative health care.
Source: Han X, Liao R, Li X, Zhang C, Huo S, Qin L, Xiong Y, He T, Xiao G, Zhang T. Mesenchymal stem cells in treating human diseases: molecular mechanisms and clinical studies. Signal Transduct Target Ther. 2025 Aug 22;10(1):262. doi: 10.1038/s41392-025-02313-9. PMID: 40841367; PMCID: PMC12371117.
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