by admin | Aug 7, 2025 | Extracellular Vesicles, Pulmonary Fibrosis, Regenerative Medicine, Stem Cell Research, Stem Cell Therapy, Studies
Pulmonary fibrosis is a chronic and progressive lung disease marked by abnormal scarring of the tissue surrounding the air sacs. This process thickens and stiffens the lungs, leading to shortness of breath, fatigue, and reduced oxygen exchange.
Current medications, such as pirfenidone and nintedanib, can slow disease progression but do not reverse tissue damage. As a result, researchers are pursuing regenerative strategies that can modulate inflammation, suppress fibrosis, and promote repair.
One of the most promising emerging therapies involves extracellular vesicles (EVs) derived from mesenchymal stromal cells (MSCs). These nanosized, membrane-bound particles carry bioactive molecules—such as proteins, microRNAs (miRNAs), and metabolites—that influence immune responses and tissue repair. Importantly, MSC-EVs appear to replicate many benefits of stem cell therapy while avoiding the challenges of administering live cells, such as immune rejection or variable differentiation in vivo.
As part of this study, Li et al. examined the safety and efficacy of mesenchymal stromal cell–derived extracellular vesicles (MSC-EVs) from human umbilical cord (hUCMSC-EVs) in preclinical mouse models and in patients with pulmonary fibrosis.
Targeted Delivery Through Nebulization
Li’s research team developed a method for delivering hUCMSC-EVs via nebulization, producing a fine aerosol that can be inhaled directly into the lungs. This delivery route targets the site of disease, enhances local concentration, and minimizes systemic exposure.
In mouse models, fluorescently labeled hUCMSC-EVs rapidly accumulated in the lungs within hours of inhalation and persisted for several days, confirming targeted distribution. This lung-specific retention supports nebulization as a practical and efficient method for respiratory delivery.
Manufacturing and Quality Assurance
To ensure safety and consistency, the hUCMSC-EVs were produced under Good Manufacturing Practice (GMP) conditions using a standardized cell bank. Multiple critical quality control points were implemented throughout production, verifying vesicle size (50–400 nm), morphology, surface markers (CD9, CD63, CD81), and sterility.
Tests confirmed the absence of bacterial, viral, and mycoplasma contamination and validated biological activity through immune-modulating assays. Analysis of the vesicles’ RNA, protein, and metabolite content demonstrated high batch-to-batch reproducibility, underscoring their stability and reliability as a biologic product.
Molecular Composition and Mechanisms of Action
Comprehensive profiling revealed that microRNAs made up nearly 60% of the total RNA cargo within the hUCMSC-EVs, with over 1,400 unique miRNAs identified. Many are involved in regulating inflammation, cell differentiation, angiogenesis, and extracellular matrix remodeling—key pathways disrupted in fibrosis.
Proteomic analysis identified more than 1,000 proteins enriched in processes such as wound healing, cytoskeletal organization, and cell adhesion, while metabolomic profiling revealed over 100 metabolites related to amino acid and energy metabolism. According to the authors, these findings suggest that hUCMSC-EVs deliver a coordinated set of molecular signals that can reduce inflammation, inhibit fibroblast activation, and support tissue regeneration.
Preclinical Results in Pulmonary Fibrosis Models
Using the bleomycin-induced pulmonary fibrosis mouse model, the researchers assessed both safety and efficacy. Mice received various doses of nebulized hUCMSC-EVs, followed by imaging, physiological measurements, and histological evaluation.
The treatment significantly improved survival, restored lung volume, and reduced fibrotic lesions compared to control groups. Micro-CT scans showed reduced tissue density and less bronchial distortion, while histology confirmed preservation of alveolar architecture and decreased collagen accumulation.
Even when therapy began after fibrosis was established, hUCMSC-EVs slowed or partially reversed disease progression. Interestingly, moderate doses produced the most favorable outcomes, suggesting that efficacy may depend on optimizing dosage rather than simply increasing the quantity delivered.
Immune Modulation and Antifibrotic Mechanisms
Further analysis revealed that nebulized hUCMSC-EVs increased expression of miR-486-5p, a microRNA known to suppress inflammatory signaling and regulate macrophage behavior. Macrophages are central to the progression of pulmonary fibrosis: when activated into a pro-inflammatory (M1) state, they promote injury, while their alternative (M2) phenotype supports repair.
After EV treatment, Li et al. found that macrophages in the lung shifted toward an M2-dominant profile. This was accompanied by increased expression of antifibrotic and regenerative genes (IL-10, MMP13, HGF) and reduced levels of SPP1, a fibrosis-associated gene. These results indicate that hUCMSC-EVs exert their effects largely by reprogramming the immune environment, mitigating inflammation, and promoting resolution of tissue injury.
Phase I Clinical Trial: Safety and Feasibility
Following preclinical success, a randomized, single-blind, placebo-controlled Phase I clinical trial was conducted in 24 adults with pulmonary fibrosis confirmed by high-resolution CT imaging. Participants continued standard therapy; half received nebulized hUCMSC-EVs twice daily for seven days, and half received saline.
Safety was the primary endpoint. Throughout treatment and one year of follow-up, no serious adverse events, allergic reactions, or clinically significant laboratory abnormalities were observed. Blood counts, liver and kidney function, and inflammatory markers remained stable, confirming a strong safety profile for inhaled hUCMSC-EVs.
Early Clinical Indicators of Efficacy
Although designed primarily to assess safety, the study also collected exploratory measures of lung function and patient-reported outcomes.
Patients who received nebulized hUCMSC-EVs demonstrated notable improvements in forced vital capacity (FVC) and maximal voluntary ventilation (MVV) compared to the control group. Questionnaire scores also improved: St. George’s Respiratory Questionnaire results decreased, indicating reduced symptom burden, while Leicester Cough Questionnaire scores increased, reflecting improved quality of life.
Radiographic evaluation revealed stable disease in most participants, consistent with the short treatment duration, but two patients with post-inflammatory pulmonary fibrosis showed partial regression of fibrotic lesions on CT imaging. According to the authors, these cases highlight the potential for genuine structural recovery with this therapy.
Advantages of Nebulized Delivery
Nebulized administration offers several advantages for chronic lung diseases. Delivering therapy directly to the lungs ensures higher local concentrations and reduces systemic exposure, minimizing potential side effects. It also allows for noninvasive, repeatable dosing, which is more patient-friendly than intravenous infusion.
The preclinical biodistribution data align with these advantages, showing sustained lung localization with gradual clearance—an ideal profile for localized therapy in fibrotic lung disease.
Comparison with Other EV-Based Therapies
The study adds to a growing body of evidence supporting nebulized EVs as a safe and feasible approach for pulmonary diseases. Previous preclinical studies have shown benefits of EVs derived from adipose MSCs or platelets in models of emphysema and acute lung injury. However, hUCMSC-EVs may be uniquely advantageous due to their scalable production, immune compatibility, and consistent molecular content.
Current Limitations and Research Needs
Despite encouraging findings, several limitations remain. The Phase I study involved a small cohort and short treatment period. Larger, longer-term trials are necessary to evaluate sustained clinical benefit, dose optimization, and durability of effect.
Because EVs are complex biologics, their content can vary based on donor source and culture conditions. Ongoing work in standardization and molecular characterization will be critical to ensure reproducibility at scale. Future studies should also identify biomarkers to predict which patient populations—such as those with post-inflammatory fibrosis—may respond best to this therapy.
Clinical Implications and Future Outlook
For clinicians and researchers, hUCMSC-EVs represent an innovative, cell-free approach to addressing the underlying inflammation and scarring of pulmonary fibrosis. The therapy combines the biological sophistication of stem cells with the precision and safety of a targeted inhalation route.
Early evidence suggests that nebulized hUCMSC-EVs are not only safe but may improve lung function and quality of life when added to standard therapy. If validated in larger studies, this strategy could complement existing medications, offering patients a regenerative option that directly addresses tissue repair rather than symptom control alone.
Conclusion
According to Li et al., nebulized hUCMSC-EVs demonstrate strong potential as a next-generation therapy for pulmonary fibrosis. Produced under GMP conditions and characterized with rigorous quality controls, these vesicles carry bioactive molecules capable of regulating immune activity, reducing fibrosis, and supporting lung repair.
Preclinical studies showed clear survival and structural benefits in animal models, while early human data confirmed safety and signaled meaningful clinical improvement.
Although further research is required to confirm long-term efficacy and optimize treatment protocols, this study marks a significant step forward in regenerative pulmonary medicine. Nebulized MSC-derived extracellular vesicles may ultimately provide a practical, effective, and safe tool to slow or even reverse the devastating effects of pulmonary fibrosis.
Source: Li M, Huang H, Wei X, Li H, Li J, Xie B, Yang Y, Fang X, Wang L, Zhang X, Wang H, Li M, Lin Y, Wang D, Wang Y, Zhao T, Sheng J, Hao X, Yan M, Xu L, Chang Z. Clinical investigation on nebulized human umbilical cord MSC-derived extracellular vesicles for pulmonary fibrosis treatment. Signal Transduct Target Ther. 2025 Jun 4;10(1):179. doi: 10.1038/s41392-025-02262-3. Erratum in: Signal Transduct Target Ther. 2025 Jul 17;10(1):235. doi: 10.1038/s41392-025-02293-w. PMID: 40461474; PMCID: PMC12134356.
by admin | Feb 15, 2024 | Osteoarthritis, Exosomes, Extracellular Vesicles, Mesenchymal Stem Cells, Stem Cell Research, Stem Cell Therapy
Osteoarthritis (OA) is the most common form of arthritis and is estimated to affect nearly 365 million people worldwide. Characterized as an inflammatory disease, OA slowly progresses over time and results in the gradual loss of the protective cartilage found on the ends of the bones.
While the specific cause of OA has yet to be determined, a growing body of evidence suggests the chondrocyte inflammatory response resulting from elevated levels of pro-inflammatory cytokines is a critical factor in the development and progression of OA.
Recent evidence also suggests that mesenchymal stem cell-derived exomes (MSCs-Exos) exhibit beneficial anti-inflammatory responses in several inflammatory diseases, including OA.
In this study, Wang et al. explore the role of human umbilical cord-derived MSCs-Exos (hUC-MSCs-Exos) in treating the inflammation of chondrocytes and its related mechanisms.
As part of this study, the authors report that supplementing the observed chondrocyte inflammation models with hUC-MSCs-Exos demonstrated the ability to reduce the inflammation of chondrocytes caused by the inflammatory factor IL-1β.
Additionally, activation and polarization of synovial macrophages to M1 phenotypes also contribute to the progression of OS. As part of this study, Wang et al. report that hUC-MSC-Exos demonstrated a protective effect against M1 macrophage-induced chondrocyte damage and cell death.
Wang et al. indicate that the results of this study confirm the anti-inflammatory effects of hUC-MSCs-Exos in the human articular chondrocytes inflammation model. The authors also conclude that hUC-MSCs-Exos may be used as a potential cell-free treatment for chondrocyte inflammation in OA.
Source: Wang S, Jiang W, Lv S, et al. Human umbilical cord mesenchymal stem cells-derived exosomes exert anti-inflammatory effects on osteoarthritis chondrocytes. Aging (Albany NY). 2023;15(18):9544-9560. doi:10.18632/aging.205034
by admin | Dec 21, 2023 | Lupus, Exosomes, Extracellular Vesicles, Mesenchymal Stem Cells, Regenerative Medicine, Stem Cell Research, Stem Cell Therapy
Systemic lupus erythematosus (SLE) is a common multisystemic autoimmune disease that often results in multi-organ damage when left untreated. Currently affecting over 1.5 million Americans, the etiology and pathogenesis of SLE continue to remain unclear.
At present, glucocorticoids and immunosuppressants are the most prescribed course of therapeutic treatment and mostly as a way to manage and treat symptoms of SLE, not the cause itself.
Considering that the etiology and pathogenesis of SLE are accompanied by immune disorders including abnormal proliferation, differentiation, and activation and dysfunction of T cells, and that mesenchymal stem cells (MSC) and MSC-derived extracellular vesicles (EVs) play important roles in the immunity process, researchers are increasingly turning their attention to MSCs and EVs as potential therapeutic treatment options for SLE.
In this review, Yang et al. examine the immunomodulatory effects and related mechanisms of MSCs and EVs in SLE with hopes of better understanding SLE pathogenesis and guiding biological therapy.
Examining the potential use of MSC and MSC-EVs in SLE treatment the authors found some studies have established that MSCs reduce adverse effects of immunosuppressive drugs and when combined have demonstrated distinct effects on T cell activation and bias.
Additionally, Yang et al. report that MSCs are able to participate in the immune response in two distinct ways: paracrine effect and directly through cell-to-cell interaction. Since reconstruction of immune tolerance and tissue regeneration and repair are required parts of SLE treatment and since MSCs possess high self-renewal ability, rapid expansion in vitro and in vitro, and low immunogenicity, allogeneic MSC transplantation has demonstrated strong evidence for the therapeutic potential of MSC in SLE.
Besides the ability to repair and regenerate tissue, MSCs, and MSC-EVs have strong anti-inflammatory and immunomodulatory effects, making them a potentially ideal treatment option as part of a therapeutic strategy for SLE. Considering that MSC-EVs have similar biological functions with MSCs, but are also considered cell-free, the authors point out that MSC-EVs could be the better choice for SLE treatment in the future.
Despite the potential of MSC and MSC-EVs, Yang et al. point out that genetic modification, metabolic recombination, and other priming of MSCs in vitro should be considered before MSC/MSC-EVs application for SLE treatment. The authors also recommend further clinical evaluation of the time of infusion, appropriate dosage, interval of treatment, and long-term safety of MSC/MSC-EVs in the treatment of SLE before any form of the combination is used as a treatment option.
Source: “Immunomodulatory Effect of MSCs and MSCs-Derived Extracellular ….” 16 Sep. 2021, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8481702/.
by admin | Jul 26, 2023 | Mesenchymal Stem Cells, Extracellular Vesicles, Regenerative Medicine, Stem Cell Therapy
Researchers continue to tout the potential of mesenchymal stem cells (MSCs) as an evolving approach for the repair of damaged tissue or lost cells.
Specifically, the ability of MSCs to differentiate and secrete beneficial factors and vesicles is believed to play the most influential role in the regeneration of injured tissues and cells affected by various diseases.
Recently, research into the regenerative potential of MSCs has focused on the extracellular vesicles (EVs) secreted by MSCs as an emerging and potential non-cellular therapeutic approach for healing or repairing injured or damaged tissue.
MSC-derived EVs (MSC-EVs), or cell-free therapies, in contrast to treatments based on whole cells, are easier to manage and safer due to lower amounts of membrane-bound proteins such as MHC molecules and their inability to directly form tumors.
In this review, Keshtkar et al. discuss and describe the extracellular vesicles released by MSCs and their therapeutic potential for addressing different disease models.
These EVs are membrane-packed vesicles that are secreted by a variety of cell types and found in a variety of physiological fluids. In addition to MSCs, EVs are also secreted by T cells, B cells, dendritic cells, platelets, mast cells, epithelial cells, endothelial cells, neuronal cells, cancerous cells, and embryonic cells. EVs are also found in urine, blood, breast milk, saliva, cerebrospinal fluid, synovial fluid, and amniotic fluid.
EVs have repeatedly demonstrated that they perform an important role in cell-to-cell communication and have been implicated in a number of important processes, including the immune response, homeostasis maintenance, coagulation, and inflammation.
Several studies have explored the use of MSC- EVs as therapeutic treatment options for kidney disease, liver disease, cardiovascular disease, and neurological disease. The authors of this review report the beneficial therapeutic effects of MSC-EVs in each of the disease models listed above, which include a significant reduction in inflammation, improved angiogenesis, reduced oxidative stress, the suppression of fibrosis, and increased cell proliferation.
Keshtkar et al. conclude that EVs can be easily isolated from MSCs of various origins and can be transferred to target cells to introduce therapeutic effects that include the regeneration of tissue and suppression of inflammation. Additionally, the authors point out that EVs could be an effective, safe therapeutic option.
Considering the potential therapeutic benefits of MSC-EV regenerative therapy, the authors suggest standardizing methods for EV isolation, characterization, and administration as ways to provide safe, effective, and powerful new therapies based on MSC-EVs.
Source: “Mesenchymal stem cell-derived extracellular vesicles – NCBI.” 9 Mar. 2018, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5845209/.
by admin | Oct 1, 2022 | Stem Cell Therapy, Exosomes, Extracellular Vesicles, Mesenchymal Stem Cells, Stem Cell Research
The number of people experiencing autoimmune diseases (ADs) continues to increase worldwide. Currently, it’s estimated that between 2 and 5% of the global population is afflicted with the most severe forms of these diseases, including type 1 diabetes (T1DM), systemic lupus erythematosus (SLE), and rheumatoid arthritis (RA).
An autoimmune disease can occur nearly anywhere in the body and is the result of the immune system mistakenly attacking your body instead of protecting it. While the reason this occurs is not yet fully understood, there are over 100 different types of autoimmune diseases classified into two types: organ-specific (T1DM) and multiple system-involved conditions (SLE and RA).
In addition to T1DM, SLE, and RA, other common autoimmune conditions include Crohn’s disease, ulcerative colitis, psoriasis, inflammatory bowel disease (IBS), and multiple sclerosis (MS).
In addition to not fully understanding why these conditions occur, conventional treatments (mainly in the form of immunosuppressants) alleviate associated symptoms but do not provide lasting or effective therapy for preventing or curing these diseases.
In recent years, mesenchymal stem cells (MSCs) and MSC-derived extracellular vesicles (MSC-EV) have demonstrated immunosuppressive and regenerative effects, and are now being investigated as promising new therapies for the treatment of ADs. In this review, Martinez-Arroyo et al. provide a complete analysis of current MSC and MSC-EV efforts in regard to some of the most severe ADs (T1DM, RA, and SLE) as a way to demonstrate progress in the discovery and application of new stem cell therapies for the treatment of ADs.
Initial research by the International Society of Cellular Therapy in 2006 established that MSCs are able to exert a range of biological functions, with the most well-known being immunosuppressive and regenerative effects, suggesting that MSCs-based therapies for the treatment of ADs is possible. Additional research has also demonstrated MSCs role in regenerative medicine to be safe and effective in treating a wide variety of diseases and injuries.
Further study has demonstrated that MSCs influence immune cell proliferation, differentiation, and function. While this is promising, research also suggested that the microenvironment influences the induction, increase, and maintenance of MSCs immunoregulatory role.
Considering this, the authors of this review suggest that blocking immune cell reprogramming while maintaining MSC roles in the immune microenvironment would provide new insights into identifying strategies for the biological treatment of ADs.
Current research and findings also support the use of MSC for the regeneration of tissue. This same research has also raised concerns related to cell survival, genetic instability, loss of function, and immune-mediated rejection. Because of this, Martinez-Arroyo et al. call for further study to better understand the biology, biomaterials, and tissue engineering used during MSC therapy.
The authors conclude this review by pointing out that there has been a revolutionary change in perspective in the field of MSC-based therapies for the treatment of AD primarily stemming from the use of MSC-EVs as potential therapeutic options.
Additionally, when comparing the use of MSCs to MSC-EVs, the authors highlight several advantages demonstrated by MSC-EVs. These advantages include providing stability and safety, avoiding tumorigenesis, genetic mutability, and immunogenicity when compared to MSCs, and allowing for several modifications to their surface and cargo – all enhancing their potential as viable treatment options for ADs.
While MSC-EVs demonstrate tremendous potential, the authors call attention to the fact that the use of MSC-EVs is still in the initial research and development phases and faces major obstacles and limitations in a number of areas, including overcoming the optimization of methods for MSC-EV characterization, high-scale production, and purification and improving MSC-EV targeting.
Considering these limitations, Martinez-Arroyo calls for further research with animal models and clinical assays as a way to test the safety and efficiency of using MSC-EVS as cell-free therapy for ADs.
Source: “Mesenchymal Stem Cell-Derived Extracellular Vesicles as Non ….” https://www.mdpi.com/1999-4923/14/4/733/htm.
by admin | Jul 15, 2022 | Osteoarthritis, Extracellular Vesicles, Mesenchymal Stem Cells, Stem Cell Research, Stem Cell Therapy
Osteoarthritis (OA) is the most common form of arthritis, affecting over 525 million people around the world. Characterized by pain, swelling, and stiffness resulting from the degradation of cartilage that provides cushion and protection between our bones, OA is an inflammatory condition without a clear and effective treatment.
OA most commonly affects the hands, knees, hips, and spine, but ultimately can cause damage to any joint in the body. Currently, most treatments for OA are designed to minimize the symptoms of the condition, not to treat or prevent the condition itself.
In recent years, pre-clinical studies of mesenchymal stem cells (MSCs) have demonstrated to be successful in resurfacing areas of degenerated cartilage and early-phase clinical trials found that intra-articular (IA) administration of MSCs leads to a reduction in pain and improved cartilage protection and healing.
In this review, Mancuso et al. provide an overview of the functions and mechanisms of MSC-secreted molecules found in in-vitro and in-vivo models of OA. Although MSCs disappear from the target area soon after administration, they have been found to demonstrate a rich secretory profile that is enhanced by exposure to inflammatory signals and is still able to deliver immunomodulatory effects.
Mancuso et al. highlight that, although chondrocyte apoptosis has long been associated with OA and despite the fact that there is no conclusive report identifying anti-apoptosis effects associated with MSCs, indirect evidence suggests that they have inhibited of ex-vitro cultured OA chondrocytes. Considering this, the authors recommend future studies of joint-associated MSC anti-apoptotic effects as a way to identify direct mediators of the process.
According to the authors of this review, the role of inflammation in the establishment and maintenance of OA is now widely accepted with synovial membrane inflammation a hallmark of OA pathology. Additionally, the biological markers of inflammation positively correlate with knee pain and clinical progression of OA. Studies have demonstrated that licensed MSCs secrete an array of anti-inflammatory cytokines which can help re-establish an equilibrium in the inflamed synovium and reduce inflammation in joints affected by OA.
After being administered, MSCs tend to undergo biological changes more radical than differentiation or licensing, with most completely disappearing 10 days post-injection. However, even after this occurs, there have been significant therapeutic effects observed.
Researchers have found that these apoptotic MSCs communicate with immune cells both directly and indirectly with patient responsiveness to MSCs correlating with their cytotoxic capacity. Mancuso et al. conclude that these findings provide evidence that apoptosis is one of the driving mechanisms of MSC-mediated immunosuppression.
Findings also suggest that the paracrine action of MSCs is not limited to soluble factors and has been shown to produce extracellular vesicles (ECVs). In pre-clinical models, ECVs have been observed to have anti-apoptotic, anti-fibrotic, pro-angiogenic, and anti-inflammatory effects. In addition, these ECVs – when derived from MSCs – inhibit the proliferation of lymphocytes, macrophages, and B cells.
MSC-derived ECVs have shown to be promising in rat models of osteoporosis and have recently been tested in OA animal models with promising results. The authors point out that while further study is required, the initial findings indicate that the use of MSC-ECVs in therapy designed for OA would bring many advantages when compared to cell-derived products. The authors also point out that several issues with ECVs still have to be considered, including the need for them to be specifically tailored for the specific indication being treated.
Mancuso et al. conclude that MSCS has already proved to be a valuable tool for many conditions and there is significant potential for their use in OA. Phase I clinical trials have established that the direct IA administration of MSCs in OA patients is safe and pain reduction and increased cartilage thickness have been observed after injection. However, they also call for additional studies to examine the role of cell death in mediating the therapeutic effects of MSCs.
Source: Mesenchymal Stem Cell Therapy for Osteoarthritis: The Critical Role ….” 11 Jan. 2019, https://www.frontiersin.org/articles/10.3389/fbioe.2019.00009/full.
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