A review of exosomes derived from mesenchymal stem cells as a treatment approach for temporomandibular disorders

Introduction: Chronic wounds in patients with complex comorbidities such as diabetes mellitus (DM), hypertension (HPT), and chronic kidney disease (CKD) are notoriously difficult to heal due to impaired angiogenesis, persistent inflammation, and fibroblast dysfunction which are frequently refractory to standard wound care. Mesenchymal stem cell (MSC) secretome, acellular biologic rich in growth factors, cytokines, and extracellular vesicles, has emerged as a promising therapeutic strategy demonstrated regenerative, angiogenic, and immunomodulatory properties capable of reactivating stalled wound healing processes Objectives: To evaluate the effectiveness of adjunctive MSC secretome therapy in a patient with a 7-year history of chronic, non-healing wound with multiple comorbidities who failed to respond to conventional and advanced wound care modalities. Case Summary: Case report was conducted on a 67-year-old male with a stable DM, HPT, and CKD with a 7- year history of chronic wounds on the right lateral leg. MSC secretome (5 mL) was administered via subcutaneous injection twice weekly at the wound edges, alongside standard wound care based on the TIME framework. Wound surface area was calculated as length × width (cm 2 ) and photographic progression were documented over 126 days. Results: The total wound surface area initially measured 19.65 cm 2 . A transient increase to 33.32 cm 2 was observed on Day 32 due to coalescence of wound margins, followed by steady and progressive reduction. By Day 126, the area had decreased to 2.4 cm 2 . Despite an initial increase in wound area due to margin coalescence, a steady reduction followed, culminating in an 87.79% total wound surface area reduction (from 19.65 cm² to 2.4 cm²). Clinical improvement in granulation tissue formation and partial to complete epithelialization was observed. Discussion: In this case report, wound healing progressed steadily despite pale granulation, indicating that MSC secretome may exert its effects by activating cellular repair pathways through paracrine signalling before structural tissue changes are clinically apparent. MSC secretome components including growth factors, cytokines, and extracellular vesicles such as exosomes are believed to modulate inflammation, promote angiogenesis, and stimulate fibroblast activity, which may help overcome the impaired healing typical in patients with multiple comorbidities.

What's in a Name?

BackgroundThe mechanisms underpinning the regenerative capabilities of mesenchymal stem cells (MSC) were originally thought to reside in their ability to recognise damaged tissue and to differentiate into specific cell types that would replace defective cells. However, recent work has shown that molecules produced by MSCs (secretome), particularly those packaged in extracellular vesicles (EVs), rather than the cells themselves are responsible for tissue repair.MethodsHere we have produced a secretome from adipose-derived mesenchymal stem cells (ADSC) that is free of exogenous molecules by incubation within a saline solution. Various in vitro models were used to evaluate the effects of the secretome on cellular processes that promote tissue regeneration. A cardiotoxin-induced skeletal muscle injury model was used to test the regenerative effects of the whole secretome or isolated extracellular vesicle fraction in vivo. This was followed by bioinformatic analysis of the components of the protein and miRNA content of the secretome and finally compared to a secretome generated from a secondary stem cell source.ResultsHere we have demonstrated that the secretome from adipose-derived mesenchymal stem cells shows robust effects on cellular processes that promote tissue regeneration. Furthermore, we show that the whole ADSC secretome is capable of enhancing the rate of skeletal muscle regeneration following acute damage.We assessed the efficacy of the total secretome compared with the extracellular vesicle fraction on a number of assays that inform on tissue regeneration and demonstrate that both fractions affect different aspects of the process in vitro and in vivo.Our in vitro, in vivo, and bioinformatic results show that factors that promote regeneration are distributed both within extracellular vesicles and the soluble fraction of the secretome.ConclusionsTaken together, our study implies that extracellular vesicles and soluble molecules within ADSC secretome act in a synergistic manner to promote muscle generation.

Lipid bicontinuous cubic phases are precursors to cubosomes–a promising type of nanoparticle for the delivery of multicomponent biomolecular mixtures for applications in health such as regenerative medicine and wound healing. In this study, we showed that the secretome of mesenchymal stem cells (MSCs), a complex mixture of growth factors, cytokines, extracellular vesicles, and other cell-secreted molecules with therapeutic potential, can be fully incorporated into the bicontinuous cubic phases of phytantriol and monoolein. When the secretome was added to dry lipid films, the resulting partial phase diagrams of these lipid-secretome systems, although more complex, resemble those of their lipid-water analogs. Remarkably, visual inspections and Small-Angle X-ray Scattering (SAXS) studies showed composition regions of homogeneous solid-like lipid mesophases without excess liquid phase-separation. This indicates that the diverse secretome components, even with their varied sizes and structures, are fully integrated into the cubic phases. SAXS showed patterns dominated by bicontinuous cubic phases with structural parameters close to the lipid-water systems. This suggests that water-soluble proteins likely localize within the water channels of the bicontinuous cubic phase, which must exhibit flexibility to accommodate proteins of diverse sizes, likely through the formation of locally disordered channels. Extracellular vesicles and associated membrane proteins, on the other hand, are likely fusing with and integrating into the cubic membranes. These findings underscore the potential of such liquid crystalline materials as matrices for the entire secretome, paving the way for future secretome-based cell-free therapeutics such as tissue regeneration, neuroprotective and anti-inflammatory treatments.

A comparative study on adipose-derived mesenchymal stem cells secretome delivery using microneedling and fractional Co 2 laser for facial skin rejuvenation" published in Clinical, Cosmetic and Investigational Dermatology.We solemnly appreciate any valuable input to our work for improvements in the future research, especially regarding stem cell products which have an immense potential in regenerative medicine.Through this article, we would like to address our replies to the concerns raised by the mentioned reader.First, the reader argued that our clinical trial was established to demonstrate the efficacy and safety of adipose-derived mesenchymal stem cells (ADMSCs) secretome for skin rejuvenation in a dose-dependent manner.While we agree with the importance of secretome dosage for such purpose, as we have explicitly stated in the introduction of our manuscript, the study aims to investigate which administration method (microneedling or fractional CO 2 ) is the best to deliver ADMSCs secretome for alleviating skin aging features. 1Numerous previous studies have reported the effects of stem cell derivatives in the field of dermatology.For instance, a study by Kim et al showed that the conditioned growth medium of ADMSCs incorporated in cosmetic products may exert antiaging properties through collagen synthesis, damaged skin restoration, and dermal density increment. 2Another research by Ahangar et al suggested that a vast repertoire of trophic factors contained in stem cell secretome may support wound repair through paracrine signaling, thus improving reepithelization, promoting angiogenesis, and controlling inflammation in human skin. 3Damayanti, Rusdiana, and Wathoni also conducted a literature review summarizing the utilization of mesenchymal stem cell secretome in dermatology, eg, protection against photoaging, accelerate hair growth, and treating psoriasis. 4Given the massive prospects of stem cell secretome that have already been discovered, there will be no novelty in performing another clinical trial to explore the efficacy of ADMSCs secretome for the treatment of cutaneous senescence; hence, that is not an interest in our current study.In addition, the reader emphasized the lack of characterization and protein concentrations of ADMSCs secretome used in our clinical trial.We acknowledge the imperative role of providing detailed delineation of study materials to ensure the replicability of our research.As per written descriptions in our latest paper, we performed quality analysis to our ADMSCs secretome, including the quantitative measurement of its protein contents.However, since our secretome is still prototype and yet to be registered for Intellectual Property Rights to date, we cannot provide the exact concentration

Mesenchymal stem cell-derived exosomes from different sources selectively promote neuritic outgrowth

Well-orchestrated physico-chemical and biological factors for enhanced secretion of osteogenic and angiogenic extracellular vesicles by mesenchymal stem cells in a 3D culture format.

Synovial Mesenchymal Stem Cell-Derived EV-Packaged miR-31 Downregulates Histone Demethylase KDM2A to Prevent Knee Osteoarthritis

Background & Objective: Thin endometrium (<7 mm) impairs receptivity and reduces pregnancy rates in Assisted Reproductive Technology (ART). Conventional therapies such as estrogen, vasodilators, Granulocyte Colony-Stimulating Factor (G-CSF), and platelet-rich plasma (PRP) showed inconsistent efficacy. Mesenchymal Stem Cell (MSC) secretome has emerged as a promising regenerative strategy. The narrative review was conducted with aim to synthesize evidence on the therapeutic potential of MSCs secretome for the treatment of thin endometrium.Materials & Methods: This narrative review was conducted through search in databases of PubMed, Scopus, and Google Scholar for studies up to 2025 using the keywords of “thin endometrium,” “mesenchymal stem cells,” “secretome,” and “exosomes.” Preclinical and clinical studies were included, with emphasis on human trials reporting endometrial thickness, receptivity, and pregnancy outcomes.Results: Preclinical studies demonstrate that the MSCs secretome enhances angiogenesis, modulates immune tolerance, reduces fibrosis, and promotes endometrial repair. Early clinical studies using bone marrow–, umbilical cord–, adipose tissue–, and menstrual blood–derived MSCs or their secretome report increased endometrial thickness and improved implantation, with some pregnancies and live births achieved. Safety data are favorable, particularly for secretome-derived extracellular vesicles, which avoid risks linked to cell transplantation.Conclusion: MSC secretome, based therapy offers a promising cell-free approach to manage thin endometrium through multimodal regenerative effects. While preliminary clinical findings are encouraging, larger controlled trials are needed to confirm the efficacy, optimize delivery, and establish long-term safety.

Over the last decade, mesenchymal stem cells (MSCs) have been considered a suitable source for cell-based therapy, especially in regenerative medicine. First, the efficacy and functions of MSCs in clinical applications have been attributed to their differentiation ability, called homing and differentiation. However, it has recently been confirmed that MSCs mostly exert their therapeutic effects through soluble paracrine bioactive factors and extracellular vesicles, especially secretome. These secreted components play critical roles in modulating immune responses, improving the survival, and increasing the regeneration of damaged tissues. The secretome content of MSCs is variable under different conditions. Oxidative stress (OS) is one of these conditions that is highly important in MSC therapy and regenerative medicine. High levels of reactive oxygen species (ROS) are produced during isolation, cell culture, and transplantation lead to OS, which induces cell death and apoptosis and limits the efficacy of their regeneration capability. In turn, the preconditioning of MSCs in OS conditions contributes to the secretion of several proteins, cytokines, growth factors, and exosomes, which can improve the antioxidant potential of MSCs against OS. This potential of MSC secretome has turned it into a new promising cell-free tissue regeneration strategy.This review provides a view of MSC secretome under OS conditions, focusing on different secretome contents of MSCs and thier possible therapeutic potential against cell therapy.

Immunosuppression in sepsis is hypothesized to result from the increased expression of the immune checkpoint molecules programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1). PD-1 and PD-L1 blockade therapies have been reported to increase survival in septic animals. Currently, the interleukin (IL)-10 within mesenchymal stem cell (MSC) secretome is known for its immunomodulatory capacity. To study the effect of IL-10 within MSC secretome on the expression of immune checkpoints in the rat model of sepsis. Methods: We used 48 male Rattus norvegicus rats in this research and divided them into four groups: sham (rats without sepsis induction and treatment), control (sepsis-induced rats without treatment), T1 (sepsis-induced rats treated with 150 μL of secreted IL-10 from MSC), and T2 (sepsis-induced rats treated with 300 μL of secreted IL-10 from MSC). Forty-eight hours after sepsis induction, we terminated the rats and collected the blood to examine the PD-1 and PD-L1 expression levels. We found a decrease in the relative expression of PD-1 in the septic rat group given 150 μL and 300 μL of secreted IL-10 from MSC compared to the control group, but the decrease was not significant. We also found a decrease in the relative expression of PD-L1 mRNA in the septic rat group given 150 μL and 300 μL of secreted IL-10 from MSC compared to the control group. Administering secreted IL-10 from MSC reduces the expression of PD-1 and PD-L1 in sepsis. These findings suggest that MSC secretome can improve the immunosuppression in sepsis.

Low back pain (LBP) is one of the most frequent symptoms associated with intervertebral disc degeneration (IDD) and affects more than 80% of the population, with strong psychosocial and economic impacts. The main cause of IDD is a reduction in the proteoglycan content within the nucleus pulposus (NP), eventually leading to the loss of disc hydration, microarchitecture, biochemical and mechanical properties. The use of mesenchymal stem cells (MSCs) has recently arisen as a promising therapy for IDD. According to numerous reports, MSCs mediate their regenerative and immunomodulatory effects mainly through paracrine mechanisms. Recent studies have suggested that extracellular vesicles (EVs) extracted from MSCs may be a promising alternative to cell therapy in regenerative medicine. EVs, including exosomes and microvesicles, are secreted by almost all cell types and have a fundamental role in intercellular communication. Early results have demonstrated the therapeutic potential of MSCs-derived EVs for the treatment of IDD through the promotion of tissue regeneration, cell proliferation, reduction in apoptosis and modulation of the inflammatory response. The aim of this review is to focus on the biological properties, function, and regulatory properties of different signaling pathways of MSCs-derived exosomes, highlighting their potential applicability as an alternative cell-free therapy for IDD.

Injectable glycol chitosan thermogel loaded with placental mesenchymal stem cells secretome for enhanced wound healing and tissue regeneration.

The mesenchymal stem cell (MSC) secretome has been considered an innovative therapeutic biological approach, able to modulate cellular crosstalk and functionality for enhanced tissue repair and regeneration. This study aims to evaluate the functionality of the secretome isolated from periosteum-derived MSCs, from either basal or osteogenic-induced conditions, in the healing of a critical size calvarial bone defect in the rabbit model. A bioceramic xenograft was used as the vehicle for secretome delivery, and the biological response to the established biocomposite system was assessed by clinical, histological, histomorphometric, and microtomographic analysis. A comparative analysis revealed that the osteogenic-induced secretome presented an increased diversity of proteins, with emphasis on those related to osteogenesis. Microtomographic and histological morphometric analysis revealed that bioceramic xenografts implanted with secretomes enhanced the new bone formation process, with the osteogenic-induced secretome inducing the highest bone tissue formation. The application of the MSC secretome, particularly from osteogenic-induced populations, may be regarded as an effective therapeutic approach to enhance bone tissue healing and regeneration.

Milking mesenchymal stem cells: Updated protocols for cell lysate, secretome, and exosome extraction, and comparative analysis of their therapeutic potential.