Exosomes derived from adipose tissue‐derived mesenchymal stem cells (AD‐MSCs) have immunomodulatory effects of T‐cell inflammatory response and reduction of clinical symptoms on ...streptozotocin‐induced of the type‐1 diabetes mellitus (T1DM). Beside control group and untreated T1DM mice, a group of T1DM mice was treated with intraperitoneal injections of characterized exosomes derived from autologous AD‐MSCs. Body weight and blood glucose levels were measured during the procedure. Histopathology and immunohistochemistry were used for evaluation of pancreatic islets using hemotoxylin and eosin (H&E) staining and anti‐insulin antibody. Isolated splenic mononuclear cells (MNCs) were subjected to splenocytes proliferation assay using 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide, immunophenotyping of regulatory T cells and cytokines. A significant increase in the levels of interleukin‐4 (IL‐4), IL‐10, and transforming growth factor‐β, and a decrease in the levels of IL‐17 and interferon‐γ in concordance with the significant increase in the Treg cell ratio in splenic MNCs (P < 0.05) was shown in T1DM mice treated with AD‐MSC's exosomes as compared to T1DM untreated mice. This amelioration of autoimmune reaction after treatment of T1DM mice with the AD‐MSC exosomes was confirmed with a significant increase in islets using H&E staining and Immunohistochemistry analyses. As expected, body weight, blood glucose levels in a survival of T1DM mice treated with AD‐MSC's exosomes were maintained stable in comparison to untreated T1DM mice. It can be concluded that AD‐MSC's exosomes exert ameliorative effects on autoimmune T1DM through increasing regulatory T‐cell population and their products without a change in the proliferation index of lymphocytes, which makes them more effective and practical candidates.
Exosomes derived from adipose tissue‐derived mesenchymal stem cells (AD‐MSCs) have immunomodulatory effects of T‐cell inflammatory response and reduction of clinical symptoms on streptozotocin‐induced of the type‐1 diabetes mellitus (T1DM).
•Imbalance of RAAS system and hyper-activation of the Ang-II/AT1R axis promote hyper-inflammatory state and cytokine storm leading to end-organ damages.•Activation of inflammasomes, JAK/STAT, IFN, ...NF-κB and TLR pathways are involved in COVID-19-associated cytokine storm.•SARS-CoV-2 promotes ROS production via activation of the NF-kB pathway and inducing mitochondrial damage leading to cell and tissue degeneration.•Elevated levels of IL-1, TNF-α, IFN-γ and IL-6 results in recruitment of various immune cells and subsequent tissue damage.•Exaggerated inflammation can affect remote organs and cause multi-organ failure.
Coronavirus disease 2019 (COVID-19) outbreak has become a global public health emergency and has led to devastating results. Mounting evidence proposes that the disease causes severe pulmonary involvement and influences different organs, leading to a critical situation named multi-organ failure. It is yet to be fully clarified how the disease becomes so deadly in some patients. However, it is proven that a condition called “cytokine storm” is involved in the deterioration of COVID-19. Although beneficial, sustained production of cytokines and overabundance of inflammatory mediators causing cytokine storm can lead to collateral vital organ damages. Furthermore, cytokine storm can cause post-COVID-19 syndrome (PCS), an important cause of morbidity after the acute phase of COVID-19. Herein, we aim to explain the possible pathophysiology mechanisms involved in COVID-19-related cytokine storm and its association with multi-organ failure and PCS. We also discuss the latest advances in finding the potential therapeutic targets to control cytokine storm wishing to answer unmet clinical demands for treatment of COVID-19.
Dendritic cells (DCs) orchestrate innate inflammatory responses and adaptive immunity through T‐cell activation via direct cell–cell interactions and/or cytokine production. Tolerogenic DCs (tolDCs) ...help maintain immunological tolerance through the induction of T‐cell unresponsiveness or apoptosis, and generation of regulatory T cells. Mesenchymal stromal cells (MSCs) are adult multipotent cells located within the stroma of bone marrow (BM), but they can be isolated from virtually all organs. Extracellular vesicles and exosomes are released from inflammatory cells and act as messengers enabling communication between cells. To investigate the effects of MSC‐derived exosomes on the induction of mouse tolDCs, murine adipose‐derived MSCs were isolated from C57BL/6 mice and exosomes isolated by ExoQuick‐TC kits. BM‐derived DCs (BMDCs) were prepared and cocultured with MSCs‐derived exosomes (100 μg/ml) for 72 hr. Mature BMDCs were derived by adding lipopolysaccharide (LPS; 0.1μg/ml) at Day 8 for 24 hr. The study groups were divided into (a) immature DC (iDC, Ctrl), (b) iDC + exosome (Exo), (c) iDC + LPS (LPS), and (d) iDC + exosome + LPS (EXO + LPS). Expression of CD11c, CD83, CD86, CD40, and MHCII on DCs was analyzed at Day 9. DC proliferation was assessed by coculture with carboxyfluorescein succinimidyl ester‐labeled BALB/C‐derived splenocytes p. Interleukin‐6 (IL‐6), IL‐10, and transforming growth factor‐β (TGF‐β) release were measured by enzyme‐linked immunosorbent assay. MSC‐derived exosomes decrease DC surface marker expression in cells treated with LPS, compared with control cells ( ≤ .05). MSC‐derived exosomes decrease IL‐6 release but augment IL‐10 and TGF‐β release (p ≤ .05). Lymphocyte proliferation was decreased (p ≤ .05) in the presence of DCs treated with MSC‐derived exosomes. CMSC‐derived exosomes suppress the maturation of BMDCs, suggesting that they may be important modulators of DC‐induced immune responses.
Mesenchymal stromal cell‐derived exosomes suppress bone marrow‐derived dendritic cell maturation, implicating them as important modulators of dendritic cell‐induced immune responses.
The outbreak of COVID-19 in December 2019, has become an urgent and serious public health emergency. At present, there is no effective treatment or vaccine for COVID-19. Therefore, there is a crucial ...unmet need to develop a safe and effective treatment for COVID-19 patients. Mesenchymal stem cells (MSCs) are widely used in basic science and in a variety of clinical trials. MSCs are able to engraft to the damaged tissues after transplantation and promote tissue regeneration, besides MSCs able to secrete immunomodulatory factors that suppress the cytokine storms. Moreover, the contribution of MSCs to prevent cell death and inhibit tissue fibrosis is well established. In the current review article, the potential mechanisms by which MSCs contribute to the treatment of COVID-19 patients are highlighted. Also, current trials that evaluated the potential of MSC-based treatments for COVID-19 are briefly reviewed.
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We determined the seroprevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in an affected area in northern Iran in April 2020. Antibodies to SARS-CoV-2 were detected in 528 ...persons by using rapid tests. Adjusted prevalence of SARS-CoV-2 seropositivity was 22.2% (95% CI 16.4%-28.5%).
Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, is an inflammatory condition that results in gastrointestinal tract damage. Various factors, including ...environmental and genetic agents, disrupt the function of the intestinal immune system that can lead to IBD. Mesenchymal stem cells (MSCs) display an immunoregulatory function and demonstrate regenerative potential by paracrine action. In this study, we evaluated the immunomodulatory effects of MSCs’ derived exosomes in the acute form of dextran sulfate sodium (DSS)‐induced colitis. Exosomes were isolated from adipose‐derived MSCs. Acute colitis was induced by DSS. The exosome was used by intraperitoneal injection into mice with acute colitis. Stool consistency, body weight changes, bleeding severity, colon length, and weight were examined. At the experimental endpoint (Day 7), the changes in the colon tissue were evaluated. The level of cytokines of interferon‐γ (IFN‐γ), tumor necrosis factor‐α (TNF‐α), interleukin‐17 (IL‐17), IL‐4, IL‐12, transforming growth factor‐β (TGF‐β) and, IL‐10, and Treg cells percentage were assayed. Results showed that exosome administration diminished colon shortening, bodyweight loss, bleeding, and colon injury. The levels of IFN‐γ, TNF‐α, IL‐12, and IL‐17 were decreased, and the level of TGF‐β, IL‐4, and IL‐10 were increased in lymph node and spleen of mice treated with exosome. Percentages of CD4+ CD25+ Foxp3+ Treg cells were grown in the lymph node and spleen of mice treated with exosomes. Overall, current data suggest that MSC‐derived exosome could regulate the Treg population and improves inflammation in DSS‐induced acute colitis.
Mesenchymal stem cells (MSC)‐derived exosome ameliorates clinical and histopathological features of dextran sulfate sodium (DSS)‐induced acute colitis by Treg induction and reduction of inflammatory cytokines.
Severe side effects of chemotherapy agents on vital organs are the major causes of cancer-related mortality, not merely cancer disease. Encapsulating chemotherapeutic molecules in nanocarriers is a ...justifiable solution in decreasing the risk of their side effects and boosting the efficiency of treatment. The present study has developed the doxorubicin (DOX)-loaded AS1411 (anti-nucleolin) aptamer surface-functionalized exosome (DOX-Apt-Exo) to treat colorectal cancer in both in-vitro and in-vivo experimental models. HEK293-derived exosomes were loaded with DOX through the incubation method with a nearly 13% encapsulation efficiency. Afterwards, the 5-terminal carboxyl group of AS1411-aptamer was converted into amine-reactive NHS esters with EDC/NHS amide coupling chemistry before being conjugated to the amine groups on the exosome surface. DLS and TEM estimated the designed formulation (DOX-Apt-Exo) size of about 200 nm. Aptamer-binding affinity and cellular uptake of DOX-Apt-Exo by nucleolin-overexpressing cancer cells were depicted through fluorescence microscopy. Comparing the in-vitro cytotoxicity impact of DOX-loaded exosomes, either targeted or non-targeted by MTT assay, clearly verified a high effectiveness of ligand-receptor mediated target therapy. Subsequently, in-vivo experiments which were conducted on four groups of ectopic mouse models of colon cancer (5 in each group) demonstrated the tumor growth suppression through professional long-term accumulation and retention of DOX-Apt-Exo at the tumor site by ligand-receptor interaction. The results suggested that AS1411 aptamer-functionalized exosomes can be recommended as a safe and effective system to site-specific drug delivery in possible clinical applications of colon cancer.
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•An anti-nucleolin targeted exosome system containing doxorubicin has been engineered to treat colon cancer.•DOX-Apt-Exo depicts a uniform size distribution, desired biocompatibility and homing tumor ability.•The DOX-Apt-Exo, can slow the proliferation of cancer cells after intraperitoneal administration in colorectal cancer xenograft mouse model.•AS1411 + exosome suggests as a functionalized natural non-immunogenic delivery vehicle for cancer treatment.
Ocular melanoma is a rare kind of eye malignancy that threatens the patient's eyesight. Radiotherapy and surgical removal are the most commonly used therapeutic modalities, and nanomedicine has ...lately entered this field. Brachytherapy using Ruthenium-106 (
Ru) ophthalmic plaques has been used for decades to treat ocular melanoma, with the applicator placed on the patient's eyes until the prescribed dose reaches the tumor apex.
To investigate the efficiency of hydrogen nanobubbles (H
-NBs) employment during intraocular melanoma brachytherapy using a
Ru electron emitter plaque.
The Monte Carlo (MC) simulation and experimental investigation using a 3D-designed phantom and thermoluminescence dosimetry (TLD) were employed. Various concentrations of H
-NBs with a diameter of 100 nm were simulated inside tumor tissue. The results were presented as deposited energy and dose enhancement factor (DEF). An equivalent Resin phantom of the human eyeball was made using AutoCAD and 3D-Printer technologies. The glass-bead TLDs dosimeter were employed and placed inside the phantom.
Using a 1% concentration of H
-NBs, a DEF of 93% and 98% were achieved at the tumor apex of 10 mm from the experimental setup and MC simulation, respectively. For simulated concentrations of 0.1%, 0.3%, 0.5%, 1%, and 4% H
-NBs, a maximum dose enhancement of 154%, 174%, 188%, 200%, and 300% were achieved, respectively, and a dose reduction was seen at about 3 mm from the plaque surface.
H
-NBs can be used as an absorbed dose enhancer in
Ru eye brachytherapy because of their unique physical characteristics. Reducing plaque implantation time on the patient's eye, reducing sclera absorbed dose, and decreasing the risk of patients' healthy organs irradiation are reported as some of the potential benefits of using H2-NBs.
Mesenchymal stem cells (MSCs) are multipotent cells with the potential to differentiate into different cell types. Owing to their immunosuppressive and anti‐inflammatory properties, they are widely ...used in regenerative medicine, but they have a dual effect on cancer progression and exert both growth‐stimulatory or ‐inhibitory effects on different cancer types. It has been proposed that these controversial effects of MSC in tumor microenvironment (TME) are mediated by their polarization to proinflammatory or anti‐inflammatory phenotype. In addition, they can polarize the immune system cells that in turn influence tumor progression. One of the mechanisms involved in the TME communications is extracellular vesicles (EVs). MSCs, as one of cell populations in TME, produce a large amount of EVs that can influence tumor development. Similar to MSC, MSC‐EVs can exert both anti‐ or protumorigenic effects. In the current study, we will investigate the current knowledge related to MSC role in cancer progression with a focus on the MSC‐EV content in limiting tumor growth, angiogenesis, and metastasis. We suppose MSC‐EVs can be used as safe vehicles for delivering antitumor agents to TME.
Owing to immunosuppressive and anti‐inflammatory properties of mesenchymal stem cell (MSCs), they are widely used in regenerative medicine but they have a dual effect on cancer progression and exert both growth‐stimulatory or ‐inhibitory effects on different cancer types. They can polarize the immune system cells and affect TME communications using extracellular vesicles (EVs). We suppose MSC‐EVs can be used as safe vehicles for delivering antitumor agents to TME.
Cell therapy is one of the newest therapeutic approaches for treating tissue destruction diseases and replacing damaged parts in defective tissues. Among different cells, mesenchymal stem cells ...(MSCs) have received a lot of attention due to their advantages and desirable properties. Also, MSCs-derived secretome, which includes various growth factors, cytokines, and extracellular vesicles (EVs), is used in the treatment of different types of diseases. However, the application of MSCs in an intact form brings their functionality with limitations. For this reason, different methods are recommended to increase their efficiency and the extracellular vesicles derived from them. One of these methods is gene editing of these cells. Among the different techniques for MSCs gene editing, CRISPR/Cas9 can increase the therapeutic potential of MSCs in a targeted manner due to its advantages. In order to achieve the desired result, various genes have been manipulated in MSCs, including genes involved in stemness, aging, migration, proliferation, survival, and inflammatory responses. Engineering MSCs with this method affects the cells' characteristics, changes their cytokine and different growth factors secretions, and increases their therapeutic efficiency.
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•CRISPR/Cas9 engineering increases the MSCs angiogenic potential.•CRISPR/Cas9 engineering increases the immunomodulatory potential of MSCs.•CRISPR/Cas9 engineering increases the stemness potential of MSCs.•CRISPR/Cas9 engineering increases the survival of MSCs by inducing the production of anti-apoptotic proteins, including Bcl-2.•CRISPR/Cas9 engineering decreases the apoptosis of MSCs.
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