MSC-derived Exosomes Research Articles

MESENCHYMAL STEM CELL-DERIVED EXOSOMES AND TREATMENT IN ATHEROSCLEROSIS: A SCOPING REVIEW

Atherosclerosis is an inflammatory disease that involves the formation of plaque in large arteries. It is a leading cause of vascular death worldwide and current therapy does not effective to all patients. Recently, mesenchymal cell (MSC) derived exosome particles shown potential as treatment for this disease. Therefore, this scoping review aims to give an overview and find out the extend of research on its medicinal potential in atherosclerosis. A total of five online databases were used in the article searching namely Scopus, Science Direct, Cambridge Journal, PubMed, and Cochrane Library. Keywords (atherosclerosis OR atherogenesis) AND (‘mesenchymal cell’ OR ‘stem cell’) AND (exosome OR exosomes) were used. 10 relevant papers were chosen to be used in this review after being filtered out using PRISMA 2020 method and the relevant information was extracted. The summary of the core concepts that were used in all relevant papers showed that inflammation is the most targeted process in this disease development followed by inhibition of apoptosis, and facilitation of movement of cells that contributes to the atherogenesis. In most papers, MSC exosome was used as vehicles to transport biological components to the targeted site. In conclusion, there are a lot of research gaps that should be addressed in order to use MSC-derived exosomes in atherosclerosis treatment.

Cutting-edge insights into liver fibrosis: advanced therapeutic strategies and future perspectives using engineered mesenchymal stem cell-derived exosomes.

Liver fibrosis is still a serious health concern worldwide, and there is increasing interest in mesenchymal stem cells (MSCs) with tremendous potential for treating this disease because of their regenerative and paracrine effects. Recently, many researches have focused on using the released exosomes (EXOs) from stem cells to treat liver fibrosis rather than using parent stem cells themselves. MSC-derived EXOs (MSC-EXOs) have demonstrated favourable outcomes similar to cell treatment in terms of regenerative, immunomodulatory, anti-apoptotic, anti-oxidant, anti-necroptotic, anti-inflammatory and anti-fibrotic actions in several models of liver fibrosis. EXOs are superior to their parent cells in several terms, including lower immunogenicity and risk of tumour formation. However, maintaining the stability and efficacy of EXOs after in vivo transplantation remains a major challenge in their clinical applicability. Therefore, several strategies have been applied in EXOs engineering, such as parental cell modification or modifying EXOs directly to achieve optimum performance of EXOs in treating liver fibrosis. Herein, we discuss the underlying mechanisms of liver fibrosis with an overview of the available therapies, among them EXOs. We also summarise the recent developments in improving the effectiveness of EXOs with the advantages and limitations of these approaches in terms of the upcoming clinical applications.

Stem cell-derived exosome treatment for acute spinal cord injury: a systematic review and meta-analysis based on preclinical evidence

BackgroundThe study aims were to systematically review and analyze preclinical research on the efficacy of exosomes derived from various mesenchymal stem cell sources (MSC-exos) for the treatment of spinal cord contusion injury (SCI) in small animal models.MethodsWe conducted a systematic search of PubMed, Embase and Google Scholar databases from their inception through February 29, 2024, to identify eligible English-language studies based on predefined inclusion and exclusion criteria. Two independent investigators performed literature screening, data extraction and bias assessment.ResultsA total of 235 rats were used to assess locomotor recovery at the initial assessment, and exhibited significant improvement in hind limb movement in those treated with exosomes, as indicated by a statistically significant increase in Basso-Beattie-Bresnahan (BBB) scores (MD: 1.26, 95% CI: 1.14–1.38, p < 0.01) compared to the controls. This trend persisted in final assessment data across 21 studies, with pooled analysis confirming similar results (MD: 1.56, 95% CI: 1.43–1.68, p < 0.01). Funnel plot analysis indicated asymmetry in the pooled BBB scores at both baseline and endpoint assessments, suggesting potential publication bias. Exosomes were derived from bone marrow, adipose tissue, umbilical cord or human placental MSCs. Meta-analysis results showed no statistically significant differences in therapeutic efficacy among these MSC-exos sources at various treatment time points.ConclusionMSC-exos demonstrated considerable promise in improving motor function in SCI-affected rats, with bone marrow MSC-derived exosomes having particularly notable effectiveness.

Exploring the landscape of exosomes in heart failure: a bibliometric analysis.

Exosomes, which carry bioactive RNAs, proteins, lipids, and metabolites, have emerged as novel diagnostic markers and therapeutic agents for heart failure (HF). This study aims to elucidate the trends, key contributors, and research hotspots of exosomes in HF. We collected publications related to exosomes in HF from the Web of Science Core Collection. Using VOSviewer, CiteSpace, Excel, and SRplot software, we performed a visualization analysis of authors, countries, institutions, keywords, and references. The publications on exosomes in the field of HF (N =2127) has grown rapidly. China (N =245, 42.683%) and the United States (N =170, 29.617%) are the leading contributors in this area. Wang L (N =14, 2.443%) is the most prolific author in the field. Key areas of exosome research in HF include mesenchymal stem cells (MSCs), angiogenesis, and microRNAs. Additionally, keywords and references analysis reveal that exosome research in HF is primarily focused on the role of exosomes in intercellular communication in HF, the value of miRNAs in exosomes as diagnostic markers, and the therapeutic mechanisms of MSC-derived exosomes. Exosomes are receiving increasing attention in the field of HF. Mapping the development landscape of exosomes in HF will help researchers accelerate progress in this area.

The Role of Mesenchymal Stem Cell-Derived Exosomes in Skin Regeneration, Tissue Repair, and the Regulation of Hair Follicle Growth.

Skin regeneration, repair, and the promotion of hair growth are intricate and dynamic processes essential for preserving the overall health, functionality, and appearance of both skin and hair. These processes involve a coordinated interplay of cellular activities and molecular signaling pathways that ensure the maintenance and restoration of skin integrity and hair vitality. Recent advancements in regenerative medicine have underscored the significant role of mesenchymal stem cell (MSC)-derived exosomes as key mediators in these processes. Exosomes, emerging as a promising cell-free therapy in tissue engineering, hold substantial potential due to their ability to influence various biological functions. This review explores the mechanisms by which MSC-derived exosomes facilitate skin regeneration and repair, and hair growth, their therapeutic applications, and the future research directions in this emerging field.

The Potential of Mesenchymal Stem Cell-Derived Exosomes to Treat Diabetes Mellitus.

Diabetes mellitus (DM) is a fatal metabolic disease characterized by persistent hyperglycemia. In recent studies, mesenchymal stem cell (MSC)-derived exosomes, which are being investigated clinically as a cell-free therapy for various diseases, have gained attention due to their biomimetic properties that closely resemble natural cellular communication systems. These MSC-derived exosomes inherit the regenerative and protective effects from MSCs, inducing pancreatic β-cell proliferation and inhibiting apoptosis, as well as ameliorating insulin resistance by suppressing the release of various inflammatory cytokines. Consequently, MSC-derived exosomes have attracted attention as a novel treatment for DM as an alternative to stem cell therapy. In this review, we will introduce the potential of MSC-derived exosomes for the treatment of DM by discussing the studies that have used MSC-derived exosomes to treat DM, which have shown therapeutic effects in both type 1 and type 2 DM.

Unlocking Therapeutic Potential: Mesenchymal Stem Cells-derived Exosomes in IUA Treatment, Current Status and Perspectives.

Intrauterine adhesion (IUA) is a condition caused by damage to the basal uterine layer which can lead to partial or full occlusion of the uterine cavity. Although traditional treatment options have been useful in mild and moderate cases, they have been unsatisfactory in severe IUA cases. Therefore, it is essential to improve the treatment strategies of IUA. Recent studies have demonstrated that Mesenchymal stem cells (MSCs) exert their therapeutic effects via the paracrine secretion of several substances including extracellular vesicles (EV) also called exosomes. MSC-derived exosomes (MSC-Exos) do not have the limitations of MSCs including immunogenicity and tumorigenicity. However, exosomes have limitations in terms of identification, isolation, purification, and origin. The clinical application of exosomes requires quality control and increased standardization in isolation and culture serum. This review summarizes therapeutic potentials of MSC-Exos and explores their potential clinical implications as diagnostic, therapeutic targets as well as prognostic markers in managing IUA.

Advances in the research of immunomodulatory mechanism of mesenchymal stromal/stem cells on periodontal tissue regeneration.

Periodontal disease is a highly prevalent disease worldwide that seriously affects people's oral health, including gingivitis and periodontitis. Although the current treatment of periodontal disease can achieve good control of inflammation, it is difficult to regenerate the periodontal supporting tissues to achieve a satisfactory therapeutic effect. In recent years, due to the good tissue regeneration ability, the research on Mesenchymal stromal/stem cells (MSCs) and MSC-derived exosomes has been gradually deepened, especially its ability to interact with the microenvironment of the body in the complex immunoregulatory network, which has led to many new perspectives on the therapeutic strategies for many diseases. This paper systematically reviews the immunomodulatory (including bone immunomodulation) properties of MSCs and their role in the periodontal inflammatory microenvironment, summarizes the pathways and mechanisms by which MSCs and MSC-EVs have promoted periodontal regeneration in recent years, lists potential areas for future research, and describes the issues that should be considered in future basic research and the direction of development of "cell-free therapies" for periodontal regeneration.

Exosomes derived from hUC-MSCs exhibit ameliorative efficacy upon previous cesarean scar defect via orchestrating β-TrCP/CHK1 axis

Previous cesarean scar defect (PCSD), also acknowledged as the myometrium of uterus defects, which commonly results in myometrial discontinuity between the uterine and cervical cavity. Current literatures have indicated the efficacy of MSCs and MSC-derived exosomes (MSC-Exos) for diverse refractory disease administration, yet the feasibility of MSC-Exos for PCSD treatment is largely obscure. In this study, we took advantage of the in vivo myofibrotic model for mimicking the typical manifestation of PCSD and the assessment of fertility. Meanwhile, the ex vivo scratch wound healing model is used for exploring the underlying molecular mechanism. On the one hand, we took advantage of the TGF-β-induced in vitro myofibrotic model and the full-thickness uterine injury rat model to verify the efficacy of human umbilical cord MSC-derived exosomes (hUC-MSC-Exos). On the other hand, with the aid of CHK1 overexpression and β-TrCP knockdown, together with multifaceted biological analyses (e.g., histopathological sections, qRT-PCR assay, western-blotting analysis, Co-IP assay, protein degradation and ubiquitination), we further dissected the underlying regulatory mechanism. We identified hUC-MSC-Exos and verified the suppressive effect of hUC-MSC-Exos upon TGF-β-induced in vitro myofibrotic model and full-thickness uterine injury in rats via delivering β-TrCP. Furthermore, we found that β-TrCP in hUC-MSC-Exos facilitated the ubiquitination degradation of CHK1 and inhibited the myofibrosis. Collectively, our data indicated the preferable ameliorative effect of hUC-MSC-Exos upon both the in vitro and in vivo myofibrotic models, together with the β-TrCP and CHK1-mediated regulatory mechanism. Our findings provided new references of hUC-MSC-Exos-based regimens for PCSD management in future.

Stem Cell-Derived Exosomes as a Therapeutic Option for Spinal Cord Injuries; a Systematic Review and Meta-Analysis.

Exosomes function as cell signaling carriers and have drawn much attention to the cell-free treatments of regenerative medicine. This meta-analysis aimed to investigate the efficacy of mesenchymal stem cell-derived (MSC-derived) exosomes in animal models of spinal cord injuries (SCI). A comprehensive search was conducted in Medline, Embase, Scopus, and Web of Science to attain related articles published by January 31, 2023. The eligible keywords were correlated with the spinal cord injury and MSC-derived exosomes. The evaluated outcomes were locomotion, cavity size, cell apoptosis, inflammation, neuro-regeneration, and microglia activation. A standardized mean difference was calculated for each sample and a pooled effect size was reported. 65 papers fully met the inclusion criteria. Treatment with MSC-derived exosomes ultimately improved locomotion and shrunk cavity size (p<0.0001). The administration of MSC-derived exosomes enhanced the expression of beta-tubulin III, NF200, and GAP-43, and increased the number of NeuN-positive and Nissl-positive cells, while reducing the expression of glial fibrillary acidic protein (p<0.0001). The number of apoptotic cells in the treatment group decreased significantly (p<0.0001). Regarding the markers of microglia activation, MSC-derived exosomes increased the number of CD206- and CD68-positive cells (p=0.032 and p<0.0001, respectively). Additionally, MSC-derived exosome administration significantly increased the expression of the anti-inflammatory interleukin (IL)-10 and IL-4 (p<0.001 and p=0.001, respectively) and decreased the expression of the inflammatory IL-1b, IL-6, and TNF-a (p<0.0001). MSC-derived exosome treatment resulted in a significantly improved locomotion of SCI animals through ameliorating neuroinflammation, reducing apoptosis, and inducing neuronal regrowth by facilitating a desirable microenvironment.

Application of Stem Cell-Derived Exosomes in Anterior Segment Eye Diseases: A Comprehensive Update Review.

Mesenchymal stem cell (MSC) therapy has emerged as a promising approach for addressing various eye-related conditions. Yet, its clinical application faces challenges due to issues such as limited biocompatibility and difficulties in effectively delivering treatment to specific ocular tissues. Recent studies have shifted attention towards MSC-derived exosomes, which share similar regenerative, reparative, and immunomodulatory capabilities with their origin cells. This review delves into the latest research on the use of MSC-derived exosomes for treating anterior segment diseases of the eye. It explores the exosomes' composition, biological functions, and the methods used for their isolation, as well as their roles in disease progression, diagnosis, and therapy. The review critically assesses the therapeutic advantages and mechanisms of action of MSC-derived exosomes in treating conditions like dry eye disease, Sjogren's syndrome, keratoconus, corneal lesions, and corneal allograft rejection. Additionally, it discusses the obstacles and future prospects of employing MSC-derived exosomes as innovative therapies for anterior segment eye diseases. This comprehensive overview underscores the significant potential of MSC-derived exosomes in transforming the treatment paradigm for anterior segment eye disorders, while also highlighting the necessity for further research to enhance their clinical application.

Mesenchymal Stem Cell-Sourced Exosomes as Potentially Novel Remedies for Severe Dry Eye Disease.

Severe dry eye disease (DED) is an inflammatory condition characterized by a lack of sufficient moisture or lubrication on the surface of the eye, significantly impacting the quality of life and visual function. Since detrimental immune response is crucially responsible for the development and aggravation of DED, therapeutic agents which modulate phenotype and function of eye-infiltrated inflammatory immune cells could be used for the treatment of severe DED. Due to their potent immunomodulatory properties, mesenchymal stem cells (MSCs) represent potentially new remedies for the treatment of inflammatory eye diseases. The majority of MSC-sourced bioactive factors are contained within MSC-derived exosomes (MSC-Exos), nano-sized extracellular vesicles which, due to their nanosize dimension and lipid envelope, easily by pass all biological barriers in the body and deliver their cargo directly into the target immune cells. MSC-Exos contain a variety of bioactive proteins (growth factors, immunoregulatory molecules, cytokines, and chemokines) lipids, and microRNAs (miRNAs) which affect viability, proliferation, phenotype, and function of eye-infiltrated immune cells. Accordingly, MSC-Exos may modulate the progression of inflammatory eye diseases, including DED. Therefore, in this review article, we summarized the current knowledge regarding molecular and cellular mechanisms which were responsible for trophic, anti-inflammatory, immunoregulatory, and regenerative properties of MSC-Exos in the treatment of severe DED. For this purpose, an extensive literature review was carried out in February 2024 across several databases (Medline, Embase, and Google Scholar), from 2000 to the present. Eligible studies delineated molecular and cellular mechanisms responsible for the MSC-Exos-based modulation of immune cell-driven eye inflammation in DED, and their findings were analyzed in this review. Results obtained in these studies demonstrated beneficial effects of MSC-Exos in the treatment of severe DED, paving the way for their future clinical use in ophthalmology. Trial Registration: ClinicalTrials.gov identifier: NCT04213248, NCT06475027, NCT06543667, NCT05738629.

MSC-derived exosomal circMYO9B accelerates diabetic wound healing by promoting angiogenesis through the hnRNPU/CBL/KDM1A/VEGFA axis

Diabetic foot ulcer (DFU) is a common but devastating complication of diabetes mellitus and might ultimately lead to amputation. Elucidating the regulatory mechanism of wound healing in DFU is quite important for developing DFU management strategies. Here, we show, mecenchymal stem cell (MSC)-derived exosomes promoted the proliferation, migration and angiogenesis of high glucose-treated endothelial cells and reduced cell apoptosis. These effects were further enhanced by MSC-derived exosomes carrying circMYO9B overexpression. Mechanistically, circMYO9B promoted the translocation of hnRNPU from nucleus to cytoplasm and consequently destabilized CBL, thereby reducing the ubiquitination and degradation of KDM1A to promote VEGFA expression in endothelial cells. MSC-derived exosomes carrying circMYO9B promotes angiogenesis and thus accelerates diabetic wound healing through regulating the hnRNPU/CBL/KDM1A/VEGFA axis, indicating potential therapeutic targets and strategies for DFU treatment.

Immunomodulatory features of MSC-derived exosomes decorated with DC-specific aptamer for improving sublingual immunotherapy in allergic mouse model

IntroductionSublingual immunotherapy (SLIT) is an effective and injection-free route for allergen-specific immunotherapy (AIT). Mesenchymal stromal/stem cell (MSC)-derived exosomes (Exo) has been identified as a novel delivery platform with immunomodulatory capacities. In addition, targeting agents such as aptamers (Apt) have been extensively used for specific delivery approaches such as direct delivery of allergen formulations to dendritic cells (DC) to improve the efficacy of specific immunotherapy. In this study, we assessed the effects of MSC-derived Exos containing ovalbumin (Ova) which decorated with DC-specific aptamer in allergic rhinitis mice model.Materials and methodsExos were harvested from adipose tissue-derived MSCs, and Exo-Apt-Ova complex was formulated. Then, Ova-induced allergic asthma model was simulated and sensitized BALB/c mice were treated sublingually with Exo-Apt-Ova complex (5 µg Ova) twice weekly for 8 weeks. Ova-specific IgE levels in serum and concentrations of interferon-gamma (IFN-γ), interleukin (IL)-4, and transforming growth factor-beta (TGF-β) in the supernatant of cultured splenocytes were evaluated using enzyme-linked immunosorbent assay (ELISA). In addition, lung histologic analysis and nasopharyngeal lavage fluid (NALF) cell count were performed.ResultsAdministration of Ova-incorporated Apt-modified Exos dramatically increased IFN-γ and TGF-β levels, and decreased IL-4 and IgE levels. In addition, inflammatory responses in the lung tissue and the number of eosinophils in NALF decreased.ConclusionSLIT using Exo-Ova (5 µg) decorated with DC-specific aptamer induced immunomodulatory responses and remarkably attenuated allergic airway inflammation in mice.

Exosomes derived from umbilical cord mesenchymal stem cells ameliorate ischemic brain injury in mice by regulating AAK1 via miR-664a-5p

Objective To identify the molecular targets of MSC-derived exosomes in treating cerebral ischemia and elucidate their therapeutic mechanisms. Methods We utilized a mouse model of middle cerebral artery occlusion (MCAO) and treated mice with umbilical cord mesenchymal stem cells (uc-MSCs) derived exosomes. Proteomic analysis identified AAK1(AP2 associated kinase 1) as a key target protein. Functional studies confirmed that AAK1 modulates the NF-κB signaling pathway in ischemic stroke. MicroRNA profiling, bioinformatic prediction, and cell experiments identified miR-664a-5p as the specific microRNA regulating AAK1 expression. Finally, we validated the therapeutic effects of uc-MSCs-derived exosomes using engineered miR-664a-5p-deficient exosomes. Results Our findings demonstrate that uc-MSCs-derived exosomes exert neuroprotective effects in ischemic stroke by modulating the AAK1/NF-κB axis via miR-664a-5p. Conclusion This study provides novel insights into the therapeutic mechanism of MSC-derived exosomes in ischemic stroke, highlighting their potential for developing exosome-based therapies.

Fully Bioactive Nanodrugs: Stem Cell-Derived Exosomes Engineered with Biomacromolecules to Treat CCl4- and Extreme Hepatectomy-Induced Acute Liver Failure.

Acute liver failure (ALF) is a serious global disease characterized by rapid onset and high mortality. Currently, the clinical treatment of ALF faces considerable hurdles due to limited medication options and the scarcity of liver transplants. Despite biomacromolecules such as hepatocyte growth factor (HGF) and glutathione (GSH) having been applied for ALF symptom relief in the clinic, they still face substantial challenges including poor stability, difficulty in acting on intracellular targets, and inadequate therapeutic outcome. In this work, by taking advantage of the innate targeting and regenerative capabilities of mesenchymal stem cells (MSCs), we harnessed MSC-derived exosomes as natural bioactive carriers for the simultaneous delivery of HGF and GSH, forming a fully bioactive nanodrug termed HG@Exo. Impressively, the HG@Exo demonstrated potent therapeutic effects against both carbon tetrachloride (CCl4)- and extreme hepatectomy-induced ALF through multiple mechanisms, including regulation of oxidative stress, reduction of inflammation, and promotion of hepatocyte regeneration, which were facilitated by its inflammation-targeting to damaged liver tissues. Furthermore, an FDA-approved near-infrared fluorescent dye, indocyanine green (ICG), has been incorporated into the exosomes (HGI@Exo) to endow them with real-time in vivo tracking capability, which showed favorable liver accumulation of the HGI@Exo in both CCl4- and surgery-induced ALF animal models, providing crucial insights into their biodistribution and therapeutic efficacy. Overall, the presented fully bioactive nanodrugs with targeting and theranostic abilities hold significant promise for potentiating the therapeutic efficacy of biomacromolecules for the improved treatment of ALF and other inflammatory diseases.

Recent research progress on microRNAs from mesenchymal stem cell-derived exosomes for tumor therapy: A review.

Mesenchymal stem cells (MSCs) are a class of protocells that can differentiate into various cell types and have robust replication and renewal capabilities. MSCs secrete various nutritional factors to regulate the microenvironment of tumor tissues. The mechanism by which they inhibit or promote tumor growth may be closely related to MSC-derived exosomes (MSC-Exo). However, the role of MSC-Exo vesicles in tumors remains controversial. This review discusses the potential applications of microRNAs in exosomes derived from MSCs in treating tumors.

Innovative approaches in stem cell therapy: revolutionizing cancer treatment and advancing neurobiology - a comprehensive review.

Stem cell therapy represents a transformative frontier in medical science, offering promising avenues for revolutionizing cancer treatment and advancing our understanding of neurobiology. This review explores innovative approaches in stem cell therapy that have the potential to reshape clinical practices and therapeutic outcomes in cancer and neurodegenerative diseases. In this dynamic and intriguing realm of cancer research, recent years witnessed a surge in attention toward understanding the intricate role of mesenchymal stem cells (MSCs). These cells, capable of either suppressing or promoting tumors across diverse experimental models, have been a focal point in the exploration of exosome-based therapies. Exosomes released by MSCs have played a pivotal role, in unraveling the nuances of paracrine signaling and its profound impact on cancer development. Recent studies have revealed the complex nature of MSC-derived exosomes, showcasing both protumor and antitumor effects. Despite their multifaceted involvement in tumor growth, these exosomes show significant promise in influencing both tumor development and chemosensitivity, acting as a pivotal factor that increases stem cells' potential for medicinal use. Endogenous MSCs, primarily originating from the bone marrow, exhibited a unique migratory response to damaged tissue sites. The genetic modification of stem cells, including MSCs, opened avenues for the precise delivery of therapeutic payloads in the milieu around the tumor (TME). Stem cell therapy offers groundbreaking potential for treating neurodegenerative and autoimmune disorders by regenerating damaged tissues and modulating immune responses. This approach aims to restore lost function and promote healing through targeted cellular interventions. In this review, we explored the molecular complexities of cancer and the potential for breakthroughs in personalized and targeted therapies. This analysis offers hope for transformative advancements in both cancer treatment and neurodegenerative disorders, highlighting the promise of precision medicine in addressing these challenging conditions.

Mesenchymal Stem Cell-Exosomal miR-99a Attenuate Silica-Induced Lung Fibrosis by Inhibiting Pulmonary Fibroblast Transdifferentiation.

Silicosis is one of the most prevalent and fatal occupational diseases worldwide, with unsatisfactory clinical outcomes. This study aimed to investigate the therapeutic effect and related molecular mechanisms of how mesenchymal stem cell (MSC)-secreted exosomes alleviate SiO2-induced pulmonary fibrosis. miR-99a-5p was significantly downregulated in silicosis models via high-throughput miRNA screening, and was overlapped with miRNAs in exosomes from MSCs. miR-99a-5p was significantly downregulated in the lung of a mice silicosis model and in TGFβ1-induced NIH-3T3 cells. In contrast, fibroblast growth factor receptor 3 (FGFR3), a direct target gene of miR-99a-5p, was upregulated in vitro and in vivo. Furthermore, we demonstrated that MSC-derived exosomes deliver enriched miR-99a-5p to target cells and inhibit TGF-β1-induced fibroblast transdifferentiation to reduce collagen protein production. Similarly, in a silicosis mouse model, MSC-derived exosome treatment through the tail veins of the mice counteracted the upregulation of fibrosis-related proteins and collagen deposition in the lung of the mice. By constructing exosomal therapeutic cell models with different miR-99a expressions, we further demonstrated that miR-99a-5p might attenuate pulmonary fibrosis by regulating target protein FGFR3 and downstream mitogen-activated protein kinase (MAPK) signalling pathways. Our study demonstrated that MSC-derived exosomes ameliorate SiO2-induced pulmonary fibrosis by inhibiting fibroblast transdifferentiation and represent an attractive method of pulmonary fibrosis treatment.

Multiomics Analysis of Molecules Associated with Cancer in Mesenchymal-Stem-Cell-(MSC)-Derived Exosome-Treated Hepatocellular Carcinoma Cells.

Hepatocellular carcinoma (HCC) is the most common form of liver cancer in humans, with an increasing incidence worldwide. The current study aimed to explore the molecular mechanisms that inhibit the proliferation of HepG2 cells, a hepatoblastoma-derived cell line. MSC-derived exosomes (UC-MSCs) were prepared with a median particle size (N50) of 135.8 nm. Concentrations of UC-MSCs ranging from 10 μg/mL to 1000 μg/mL were applied to HepG2 cell cultures and compared to untreated and anticancer drug-treated HepG2 cells. A combined approach was employed, integrating a proteomic analysis of UC-MSCs, metabolomic analysis of HepG2 cells, and transcriptomic profiling of HepG2 cells to decipher the inhibitory mechanisms of UC-MSC exosomes on HepG2 cell growth. Treatment with a high concentration of UC-MSCs led to a notable reduction in HepG2 cell viability, with survival decreasing by 65%. A proteomic analysis of UC-MSCs revealed enriched degranulation processes in Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, in addition to the known exosomal pathways. Transcriptomic profiling showed distinct changes in the expression of genes related to hepatocellular diseases in UC-MSC-treated HepG2 cells, contrasting with changes observed in HepG2 cells treated with the chemotherapeutic agent doxorubicin (DOX). Combined with a metabolomic analysis, the detailed GO and KEGG pathway analyses indicated that pathways associated with neutrophil extracellular trap formation played a critical role in mediating protein degradation and suppressing central carbon metabolism in cancer cells. Our results revealed that the UC-MSC treatment mimicked molecular mechanisms similar to those involved in neutrophil extracellular trap formation, exhibiting effects on HepG2 cell growth suppression that differed from those of chemical cancer drugs. Notably, the UC-MSC treatment demonstrated that protein degradation in HepG2 cells was regulated through canonical signaling pathways activated by bacterial peptides in neutrophils. This research has provided valuable insights into the potential of MSC-derived exosomes as a therapeutic approach for cancer treatment in the future.