Harnessing the therapeutic potential of mesenchymal stem/stromal cell-derived extracellular vesicles as a novel cell-free therapy for animal models of multiple sclerosis.

Multiple sclerosis (MS) is a chronic, neuroinflammatory, and demyelinating disease of the central nervous system (CNS). Current treatments offer only limited relief from symptoms, and there is no cure. Mesenchymal stem/stromal cells (MSCs) have demonstrated therapeutic potential for MS. However, their clinical application faces challenges, including immune rejection and the potential for tumor formation. Recent studies suggest that MSCs exert their effects through extracellular vesicles (EVs) released from the cells, rather than direct cellular engraftment or differentiation. This discovery has sparked interest in the potential of MSC-derived EVs as a cell-free therapy for MS. This review explores the existing literature on the effects of MSC-EVs in animal models of MS. Administration of MSC-EVs from various tissue sources, such as bone marrow, adipose tissue, and umbilical cord, was found to reduce clinical scores and slow down disease progression in experimental autoimmune encephalomyelitis (EAE), the primary mouse model of MS. The mechanisms involved immunomodulation through effects on T cells, cytokines, CNS inflammation, and demyelination. Although the impact on CNS repair markers remained unclear, MSC-EVs exhibited the potential to modulate neuroinflammation and suppress harmful immune responses in EAE. Further studies are still required, but MSC-EVs demonstrate promising therapeutic effects for MS and warrant further exploration as a novel treatment approach.

A population-based and symptom-based COVID-19 prevalence survey.

The current study aimed to determine the community-based COVID-19 prevalence and compare the symptom-based and test-based prevalence rates in the Omicron peak (February 20 to March 20, 2022) to assess community involvement and provide effective healthcare. This cross-sectional and population-based study examined the prevalence of COVID-19 from February 20 to March 20, 2022, in the city of Khomein in Markazi Province (located in central Iran) through random cluster sampling. The period prevalence of recurrent Omicron symptoms was 37.69%. Factors such as residence in urban areas (OR = 1.25, 95% CI: 0.95-1.66), number of COVID-19 vaccine doses (OR = 0.80, 95% CI: 0.67-0.95), the interval of last vaccination dose (OR = 1.04, 95% CI: 0.97-1.11) and a history of COVID-19 (OR =1.20, 95% CI: 1.04-1.39) were among the most important risk factors for Omicron. Ongoing efforts to vaccinate high-risk populations as well as stronger actions to diminish the Omicron consequences are fundamental obligations of the health system.

Dual role of Exosome in neurodegenerative diseases: a review study.

INTRODUCTION: Extracellular vesicles (EVs) are one of the crucial means of intercellular communication, which takes many different forms. They are heterogeneous, secreted by a range of cell types, and can be generally classified into microvesicles and exosomes depending on their location and function. Exosomes are small EVs with diameters of about 30-150 nm and diverse cell sources. METHODS: The MEDLINE/PubMed database was reviewed for papers written in English and publication dates of recent years, using the search string "Exosome" and "Neurodegenerative diseases." RESULTS: The exosomes have attracted interest as a significant biomarker for a better understanding of disease development, gene silencing delivery, and alternatives to stem cell-based therapy because of their low-invasive therapeutic approach, repeatable distribution in the central nervous system (CNS), and high efficiency. Also, they are nanovesicles that carry various substances, which can have an impact on neural plasticity and cognitive functioning in both healthy and pathological circumstances. Therefore, exosomes are conceived as nanovesicles containing proteins, lipids, and nucleic acids. However, their composition varies considerably depending on the cells from which they are produced. CONCLUSION: In the present review, we discuss several techniques for the isolation of exosomes from different cell sources. Furthermore, reviewing research on exosomes' possible functions as carriers of bioactive substances implicated in the etiology of neurodegenerative illnesses, we further examine them. We also analyze the preclinical and clinical research that shows exosomes to have therapeutic potential.

Influence of hormones in multiple sclerosis: focus on the most important hormones.

Hormonal imbalance may be an important factor in the severity of multiple sclerosis (MS) disease. In this context, hormone therapy has been shown to have immunoregulatory potential in various experimental approaches. There is increasing evidence of potentially beneficial effects of thyroid, melatonin, and sex hormones in MS models. These hormones may ameliorate the neurological impairment through immunoregulatory and neuroprotective effects, as well as by reducing oxidative stress. Expanding our knowledge of hormone therapy may be an effective step toward identifying additional molecular/cellular pathways in MS disease. In this review, we discuss the role of several important hormones in MS pathogenesis in terms of their effects on immunoregulatory aspects and neuroprotection.

The Immunological Therapeutic Strategies for Controlling Multiple Sclerosis: Considerations during the COVID-19 Pandemic.

A growing body of evidence initially suggested that patients with multiple sclerosis (MS) might be more susceptible to coronavirus disease 2019 (COVID-19). Moreover, it was speculated that patients with MS treated with immunosuppressive drugs might be at risk to develop a severe diseases course after infection with the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV2). However, the recently published data have shown that MS patients do not have a higher risk for severe COVID-19. Although there is no indication that patients with MS and immunomodulatory/immunosuppressive therapy are generally at a higher risk of severe COVID-19, it is currently being emphasized that the hazards of poorly treated MS may outweigh the putative COVID-19 dangers. In this review, we discuss the challenges and considerations for MS patients in the COVID-19 pandemic.

Assessment of ability of human adipose derived stem cells for long term overexpression of IL-11 and IL-13 as therapeutic cytokines.

Adipose-derived stem cells (ADSCs) are a type of mesenchymal stem cells with the therapeutic effects that make them one of the best sources for cell therapy. In this study, we aimed to assess the ability of human ADSCs for constant expression of IL-11 and IL-13, simultaneously. In this study, the characterized hADSCs were transduced with a lentiviral vector (PCDH-513B) containing IL-11 and IL-13 genes, and the ability of long-term expression of the transgenes was evaluated by ELISA technique on days 15, 45 and 75 after transduction. Our results indicated a high rate of transduction (more than 90%) in the isolated hADSCs. Our data showed the highest rate of expression on days 75 after transduction which was 242.67 pg/ml for IL-11 and 303.6 pg/ml for IL-13 compared with 35.2 pg/ml and 35.6 pg/ml in untreated cells, respectively (p = 0.001). Besides, MTT assay showed transduction of hADSCs with lentiviral viruses containing IL-11 and IL-13 had no adverse effect on hADSCs proliferation (p-value = 0.89). Finally, we successfully constructed a hADSC population stably overexpressing IL-11 as the neurotrophic cytokine and IL-13 as the anti-inflammatory cytokine and this transduced cells can be used for further studies in EAE mice model.

The immunoregulatory and neuroprotective effects of human adipose derived stem cells overexpressing IL-11 and IL-13 in the experimental autoimmune encephalomyelitis mice.

Multiple sclerosis (MS) is an inflammatory demyelination disease in the central nervous system (CNS) characterized by incomplete endogenous remyelination in the chronic phase. A shift of the balance between pro and anti-inflammatory cytokines is one of the important markers in the pathogenesis of MS. This study aimed to evaluate the effects of human adipose derived stem cells (hADSCs) overexpressing interleukin 11 and interleukin 13 (IL-11, 13-hADSCs) on the experimental autoimmune encephalomyelitis (EAE), an animal model of MS.12 days after immunization of C57Bl/6 female mice with MOG35-55 and initial clinical symptoms appearance, the IL-11, 13-hADSCs were injected via the tail vein into the EAE mice. Then, the mice were sacrificed at 30 days post-immunization (DPI) and the spinal cords of experimental groups were extracted for histopathological and real-time RT-PCR studies.The results indicated that the clinical scores and mononuclear cells infiltration into the spinal cords of EAE mice were significantly reduced in mice treated with IL-11, 13-hADSCs. Likewise, the remyelination and oligodendrogenesis were significantly enhanced in the mentioned treatment group. Real-time results demonstrated that pro/anti-inflammatory cytokine genes expression was reversed in IL-11, 13-hADSCs treatment group in comparison to the untreated EAE group.Expression of IL-11 as a neurotrophic cytokine and IL-13 as an anti-inflammatory cytokine by hADSCs could increase the immunomodulatory and neuroprotective effects of hADSCs and be a powerful candidate in stem cell therapy for future treatment of MS.

Therapeutic effects of extracellular vesicles from human adipose-derived mesenchymal stem cells on chronic experimental autoimmune encephalomyelitis.

Since in cell therapy, there are always concerns about immune rejection, genetic disability, and malignancies, special attention has been paid to extracellular vesicles (EVs) which are secreted by mesenchymal stem cells (MSCs). In the present study, we assessed and compared the therapeutic effects of human adipose-derived mesenchymal stem cells (hADSC) and hADSC-EVs from adipose tissue on experimental autoimmune encephalomyelitis (EAE). After induction of EAE in C57Bl/6 mice, they were treated with hADSCs, hADSC-EVs, or vehicle intravenously. The clinical score of all mice was recorded every other day. Mice were killed at Day 30 and splenocytes were isolated for proliferation assay and determination of the frequency of Treg cells by flow cytometry. Leukocyte infiltration by hematoxylin and eosin, percentages of demyelination areas by luxol fast blue, and mean fluorescence intensity of oligodendrocyte transcription factor 2 (OLIG2) and myelin basic protein (MBP) by immunohistochemistry were assessed in the spinal cord. Our results showed that the maximum mean clinical score and myelin oligodendrocyte glycoprotein-induced proliferation of splenocytes in hADSC- and hADSC-EV-treated mice were significantly lower than the control mice (p < .05). We also demonstrated that the frequency of CD4+ CD25+ Foxp3+ cells was significantly higher in the spleen of hADSC-treated mice than EAE control mice (p = .023). The inflammation score and the percentages of demyelination areas in hADSC- and hADSC-EV-treated groups significantly declined compared with the untreated control group (p < .05). We also showed that there was no significant difference in MFI of MBP and OLIG2 in the spinal cord of studied groups. Overall, we suggest that intravenous administration of hADSC-EVs attenuates the induced EAE through diminishing proliferative potency of T cells, mean clinical score, leukocyte infiltration, and demyelination in a chronic model of multiple sclerosis.

Regulatory effect of triiodothyronine on brain myelination and astrogliosis after cuprizone-induced demyelination in mice.

Chronic demyelination and plaque formation in multiple sclerosis is accompanied by persisting astrogliosis, negatively influencing central nervous system recovery and remyelination. Triiodothyronin (T3) is thought to enhance remyelination in the adult brain by the induction of oligodendrocyte maturation. We investigated additional astrocyte-mediated mechanisms by which T3 might promote remyelination in chronically demyelinated lesions using the cuprizone mouse model. C57BL/6 mice were fed cuprizone for 12 weeks to induce lesions with an impaired remyelination capacity. While the expression of oligodenrocyte progenitor markers, i.e., platelet derived growth factor-α receptor was not affected by T3 administration, myelination status, myelin protein expression as well as total and adult oligodendrocyte numbers were markedly increased compared to cuprizone treated controls. In addition to these effects on oligodendrocyte numbers and function, astrogliosis but not microgliosis was ameliorated by T3 administration. Intermediate filament proteins vimentin and nestin as well as the extracellular matrix component tenascin C were significantly reduced after T3 exposure, indicating additional effects of T3 on astrocytes and astrogliosis. Our data clearly indicate that T3 promotes remyelination in chronic lesions by both enhancing oligodendrocyte maturation and attenuating astrogliosis.