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Introduction: Exosomes are essential in communicating intracellularly by working as means for transport of their cargos to receiver cells. Aim of the Work: This review aimed to shed light on the mesenchymal exosomes (MSC-exosomes) as well as their role in various biological aspects. Material and Methods: A narrative review was conducted on the basis of publications in PubMed and Scopus databases. MSC-exosomes together with their roles in various biological aspects were discussed. Results: In vitro and in vivo researches have shown that MSC-exosomes are related to various tissue regeneration processes (bone, dentin-pulp complex, periodontal ligaments (PDL), taste buds and paraoral tissues), treatment of different metabolic disorders (liver diseases, kidney diseases, cardiovascular diseases, diabetes types 1&2 and obesity), neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) as well as cancer. Also, they act as drug delivery mechanisms and biomarkers for multiple disorders. They also contribute in vaccines development. Conclusions: Utilization of MSC-exosomes turns out to be of great importance in cell-free therapy. MSC-exosomes contain "cargos" which enable them to contribute in cellular functions and play pivotal role in treatment of diseases and tissue repair. MSC-exosomes play great role in tissue regeneration, including the oral and paraoral tissues. Moreover, they have therapeutic effect in different metabolic disorders and neurodegenerative diseases and they have important impact as anti-tumor agents and in reducing anticancer-therapy resistance. MSC-exosomes are beneficial biomarkers for different human diseases, both in terms of diagnosis and prognosis, and they are ideal tool for drug delivery to treat a wide range of diseases. Also, they are promising in vaccine development. [ABSTRACT FROM AUTHOR]

In the fields of tissue engineering and regenerative medicine, extracellular vesicles (EVs) have become viable therapeutic tools. EVs produced from stem cells promote tissue healing by regulating the immune system, enhancing cell proliferation and aiding remodeling processes. Recently, EV has gained significant attention from researchers due to its ability to treat various diseases. Unlike stem cells, stem cell-derived EVs show lower immunogenicity, are less able to overcome biological barriers, and have a higher safety profile. This makes the use of EVs derived from cell-free stem cells a promising alternative to whole-cell therapy. This review focuses on the biogenesis, isolation, and characterization of EVs and highlights their therapeutic potential for bone fracture healing, wound healing, and neuronal tissue repair and treatment of kidney and intestinal diseases. Additionally, this review discusses the potential of EVs for the treatment of cancer, COVID-19, and HIV. In summary, the use of EVs derived from stem cells offers a new horizon for applications in tissue engineering and regenerative medicine. [ABSTRACT FROM AUTHOR]

Abstract Background Temporomandibular joint (TMJ) arthritis is a debilitating, challenging condition and different methods have been implicated for its treatment. This study aimed to test the therapeutic potentials of low-level laser therapy (LLLT) associated with adipose derived stem cells (ADSC) or their derived secretome on a murine model induced arthritis. Methods Forty eight rats were divided into four groups where group I was the sham control, the rest of animals were subjected to arthritis induction using complete Freund’s adjuvant, then divided as follows: group II received phosphate buffered saline (PBS) intraarticular injection and irradiation of 0 j/cm2, group III received ADSCs derived secretome and irradiation of 38 j/cm2, and group IV received ADSCs and irradiation of 38 j/cm2 as well. One and three weeks after treatment, animals were euthanized, and paraffin blocks were processed for histological assessment by hematoxylin and eosin stain with histomorphometrical analysis. Histochemical evaluation of joint proteoglycan content was performed through toluidine blue stain, and immunohistochemical staining by the proinflammatory marker tumor necrosis factor-α (TNF-α) was performed followed by the relevant statistical tests. Results The arthritis group showed histological signs of joint injury including cartilage atrophy, articular disc fibrosis, irregular osteochondral interface, and condylar bone resorption together with high inflammatory reaction and defective proteoglycan content. In contrast, the treated groups III and IV showed much restoration of the joint structure with normal cartilage and disc thickness. The inflammation process was significantly suppressed especially after three weeks as confirmed by the significant reduction in TNF-α positive immunostaining compared to the arthritic group, and the cartilage proteoglycan content also showed significant increase relative to the arthritic group. However, no significant difference between the results of the two treated groups was detected. Conclusion LLLT conjugated with ADSCs or ADSCs derived secretome can efficiently enhance the healing of arthritic TMJs. Stem cell secretome can be applied as a safe, potent therapy. However, further investigations are required to unravel its mechanism of action and pave its way as a safe, novel, cell free therapy. Graphical Abstract

Background: Temporomandibular joint (TMJ) arthritis is a debilitating, challenging condition and different methods have been implicated for its treatment. This study aimed to test the therapeutic potentials of low-level laser therapy (LLLT) associated with adipose derived stem cells (ADSC) or their derived secretome on a murine model induced arthritis. Methods: Forty eight rats were divided into four groups where group I was the sham control, the rest of animals were subjected to arthritis induction using complete Freund's adjuvant, then divided as follows: group II received phosphate buffered saline (PBS) intraarticular injection and irradiation of 0 j/cm2, group III received ADSCs derived secretome and irradiation of 38 j/cm2, and group IV received ADSCs and irradiation of 38 j/cm2 as well. One and three weeks after treatment, animals were euthanized, and paraffin blocks were processed for histological assessment by hematoxylin and eosin stain with histomorphometrical analysis. Histochemical evaluation of joint proteoglycan content was performed through toluidine blue stain, and immunohistochemical staining by the proinflammatory marker tumor necrosis factor-α (TNF-α) was performed followed by the relevant statistical tests. Results: The arthritis group showed histological signs of joint injury including cartilage atrophy, articular disc fibrosis, irregular osteochondral interface, and condylar bone resorption together with high inflammatory reaction and defective proteoglycan content. In contrast, the treated groups III and IV showed much restoration of the joint structure with normal cartilage and disc thickness. The inflammation process was significantly suppressed especially after three weeks as confirmed by the significant reduction in TNF-α positive immunostaining compared to the arthritic group, and the cartilage proteoglycan content also showed significant increase relative to the arthritic group. However, no significant difference between the results of the two treated groups was detected. Conclusion: LLLT conjugated with ADSCs or ADSCs derived secretome can efficiently enhance the healing of arthritic TMJs. Stem cell secretome can be applied as a safe, potent therapy. However, further investigations are required to unravel its mechanism of action and pave its way as a safe, novel, cell free therapy. [ABSTRACT FROM AUTHOR]

Intracerebral hemorrhage (ICH) is the second largest type of stroke with high mortality and morbidity. The vast majority of survivors suffer from serious neurological defects. Despite the well-established etiology and diagnose, there is still some controversy over the ideal treatment strategy. MSC-based therapy has become an attractive and promising strategy for the treatment of ICH through immune regulation and tissue regeneration. However, accumulating studies have revealed that MSC-based therapeutic effects are mainly attributed to the paracrine properties of MSC, especially small extracellular vesicles/exosome (EVs/exo) which are considered to be the key mediators of the protective efficacy from MSCs. Moreover, some papers reported that MSC-EVs/exo have better therapeutic effects than MSCs. Therefore, EVs/exo has become a new choice for the treatment of ICH stroke in recent years. In this review, we mainly concentrate on the current research progress on the use of MSC-EVs/exo in the treatment of ICH and the existing challenges in their transplation from lab to clinical practice.

Drug-induced liver injury (DILI) is one of the leading causes of acute liver injury. While many factors may contribute to the susceptibility to DILI, obese patients with hepatic steatosis are particularly prone to suffer DILI. The secretome derived from mesenchymal stem cell has been shown to have hepatoprotective effects in diverse in vitro and in vivo models. In this study, we evaluate whether MSC secretome could improve DILI mediated by amiodarone (AMI) or tamoxifen (TMX). Hepatic HepG2 and HepaRG cells were incubated with AMI or TMX, alone or with the secretome of MSCs obtained from human adipose tissue. These studies demonstrate that coincubation of AMI or TMX with MSC secretome increases cell viability, prevents the activation of apoptosis pathways, and stimulates the expression of priming phase genes, leading to higher proliferation rates. As proof of concept, in a C57BL/6 mouse model of hepatic steatosis and chronic exposure to AMI, the MSC secretome was administered endovenously. In this study, liver injury was significantly attenuated, with a decrease in cell infiltration and stimulation of the regenerative response. The present results indicate that MSC secretome administration has the potential to be an adjunctive cell-free therapy to prevent liver failure derived from DILI caused by TMX or AMI. [ABSTRACT FROM AUTHOR]

Extracellular vesicles (EVs) include a heterogeneous group of particles. Microvesicles, apoptotic bodies and exosomes are the most characterized vesicles. They can be distinguished by their size, morphology, origin and molecular composition. To date, increasing studies demonstrate that EVs mediate intercellular communication. EVs reach considerable interest in the scientific community due to their role in diverse processes including antigen-presentation, stimulation of anti-tumoral immune responses, tolerogenic or inflammatory effects. In pathogens, EV shedding is well described in fungi, bacteria, protozoan and helminths parasites. For Trypanosoma cruzi EV liberation and protein composition was previously described. Dendritic cells (DCs), among other cells, are key players promoting the immune response against pathogens and also maintaining self-tolerance. In previous reports we have demonstrate that T. cruzi downregulates DCs immunogenicity in vitro and in vivo. Here we analyze EVs from the in vitro interaction between blood circulating trypomastigotes (Tp) and bone-marrow-derived DCs. We found that Tp incremented the number and the size of EVs in cultures with DCs. EVs displayed some exosome markers and intracellular RNA. Protein analysis demonstrated that the parasite changes the DC protein-EV profile. We observed that EVs from the interaction of Tp-DCs were easily captured by unstimulated-DCs in comparison with EVs from DCs cultured without the parasite, and also modified the activation status of LPS-stimulated DCs. Noteworthy, we found protection in animals treated with EVs-DCs+Tp and challenged with T. cruzi lethal infection. Our goal is to go deep into the molecular characterization of EVs from the DCs-Tp interaction, in order to identify mediators for therapeutic purposes. [ABSTRACT FROM AUTHOR]

Extracellular vesicles (EVs) include a heterogeneous group of particles. Microvesicles, apoptotic bodies and exosomes are the most characterized vesicles. They can be distinguished by their size, morphology, origin and molecular composition. To date, increasing studies demonstrate that EVs mediate intercellular communication. EVs reach considerable interest in the scientific community due to their role in diverse processes including antigen-presentation, stimulation of anti-tumoral immune responses, tolerogenic or inflammatory effects. In pathogens, EV shedding is well described in fungi, bacteria, protozoan and helminths parasites. For Trypanosoma cruzi EV liberation and protein composition was previously described. Dendritic cells (DCs), among other cells, are key players promoting the immune response against pathogens and also maintaining self-tolerance. In previous reports we have demonstrate that T. cruzi downregulates DCs immunogenicity in vitro and in vivo. Here we analyze EVs from the in vitro interaction between blood circulating trypomastigotes (Tp) and bone-marrow-derived DCs. We found that Tp incremented the number and the size of EVs in cultures with DCs. EVs displayed some exosome markers and intracellular RNA. Protein analysis demonstrated that the parasite changes the DC protein-EV profile. We observed that EVs from the interaction of Tp-DCs were easily captured by unstimulated-DCs in comparison with EVs from DCs cultured without the parasite, and also modified the activation status of LPS-stimulated DCs. Noteworthy, we found protection in animals treated with EVs-DCs+Tp and challenged with T. cruzi lethal infection. Our goal is to go deep into the molecular characterization of EVs from the DCs-Tp interaction, in order to identify mediators for therapeutic purposes.

Although ongoing medical research is working to find a cure for a variety of cancers, it continues to be one of the major causes of death worldwide. Chemotherapy and immunotherapy, as well as surgical intervention and radiation therapy, are critical components of cancer treatment. Most anti-cancer drugs are given systemically and distribute not just to tumor tissues but also to normal tissues, where they may cause side effects. Furthermore, because anti-cancer drugs have a low delivery efficiency, some tumors do not respond to them. As a result, tumor-targeted drug delivery is critical for improving the safety and efficacy of anti-cancer treatment. Exosomes are microscopic extracellular vesicles that cells produce to communicate with one another. MicroRNA (miRNA), long non-coding RNA (lncRNA), small interfering RNA (siRNA), DNA, protein, and lipids are among the therapeutic cargos found in exosomes. Recently, several studies have focused on miRNAs as a potential therapeutic element for the treatment of cancer. Mesenchymal stem cells (MSC) have been known to have angiogenic, anti-apoptotic, anti-inflammatory and immunomodulatory effects. Exosomes derived from MSCs are gaining popularity as a non-cellular alternative to MSC-based therapy, as this method avoids unwanted lineage differentiation. Therefore more research have focused on transferring miRNAs to mesenchymal stem cells (MSC) and targeting miRNA-loaded exosomes to cancer cells. Here, we initially gave an overview of the characteristics and potentials of MSC as well as the use of MSC-derived exosomes in cancer therapy. Finally, we emphasized the utilization of MSC-derived exosomes for miRNA delivery in the treatment of cancer.

Over the past decades, new light has been shed on the efficiency of Mesenchymal Stem Cells (MSCs) in the treatment of autoimmune diseases. The therapeutic functions of MSCs partly stem from their well-recognized ability to efficiently modulate immune responses and it is well substantiated that MSC secretory components, in particular extracellular vesicles (EVs), play a critical role in this immunomodulation. In fact, almost any cell type can generate and release EVs under both pathological and physiological conditions and these nano-sized particles are believed to greatly contribute to homeostasis and cell-cell communication through transportation of a wide variety of biomolecules including nucleic acid, signaling lipids, regulatory proteins, transcription factors, cytokines, and growth factors. Lamentably, despite exhibiting promising results in both animal experiments and clinical trials, MSC therapy is still largely restricted to the experimental stage due to its critical pitfalls and drawbacks such as safety issues, poor cell survival, immune rejection and high cost. On the other hand, MSC-derived EVs, which ideally reflect the exact biophysical features of MSCs, are considered to be much safer and more effective than MSCs themselves. Therefore, introducing alternative approaches based on MSC-derived EVs can offer appreciable promise in overcoming the limitations and practical challenges observed in cell-based therapy and thus the extracellular vesicles of MSCs may also provide a far more potent therapeutic strategy for immune-related disorders. In this review, we first focus on the properties of MSC-derived EVs and then we shall provide valuable insight regarding their beneficial therapeutic opportunities to further compare this alternative approach with conventional MSC therapy. Finally, we will attempt to summarize the current findings on the influences of MSC-derived EVs on autoimmune disorders, offering a potential alternative avenue towards treatment of autoimmune diseases. • Mesenchymal stem cells (MSCs) modulate immune response through their secretory components especially exosomes. • MSCs-derived exosomes reflect the biophysical characteristic of MSCs. • MSCs-derived exosomes considered safer and have more advantage compared to MSCs. • MSCs-derived exosomes have potential to be used as cell-free therapies for autoimmune related disorders. [ABSTRACT FROM AUTHOR]