Mesenchymal Stem Cell-derived Exosomes Research Articles

Exosomes secreted from bone marrow mesenchymal stem cells suppress cardiomyocyte hypertrophy through Hippo-YAP pathway in heart failure.

Mesenchymal stem cells-derived exosomes (MSCs-exosomes) reportedly possess cardioprotective effects. This study investigated the therapeutic potential and mechanisms of MSCs-exosomes on heart failure (HF). H9c2 cells were used to establish a cardiomyocyte hypertrophy model by angiotensin II (Ang II) treatment. Isolated MSCs-exosomes were identified by transmission electron microscope and CD63 detection. Apoptosis rate was measured by terminal deoxynucleotidyl transferase (TdT) dUTP Nick-End Labeling (TUNEL) assay. Levels of inflammatory factors [interleukin (IL)-1β, IL-4, IL-6, and tumor necrosis factor (TNF)-α] and brain natriuretic peptide (BNP) were determined by ELISA. Expression of apoptosis-related proteins [Bax, B-cell lymphoma-2 (Bcl-2), and caspase 3] and Hippo-Yes-associated protein (YAP) pathway-related proteins [YAP, phosphor (p)-YAP, and tafazzin (TAZ)] was detected by western blotting. Cardiomyocyte hypertrophy of H9c2 cells induced by Ang II was ameliorated by MSCs-exosomes treatment. MSCs-exosomes downregulated Bax and caspase 3 levels and upregulated Bcl-2 level in Ang II-induced H9c2 cells. MSCs-exosomes also reduced the levels of BNP, IL-1β, IL-4, IL-6, and TNF-α in Ang II-induced H9c2 cells. Meanwhile, p-YAP was downregulated and TAZ was upregulated after MSCs-exosomes administration. In conclusion, MSCs-exosomes alleviate the apoptosis and inflammatory response of cardiomyocyte via deactivating Hippo-YAP pathway in HF.

Use of mesenchymal stem cell therapy in COVID-19 related strokes.

Coronavirus disease 2019 (COVID-19) has affected a broad demographics, eliciting a more significant effect on specific groups such as males, African Americans, and Hispanic minorities. Treatment of COVID-19 often requires antiviral drugs or monoclonal antibodies. However, immunotherapies such as mesenchymal stem cells and mesenchymal stem cells-derived exosomal vesicles should be evaluated as treatment options for COVID-19. Mesenchymal stem cell therapy offers regenerative, anti-inflammatory, and immunomodulatory properties that can speed up the recovery from COVID-19. Mesenchymal stem cell therapy can also benefit COVID-19 patients who suffer from strokes, as COVID-19 increases the risk of strokes due to increased cytokines and clotting factors. Most stroke cases that occur in COVID-19 patients are ischemic strokes. Therefore, with the help of mesenchymal stem cell therapy and mesenchymal stem cells-derived exosomes, COVID-19-induced stroke patients might benefit from dual-ended treatment. The objective of this review was to discuss COVID-19 and stroke incidence and the available treatment options.

HucMSC-derived exosomes protect ovarian reserve and restore ovarian function in cisplatin treated mice.

Anti-cancer therapy often causes premature ovarian insufficiency and infertility as the ovarian follicle reserve is extremely sensitive to chemotherapy drugs, such as cisplatin. Various fertility preservation methods have been explored for women, especially prepubertal girls undergoing radiotherapy and chemotherapy due to cancer. In recent years, mesenchymal stem cell-derived exosomes (MSC-exos) have been reported to play an important role in tissue repair and the treatment of various diseases. In the current study, we observed that human umbilical cord-derived MSC-exos (hucMSC-exos) after short-term culture improved follicular survival and development while receiving cisplatin treatment. Moreover, intravenous injection of hucMSC-exos improved ovarian function and ameliorated inflammatory environment within the ovary. The underlying mechanism of hucMSC-exos on fertility preservation was associated with the down-regulation of p53-related apoptosis and their anti-inflammatory function. Based on these findings, we propose that hucMSC-exos may be a potential approach to improve fertility in women diagnosed with cancer.

Alleviation of Spinal Cord Injury by MicroRNA 137-Overexpressing Bone Marrow Mesenchymal Stem Cell-Derived Exosomes.

Bone marrow mesenchymal stem cell (BMMSC) is reported to promote spinal cord injury (SCI) recovery via secreting exosomes to deliver RNAs, proteins, lipids, etc. The present study aimed to investigate the effect of microRNA 137 (miR-137)-overexpressing BMMSC exosomes on SCI rats. BMMSCs were extracted from Sprague-Dawley (SD) rat hind leg bone marrow, and then BMMSC-secreted exosomes were collected. MiR-137 mimic and negative control (NC) mimic were transfected into BMMSCs, and then the corresponding exosomes were collected. Subsequently, SD rats were treated with sham operation + phosphate-buffered saline (PBS), SCI operation + PBS, SCI operation + NC mimic BMMSC exosomes, or SCI operation + miR-137-overexpressing BMMSC exosomes. MiR-137 was downregulated in the spinal cord tissue of SCI rats compared to sham rats. Furthermore, BMMSC exosome injection elevated the Basso, Beattie, and Bresnahan (BBB) scores and neuronal viability and reduced tissue injury and proinflammatory cytokine expression in the spinal cord tissue of SCI rats compared to PBS treatment. Subsequently, miR-137-overexpressing BMMSC exosome injection improved the BBB score and neuron viability, and decreased tissue injury as well as proinflammatory cytokine expression in SCI rats compared to NC-overexpressing BMMSC exosomes. Additionally, miR-137-overexpressing BMMSC exosomes also diminished neuronal apoptosis in the spinal cord tissue of SCI rats compared to NC-overexpressing BMMSC exosomes. In conclusion, miR-137-overexpressing BMMSC exosomes reduce tissue injury and inflammation while improving locomotor capacity and neuronal viability in SCI rats. These findings suggest that miR-137-overexpressing BMMSC exosomes may serve as a treatment option for SCI recovery.

Retracted: ECM-Mimicking Hydrogels Loaded with Bone Mesenchymal Stem Cell-Derived Exosomes for the Treatment of Cartilage Defects.

[This retracts the article DOI: 10.1155/2022/3450672.].

Treadmill exercise exerts a synergistic effect with bone marrow mesenchymal stem cell-derived exosomes on neuronal apoptosis and synaptic-axonal remodeling.

Treadmill exercise and mesenchymal stem cell transplantation are both practical and effective methods for the treatment of cerebral ischemia. However, whether there is a synergistic effect between the two remains unclear. In this study, we established rat models of ischemia/reperfusion injury by occlusion of the middle cerebral artery for 2 hours and reperfusion for 24 hours. Rat models were perfused with bone marrow mesenchymal stem cell-derived exosomes (MSC-exos) via the tail vein and underwent 14 successive days of treadmill exercise. Neurological assessment, histopathology, and immunohistochemistry results revealed decreased neuronal apoptosis and cerebral infarct volume, evident synaptic formation and axonal regeneration, and remarkably recovered neurological function in rats subjected to treadmill exercise and MSC-exos treatment. These effects were superior to those in rats subjected to treadmill exercise or MSC-exos treatment alone. Mechanistically, further investigation revealed that the activation of JNK1/c-Jun signaling pathways regulated neuronal apoptosis and synaptic-axonal remodeling. These findings suggest that treadmill exercise may exhibit a synergistic effect with MSC-exos treatment, which may be related to activation of the JNK1/c-Jun signaling pathway. This study provides novel theoretical evidence for the clinical application of treadmill exercise combined with MSC-exos treatment for ischemic cerebrovascular disease.

Novel frontiers for bone regeneration: application progress of mesenchymal stem cell-derived exosomes in bone tissue engineering

Novel frontiers for bone regeneration: application progress of mesenchymal stem cell-derived exosomes in bone tissue engineering

The role of mesenchymal stem cell-derived exosomes in tumor progression

The role of mesenchymal stem cell-derived exosomes in tumor progression

Black phosphorus thermosensitive hydrogels loaded with bone marrow mesenchymal stem cell-derived exosomes synergistically promote bone tissue defect repair.

The osteogenic function of mesenchymal stem cells (MSCs) is mainly attributed to the paracrine effect of extracellular vesicles. MSC-derived exosomes are interesting candidates as biopharmaceuticals for drug delivery and for the engineering of biologically functionalized materials, and have emerged as cell-free regenerative medicine in recent years. In this study, bone marrow mesenchymal stem cell (BMSC)-derived exosomes were loaded with photothermal material layered black phosphorus (BP) modified poly(N-isopropylacrylamide) (PNIPAAm) thermosensitive hydrogels to explore their effects on bone defect repair. In vitro, it was confirmed that the local high heat of nano-BP irradiated using a near-infrared (NIR) laser could trigger the reversible cascade reaction of hydrogels, and that the mechanical contraction of hydrogels led to the controllable release of a large number of exosomes along with the release of water molecules. Furthermore, in vitro investigations demonstrated that BP hydrogels loaded with BMSC-derived exosomes had favourable biocompatibility and could promote the proliferation and osteogenic differentiation of MSCs. Experiments conducted in vivo confirmed that this system significantly promoted bone regeneration. Therefore, the results of our study indicated that the nanoplatform based on BP thermosensitive hydrogels could provide a new clinical treatment strategy for controlled release and on-demand drug delivery, while the cell-free system composed of BMSC-derived exosomes had great application potential in bone tissue repair with the synergism of BP.

The Improving anti-tumour activity with melatonin-stimulated mesenchymal stem cell-derived exosomes in metastatic triple-negative breast cancer

The Improving anti-tumour activity with melatonin-stimulated mesenchymal stem cell-derived exosomes in metastatic triple-negative breast cancer

Stem cell-derived exosomes in the treatment of melasma and its percutaneous penetration.

Melasma is a refractory skin disease due to its complex pathogenesis and difficult treatment. Studies have found that human umbilical cord mesenchymal stem cell-derived exosomes (hUCMSC-Exos) could serve as a novel cell-free therapeutic strategy in regenerative and esthetic medicine. It could potentially treat melasma, but the skin barrier is a challenge. In this study, we aim to explore the safety and efficacy of hUCMSC-Exos in the treatment of melasma and the means to promote its percutaneous penetration. In the animal study about the effect of penetration, percutaneous penetration of PKH67-labeled hUCMSC-Exos was studied under microneedles, 1565 nm nonablative fractional laser (NAFL), and a plasma named Peninsula Blue Aurora Shumin Master (PBASM) treatments, observed by confocal laser scanning microscopy. In the clinical application study, 60 patients with melasma treated in our department were divided into four groups. NAFL combined with normal saline treatment was used for Group A. Microneedles, NAFL, and PBASM combined with hUCMSC-Exos treatments were used for Groups B, C, and D, respectively. Each patient received four treatments at 1-month intervals. Assessments were done using the degree of pain posttreatment, melasma area and severity score, improvement rate, physician global assessment score, satisfaction, and complications. In the animal study about the effect of penetration, hUCMSC-Exos can penetrate the deep dermis under microneedles, NAFL, and PBASM treatments. In the clinical application study, compared with Group A, Groups B, C, and D showed significantly improved therapeutic effect and patient satisfaction (p < 0.05), and there was no significant difference among Groups B, C, and D.(p > 0.05). Patients in Group B reported higher pain levels than those in the other three groups (p < 0.05); the treatment experience of patients in Group D was better. hUCMSC-Exos can improve the symptoms of melasma safely and effectively. Compared with microneedles, NAFL and PBASM can also achieve a good effect toward promoting penetration. These findings are worthy of exploration and clinical application.

Tumor necrosis factor-α-primed mesenchymal stem cell-derived exosomes promote M2 macrophage polarization via Galectin-1 and modify intrauterine adhesion on a novel murine model.

Intrauterine adhesion (IUA) is a condition caused due to damage or infection of the endometrium. It is characterized by continuous inflammation and following fibrosis and dysfunction. However, the current animal IUA models have several disadvantages, including complex operation, high mortality, and many extra distractions owing to opening of the abdominal cavity to expose the uterus. Mesenchymal stem cells (MSCs), which have been used in treatment of IUA, are heterogeneous and immunosuppressive. However, their therapeutic effect is not as good as expected. Here, we successfully built a new murine IUA model, called electric tool-scratching IUA model, and applied it in our experiments to investigate the efficacy of tumor necrosis factor-α (TNF-α) primed MSCs (T-MSCs). In the new model, we used a self-made electric tool that can cause mechanical damage to the endometrium without opening the abdominal cavity. ELISA and histological staining analysis were performed to evaluate pathological features of IUA. qRT-PCR, flow cytometry and immunofluoresence staining were performed to detect the phenotypes of macrophages. TMT proteomics quantification and western blotting assay were performed to analyze the differentially expressed proteins of MSC exosomes. Based on the new IUA model, we found TNF-α pretreatment could enhance the ability of MSCs to relieve inflammation and reduce endometrium fibrosis. Mechanistically, T-MSC promoted macrophage polarization to M2 phenotype through exosomes. Subsequently, we found the expression of Galectin-1 was increased in T-MSC exosomes. Finally, we analyzed the gene expression pattern of Galectin-1 treated macrophages and found Galectin-1 promoted macrophage polarization to M2 phenotype mainly through the Jak-STAT signaling pathway. Our studies proposed an innovative mouse model and a better MSC treatment strategy for IUA.

Mesenchymal stem cell-derived exosomes: The dawn of diabetic wound healing.

Chronic wound healing has long been an unmet medical need in the field of wound repair, with diabetes being one of the major etiologies. Diabetic chronic wounds (DCWs), especially diabetic foot ulcers, are one of the most threatening chronic complications of diabetes. Although the treatment strategies, drugs, and dressings for DCWs have made great progress, they remain ineffective in some patients with refractory wounds. Stem cell-based therapies have achieved specific efficacy in various fields, with mesenchymal stem cells (MSCs) being the most widely used. Although MSCs have achieved good feedback in preclinical studies and clinical trials in the treatment of cutaneous wounds or other situations, the potential safety concerns associated with allogeneic/autologous stem cells and unknown long-term health effects need further attention and supervision. Recent studies have reported that stem cells mainly exert their trauma repair effects through paracrine secretion, and exosomes play an important role in intercellular communication as their main bioactive component. MSC-derived exosomes (MSC-Exos) inherit the powerful inflammation and immune modulation, angiogenesis, cell proliferation and migration promotion, oxidative stress alleviation, collagen remodeling imbalances regulation of their parental cells, and can avoid the potential risks of direct stem cell transplantation to a large extent, thus demonstrating promising performance as novel "cell-free" therapies in chronic wounds. This review aimed to elucidate the potential mechanism and update the progress of MSC-Exos in DCW healing, thereby providing new therapeutic directions for DCWs that are difficult to be cured using conventional therapy.

GMP-Compliant Mesenchymal Stem Cell-Derived Exosomes for Cell-Free Therapy in Cancer.

Cancer is categorized as one of the life-threatening disease in the world, which has recently been associated with a significant increase in the incidence and prevalence rate. Hence, the discovery of effective approaches for prevention, early diagnosis, and effective treatment for cancer has been prioritized by oncology researchers. In recent decades, mesenchymal stem cells show great potential to advance the field of regenerative medicine and oncology research due to representing prominent characteristics. Recently, studies indicate that mesenchymal stem cells can play an important role by secreting extracellular vesicles like exosomes in modulating the biological functions of target cells through paracrine regulation. Indeed, the exosomes derived from mesenchymal stem cells can represent the same therapeutic potential as parent cells with fewer side effects. Therefore, it can be demonstrated that exosomes can be a suitable drug delivery candidate in regenerative medicine and targeted therapy. It is also noteworthy that as the use of exosome therapy becomes more common in clinical studies, the importance of improving basic criteria such as safety, efficiency, and quality of stem cell products will also be highlighted. Based on this concept, the good manufacturing practice principles were put forward to examine the standard of cell products from different qualitative and quantitative aspects to progress the cell therapy. In other words, the principles of good manufacturing practice should be observed not only in the extraction and isolation of stem cells but also in the extraction of products related to stem cells such as exosomes in the field of treatment.

Exosomes derived from BMSCs ameliorate cyclophosphamide-induced testosterone deficiency by enhancing the autophagy of Leydig cells via the AMPK-mTOR signaling pathway.

Cyclophosphamide-induced testosterone deficiency (CPTD) during the treatment of cancers and autoimmune disorders severely influences the quality of life of patients. Currently, several guidelines recommend patients suffering from CPTD receive testosterone replacement therapy (TRT). However, TRT has many disadvantages underscoring the requirement for alternative, nontoxic treatment strategies. We previously reported bone marrow mesenchymal stem cells-derived exosomes (BMSCs-exos) could alleviate cyclophosphamide (CP)-induced spermatogenesis dysfunction, highlighting their role in the treatment of male reproductive disorders. Therefore, we further investigated whether BMSCs-exos affect autophagy and testosterone synthesis in Leydig cells (LCs). Here, we examined the effects and probed the molecular mechanisms of BMSCs-exos on CPTD in vivo and in vitro by detecting the expression levels of genes and proteins related to autophagy and testosterone synthesis. Furthermore, the testosterone concentration in serum and cell-conditioned medium, and the photophosphorylation protein levels of adenosine monophosphate-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) were measured. Our results suggest that BMSCs-exos could be absorbed by LCs through the blood-testis barrier in mice, promoting autophagy in LCs and improving the CP-induced low serum testosterone levels. BMSCs-exos inhibited cell death in CP-exposed LCs, regulated the AMPK-mTOR signaling pathway to promote autophagy in LCs, and then improved the low testosterone synthesis ability of CP-induced LCs. Moreover, the autophagy inhibitor, 3-methyladenine (3-MA), significantly reversed the therapeutic effects of BMSCs-exos. These findings suggest that BMSCs-exos promote LC autophagy by regulating the AMPK-mTOR signaling pathway, thereby ameliorating CPTD. This study provides novel evidence for the clinical improvement of CPTD using BMSCs-exos.

Bone Marrow Mesenchymal Stem Cells-Derived miR-21-5p Protects Grafted Islets Against Apoptosis by Targeting PDCD4.

The apoptosis of grafted islets is an urgent problem due to the high rate of islet loss soon after transplantation. MicroRNA-21-5p (miR-21-5p) is an essential mediator of bone marrow mesenchymal stem cells-derived exosomes (BMSCs-Exo) during anti-apoptosis, but its effect and the underlying molecular mechanism in islet transplantation remain partially understood. Here, we found that miR-21-5p could be delivered to islet cells via BMSCs-Exo. Subsequently, we demonstrated that miR-21-5p overexpression reduced apoptosis in islets and INS-1 cells, whereas miR-21-5p inhibition enhanced apoptosis. A mechanistic analysis involving RNA sequencing and bioinformatic analysis was performed to determine the interaction between miR-21-5p and its target gene programmed cell death 4 (PDCD4), which was further verified by a dual luciferase assay. In vivo, the grafted islets overexpressing miR-21-5p showed a higher survival rate, better insulin secretion function, and a lower apoptosis rate. In conclusion, these results demonstrated that miR‑21‑5p from BMSCs-Exo protects against the apoptosis of grafted islets by inhibiting PDCD4 expression. Hence, miR-21-5p can be used as a cell-free therapeutic agent to minimize β-cell apoptosis at the early stage of islet transplantation.

Bone Marrow Mesenchymal Stem Cell-Derived Exosomes Inhibit Triple-Negative Breast Cancer Cell Stemness and Metastasis via an ALKBH5-Dependent Mechanism.

Abnormal N6-methyladenosine (m6A) modification caused by m6A regulators is a common characteristic in various tumors. However, little is known about the role of m6A regulator AlkB homolog 5 (ALKBH5) in triple-negative breast cancer (TNBC). In this study, we analyzed the influence of ALKBH5 on the stemness of TNBC and the molecular mechanism using bioinformatics analysis and in vivo animal experiments. RNA expression data and single-cell RNA sequencing (scRNA-seq) data were downloaded from the TCGA and GEO databases. Following intersection analysis, key genes involved in the TNBC cell stemness were determined, which was followed by functional enrichment analysis, PPI and survival analysis. Exosomes were extracted from bone marrow mesenchymal stem cells (BMSC-Exos) where ALKBH5 inhibition assay was conducted to verify their function in the biological characteristics of TNBC cells. Bioinformatics analysis revealed 45 key genes of ALKBH5 regulating TNBC cell stemness. In addition, UBE2C was predicted as a key downstream gene and p53 was predicted as a downstream signaling of ALKBH5. In vivo data confirmed that ALKBH5 upregulated UBE2C expression by regulating the m6A modification of UBE2C and reduced p53 expression, thus promoting the stemness, growth and metastasis of TNBC cells. BMSC-Exos suppressed the tumor stemness, growth and metastasis of TNBC cells and ALKBH5 shRNA-loaded BMSC-Exos showed a more significant suppressive role. Taken together, our findings indicated that ALKBH5 shRNA-loaded BMSC-Exos reduced TNBC cell stemness, growth and metastasis and define a promising strategy to treat TNBC.

The effect of mesenchymal stem cells-derived exosomes on the prostate, bladder, and renal cancer cell lines

We aimed to explain the role of mesenchymal stem cells (MSC-exosomes) on gene expressions of epithelial to mesenchymal transition (EMT), angiogenesis, and apoptosis. Four different cell lines were employed, including ACHN, 5637, LNCaP, and PC3, as well-known representatives for renal, bladder, hormone-sensitive, and hormone-refractory prostate cancers, respectively. Cell lines were exposed to diverse concentrations of mesenchymal stem cells-derived exosomes to find IC50 values. Percentages of apoptotic cells were evaluated by Annexin/P.I. staining. Micro Culture Tetrazolium Test assessed proliferative inhibitory effect; and prostate biomarker (KLK2), EMT (E-cadherin and Snail), angiogenesis genes (VEGF-A/VEGF-C), apoptosis genes (BAX/BCL2, P53) and Osteopontin variants (OPNa/b, and c) mRNA levels were studied by realtime PCR method. All 5637, LNCaP, and PC3 following treatment with exosomes illustrated specific responses with changes in expression of different genes. The increased TP53 and decreased BCL2 expressions were seen in 5637, LNCaP, and PC3. In PC3, OPNb and OPNc have raised more than P53; in LNCap, the increase was in VEGF-c. In 5637 cells, more than TP53 and BCL2 changes, two other genes, VEGFa and B.A.X., have decreased, suggesting exosomes’ anti-apoptotic and anti-angiogenic effects. The kidney tumor cell line saw no significant gene expression change in ten targeted genes. MSC-exosomes therapy has augmented some interesting antitumor effects on prostate, bladder, and kidney cancer cell lines. This effect which originates from exosomes’ potency to persuade apoptosis and prevent the proliferation of cancer cells simultaneously, was more substantial in bladder cancer, moderate in prostate cancer, and mild in renal cancer.

Hypoxic mesenchymal stem cell-derived exosomes alleviate ulcerative colitis injury by limiting intestinal epithelial cells reactive oxygen species accumulation and DNA damage through HIF-1α.

Ulcerative colitis (UC) is an inflammatory disease with a complex pathogenic mechanism. Mounting evidence suggests that UC pathogenesis is linked to excessive production of reactive oxygen species (ROS) and cellular DNA damage. Recent studies have shown that bone mesenchymal stem cells (BMSCs) mainly exert their therapeutic effects through paracrine exosomes, and oxygen concentration is extremely important to BMSCs and exosomes. The main objective of this study was to determine whether exosomes from BMSCs under hypoxic conditions (HP-Exos) exhibit a greater therapeutic effect on UC compared to exosomes under normoxic conditions (Exos) and to resolve the mechanism of HP-Exos. We observed that hypoxia enhances the activity and migration of BMSCs and inhibits BMSC apoptosis without changing their morphological characteristics. Furthermore, HP-Exos significantly relieved UC symptoms and pathological damage. In order to further understand the mechanism of HP-Exos in UC, findings from in vivo experiments demonstrated that HP-Exos reduces ROS production, DNA damage and apoptosis in intestinal epithelial cells. As hypoxia-inducible factor 1α (HIF-1α) plays an important role in hypoxia, we knocked down HIF-1α in BMSCs. HIF-1α knockout reversed the effects of hypoxia on the activity, migration and apoptosis of BMSCs. Moreover, inhibition of HIF-1α expression also reversed the regulation of UC by HP-Exos. Therefore, we conclude that HP-Exos regulates ROS accumulation, DNA damage and immune homeostasis in intestinal epithelial cells via HIF-1α.

Bone marrow mesenchymal stem cell-derived exosomes attenuate the maturation of dendritic cells and reduce the rejection of allogeneic transplantation

Bone marrow mesenchymal stem cell-derived exosomes attenuate the maturation of dendritic cells and reduce the rejection of allogeneic transplantation