Extracellular vesicles derived from mesenchymal stem cells (MSCs) represent a novel approach for regenerative and immunosuppressive therapy. Recently, cytochalasin B-induced microvesicles (CIMVs) were shown to be effective drug delivery mediators. However, little is known about their immunological properties. We propose that the immunophenotype and molecular composition of these vesicles could contribute to the therapeutic efficacy of CIMVs. To address this issue, CIMVs were generated from murine MSC (CIMVs-MSCs) and their cytokine content and surface marker expression determined. For the first time, we show that CIMVs-MSCs retain parental MSCs phenotype (Sca-1+, CD49e+, CD44+, CD45−). Also, CIMVs-MSCs contained a cytokine repertoire reflective of the parental MSCs, including IL-1β, IL-2, IL-3, IL-4, IL-5, IL-6, IL-9, IL-10, IL-12(p40), IL-13, IL-17, CCL2, CCL3, CCL4, CCL5, CCL11, G-CSF, GM-CSF and TNF-α. Next, we evaluated the immune-modulating properties of CIMVs-MSCs in vivo using standard preclinical tests. MSCs and CIMVs-MSCs reduced serum levels of anti-sheep red blood cell antibody and have limited effects on neutrophil and peritoneal macrophage activity. We compared the immunomodulatory effect of MSCs, CIMVs and EVs. We observed no immunosuppression in mice pretreated with natural EVs, whereas MSCs and CIMVs-MSCs suppressed antibody production in vivo. Additionally, we have investigated the biodistribution of CIMVs-MSCs in vivo and demonstrated that CIMVs-MSCs localized in liver, lung, brain, heart, spleen and kidneys 48 h after intravenous injection and can be detected 14 days after subcutaneous and intramuscular injection. Collectively our data demonstrates immunomodulatory efficacy of CIMVs and supports their further preclinical testing as an effective therapeutic delivery modality.
At present a wide variety of methods have been proposed to treat eye disorders, drug therapies are most commonly used. It should be noted that effective treatment modalities especially for degeneration of the retina and optic nerve are lacking. In the last few years stem cell transplantation has been proposed as an alternative method. The opportunities that stem cells provide within clinical use are almost unlimited. These cells are presently applied to treat various traumatic and degenerative disorders due to their unique biologic properties. Stem cells have high proliferative capabilities and are a self-maintained population of cells capable of differentiating into different cell types. Thus, they are represent a very primary stage of a cell lineage. Their ability to differentiate into different pathways provides animals with great plasticity in the renewal of somatic cells in postnatal ontogenesis.Pre-clinical and clinical ophthalmology studies where mesenchymal stem cells are applied and various methods of their administration are discussed herein. In addition the safety and efficacy of using bone marrow-and adipose tissue-derived mesenchymal stem cells have been discussed.
Interleukin 2 (IL2) was one of the first cytokines used for cancer treatment due to its ability to stimulate anti-cancer immunity. However, recombinant IL2-based therapy is associated with high systemic toxicity and activation of regulatory T-cells, which are associated with the pro-tumor immune response. One of the current trends for the delivery of anticancer agents is the use of extracellular vesicles (EVs), which can carry and transfer biologically active cargos into cells. The use of EVs can increase the efficacy of IL2-based anti-tumor therapy whilst reducing systemic toxicity. In this study, human adipose tissue-derived mesenchymal stem cells (hADSCs) were transduced with lentivirus encoding IL2 (hADSCs-IL2). Membrane vesicles were isolated from hADSCs-IL2 using cytochalasin B (CIMVs-IL2). The effect of hADSCs-IL2 and CIMVs-IL2 on the activation and proliferation of human peripheral blood mononuclear cells (PBMCs) as well as the cytotoxicity of activated PBMCs against human triple negative cancer MDA-MB-231 and MDA-MB-436 cells were evaluated. The effect of CIMVs-IL2 on murine PBMCs was also evaluated in vivo. CIMVs-IL2 failed to suppress the proliferation of human PBMCs as opposed to hADSCs-IL2. However, CIMVs-IL2 were able to activate human CD8+ T-killers, which in turn, killed MDA-MB-231 cells more effectively than hADSCs-IL2-activated CD8+ T-killers. This immunomodulating effect of CIMVs-IL2 appears specific to human CD8+ T-killer cells, as the same effect was not observed on murine CD8+ T-cells. In conclusion, the use of CIMVs-IL2 has the potential to provide a more effective anti-cancer therapy. This compelling evidence supports further studies to evaluate CIMVs-IL2 effectiveness, using cancer mouse models with a reconstituted human immune system.
Extracellular vesicles (EVs) are nanosized lipid bilayer vesicles that are released by almost all cell types. They range in diameter from 30 nm to several micrometres and have the ability to carry biologically active molecules such as proteins, lipids, RNA, and DNA. EVs are natural vectors and play an important role in many physiological and pathological processes. The amount and composition of EVs in human biological fluids serve as biomarkers and are used for diagnosing diseases and monitoring the effectiveness of treatment. EVs are promising for use as therapeutic agents and as natural vectors for drug delivery. However, the successful use of EVs in clinical practice requires an understanding of their biodistribution in an organism. Numerous studies conducted so far on the biodistribution of EVs show that, after intravenous administration, EVs are mostly localized in organs rich in blood vessels and organs associated with the reticuloendothelial system, such as the liver, lungs, spleen, and kidneys. In order to improve resolution, new dyes and labels are being developed and detection methods are being optimized. In this work, we review all available modern methods and approaches used to assess the biodistribution of EVs, as well as discuss their advantages and limitations.
Background: Tendon injuries are one of the most common causes of orthopedic disorders in horses. Such injuries involve a long course of treatment and recovery. The most promising method of treating these injuries is the use of recombinant proteins and gene therapy. Aim: In this work, we evaluated the therapeutic efficacy of plasmid DNA (pDNA) containing two species-specific coding sequences, i.e. vascular endothelial growth factor 164 (VEGF164) and fibroblast growth factor 2 (FGF2), in the treatment of severe damage to the tendon of the superficial digital flexor. Methods: A pDNA construct was used to restore the damaged superficial digital flexor tendon in the horse. Results: This study showed that the administration of pDNA encoding VEGF164 and FGF2 genes at the injury area increased the regenerative activities of the damaged tendon. Conclusion: This study shows the therapeutic properties of genetic constructs (pDNA) and contributes to theadvancements in the use of these therapies. Keywords: Fibroblast growth factor 2, Plasmid DNA, Superficial digital flexor, Vascular endothelial growth factor.
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