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The current study aimed to investigate the effects of human placental mesenchymal stromal cell-derived small extracellular vesicles (hPMSC-sEVs) as a treatment for COVID-19. This double-blind, randomized, controlled clinical trial was conducted on two groups of patients with COVID-19-associated acute respiratory distress syndrome. After randomization, the control group received standard treatment and placebo, and the intervention arm received standard treatment plus hPMSC-sEVs. The number of hospital deaths was considered the primary outcome. After meeting the exclusion and inclusion criteria, 21 and 24 patients were allocated to intervention and control arms, respectively. Besides admission SpO2 levels, which were significantly lower in the intervention arm (p = 0.008), all the baseline demo-biographic and laboratory variables were similar between the groups. It was shown that hPMSC-sEVs could significantly (p = 0.015) decrease the mortality ratio in the intervention group (4/21 [19.04%]) compared to the controls (13/24 [54.16%]). The mean time to death in the intervention and control groups was 28.06 and 11.10 days, respectively (p < 0.001). This study showed that hPMSC-sEVs are a possible treatment for critically ill patients with COVID-19.
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COVID-19 , Vesículas Extracelulares , Células-Tronco Mesenquimais , Placenta , SARS-CoV-2 , Humanos , Feminino , COVID-19/terapia , Vesículas Extracelulares/metabolismo , Método Duplo-Cego , Gravidez , Células-Tronco Mesenquimais/metabolismo , Masculino , Pessoa de Meia-Idade , Adulto , Resultado do Tratamento , Síndrome do Desconforto Respiratório/terapiaRESUMO
Extracellular vesicles isolated from adipose tissue-derived mesenchymal stromal/stem cells (ADSC-EVs) have demonstrated promising potential in wound healing treatment. To determine the therapeutic efficacy of ADSC-EVs for diabetic wounds in preclinical models, we performed a meta-analysis of available studies. PubMed and Embase were searched (to April 23, 2023). All full-text articles describing the therapeutic application of ADSC-EVs in diabetic wounds were included. Study outcomes were pooled using a random effects meta-analysis, including wound closure, angiogenesis, and collagen deposition. Other outcomes were only discussed descriptively. Seventy unique records were identified from our search; 20 full-text articles were included for qualitative analysis. Twelve studies were eligible for quantitative meta-analysis. The results showed that ADSC-EVs accelerated diabetic wound healing compared to controls with a large effect (standardized mean difference (SMD) 4.22, 95% confidence interval (CI) 3.07 to 5.36). The administration of ADSC-EVs also improved neovascularization (SMD 9.27, 95% CI 4.70 to 13.83) and collagen deposition (SMD 2.19, 95% CI 0.94 to 3.44), with a large effect. The risk of bias was unclear in all included studies. Conclusively, ADSC-EV is an effective treatment for diabetic wounds in preclinical trials, and it appears justified for transfer into the clinical field.
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Autoimmune diseases are caused by an imbalance in the immune system, producing autoantibodies that cause inflammation leading to tissue damage and organ dysfunction. Systemic Lupus Erythematosus (SLE) is one of the most common autoimmune diseases and a major contributor to patient morbidity and mortality. Although many drugs manage the disease, curative therapy remains elusive, and current treatment regimens have substantial side effects. Recently, the therapeutic potential of exosomes has been extensively studied, and novel evidence has been demonstrated. A direct relationship between exosome contents and their ability to regulate the immune system, inflammation, and angiogenesis. The unique properties of extracellular vesicles, such as biomolecule transportation, biodegradability, and stability, make exosomes a promising treatment candidate for autoimmune diseases, particularly SLE. This review summarizes the structural features of exosomes, the isolation/purification/quantification method, their origin, effect, immune regulation, a critical consideration for selecting an appropriate source, and their therapeutic mechanisms in SLE.
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BACKGROUND: Doxorubicin (DOX) is a chemotherapy drug that is widely used in cancer therapy, especially in Triple-Negative Breast Cancer (TNBC) patients. Nevertheless, cytoprotective autophagy induction by DOX limits its cytotoxic effect and drug resistance induction in patients. Therefore, finding a new way is essential for increasing the effectiveness of this drug for cancer treatment. OBJECTIVE: This study aimed to investigate the effect of L-lysine on DOX cytotoxicity, probably through autophagy modulation in TNBC cell lines. METHODS: We used two TNBC cell lines, MDA-MB-231 and MDA-MB-468, with various levels of autophagy activity. Cell viability after treatment with L-lysine alone and in combination therapy was evaluated by MTT assay. Reactive Oxygen Species (ROS), nitric oxide (NO) concentration, and arginase activity were assessed using flow cytometric analysis, Griess reaction, and arginase activity assay kit, respectively. Real-time PCR and western blot analysis were used to evaluate the L-lysine effect on the autophagy-related genes and protein expression. Cell cycle profile and apoptotic assay were performed using flow cytometric analysis. RESULTS: The obtained data indicated that L-lysine in both concentrations of 24 and 32 mM increased the autophagy flux and enhanced the DOX cytotoxicity, especially in MDA-MB-231, which demonstrated higher autophagy activity than MDA-MB-468, by inducing ROS and NO production. Furthermore, L-lysine induced G2/M arrest autophagy cell death, while significant apoptotic changes were not observed. CONCLUSION: These findings suggest that L-lysine can increase DOX cytotoxicity through autophagy modulation. Thus, L-lysine, in combination with DOX, may facilitate the development of novel adjunct therapy for cancer.
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Mesenchymal stem cells (MSCs) are a promising therapy to potentially treat diabetes given their potent anti-inflammatory and immune-modulatory properties. While these regenerative cells have shown considerable promise in cell culture, their clinical translation has been challenging. In part, this can be attributed to these cells not reaching the pancreas to exert their regenerative effects following conventional intravenous (IV) injection, with the majority of cells being trapped in the lungs in the pulmonary first-pass effect. In the present study, we will therefore examine whether direct delivery of MSCs to the pancreas via an intra-arterial (IA) injection can improve their therapeutic efficacy. Using a mouse model, in which repetitive low doses of STZ induced a gentle, but progressive, hyperglycemia, we tested bone marrow-derived MSCs (BM-MSCs) which we have shown are enriched with pro-angiogenic and immunomodulatory factors. In cell culture studies, BM-MSCs were shown to preserve islet viability and function following exposure to proinflammatory cytokines (IFN-γ, IL-1ß, and TNF-α) through an increase in pAkt. When tested in our animal model, mice receiving IV BM-MSCs were not able to mitigate the effects of STZ, however those which received the same dose and batch of cells via IA injection were able to maintain basal and dynamic glycemic control, to similar levels as seen in healthy control animals, over 10 days. This study shows the importance of considering precision delivery approaches to ensure cell-based therapies reach their intended targets to enable them to exert their therapeutic effects.
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Diabetes Mellitus Experimental , Injeções Intra-Arteriais , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Animais , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Transplante de Células-Tronco Mesenquimais/métodos , Humanos , Camundongos , Diabetes Mellitus Experimental/terapia , Pâncreas , Células da Medula Óssea/citologia , Masculino , Camundongos Endogâmicos C57BL , Citocinas/metabolismoRESUMO
Background: Interstitial lung disease (ILD) is a severe systemic sclerosis (SSc) complication with no current approved or golden standard treatment. This report aims to investigate the effectiveness of treatment with placental mesenchymal stromal cell (MSC) extracellular vesicles (EVs) in a patient with ILD due to SSc. Case presentation: The patient was a 55-year-old woman with a ten years history of SSc complicated by severe ILD. Over time, her lung disease progressed to interstitial fibrosis despite being treated with mycophenolate mofetil and monthly pulses of cyclophosphamide. Thus, she was treated with eight doses of placenta MSC-EVs. Four weeks after the third dose (Day 31 after the first dose), she reported marked improvement in her clinical symptoms, such as dyspnea and cough. Also, chest computed tomography (CT) scans demonstrated a significant reduction in ground glass consolidations and fibrotic changes. The patient was subsequently followed for twelve months, with findings showing significant improvement in exercise tolerance and reduced supplemental oxygen need. Conclusion: In this single case, placental MSC-EVs were seen to provide a potentially efficient treatment for SSc-related ILD; however, further investigation and clinical trials are necessary.
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Pancreatic ß cells are central to glycemic regulation through insulin production. Studies show autophagy as an essential process in ß cell function and fate. Autophagy is a catabolic cellular process that regulates cell homeostasis by recycling surplus or damaged cell components. Impaired autophagy results in ß cell loss of function and apoptosis and, as a result, diabetes initiation and progress. It has been shown that in response to endoplasmic reticulum stress, inflammation, and high metabolic demands, autophagy affects ß cell function, insulin synthesis, and secretion. This review highlights recent evidence regarding how autophagy can affect ß cells' fate in the pathogenesis of diabetes. Furthermore, we discuss the role of important intrinsic and extrinsic autophagy modulators, which can lead to ß cell failure.
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Diabetes Mellitus , Células Secretoras de Insulina , Humanos , Células Secretoras de Insulina/metabolismo , Diabetes Mellitus/metabolismo , Insulina/metabolismo , Estresse do Retículo Endoplasmático/fisiologia , Autofagia/fisiologiaRESUMO
256Diabetes is an autoimmune disease that ensues when the pancreas does not deliver adequate insulin or when the body cannot react to the existing insulin. Type 1 diabetes is an autoimmune disease defined by continuous high blood sugar levels and insulin deficiency due to ß-cell destruction in the islets of Langerhans (pancreatic islets). Long-term complications, such as vascular degeneration, blindness, and renal failure, result from periodic glucose-level fluctuations following exogenous insulin therapy. Nevertheless, the shortage of organ donors and the lifelong dependency on immunosuppressive drugs limit the transplantation of the entire pancreas or pancreas islet, which is the therapy for this disease. Although encapsulating pancreatic islets using multiple hydrogels creates a semi-privileged environment to prevent immune rejection, hypoxia that occurs in the core of the capsules is the main hindrance that should be solved. Bioprinting technology is an innovative process in advanced tissue engineering that allows the arranging of a wide array of cell types, biomaterials, and bioactive factors as a bioink to simulate the native tissue environment for fabricating clinically applicable bioartificial pancreatic islet tissue. Multipotent stem cells have the potential to be a possible solution for donor scarcity and can be a reliable source for generating autograft and allograft functional ß-cells or even pancreatic islet-like tissue. The use of supporting cells, such as endothelial cells, regulatory T cells, and mesenchymal stem cells, in the bioprinting of pancreatic islet-like construct could enhance vasculogenesis and regulate immune activity. Moreover, scaffolds bioprinted using biomaterials that can release oxygen postprinting or enhance angiogenesis could increase the function of ß-cells and the survival of pancreatic islets, which could represent a promising avenue.
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Introduction: Cancer is among the leading causes of death worldwide and affects a considerable number of individuals. Chemotherapy is one the most common treatment for this condition and hair loss is among one of the most prevalent side effects. In this study, we report successful treatment of a patient suffering from persistent chemotherapy-induced alopecia (PCIA) with extracellular enriched vesicles (EVs) derived from human placental mesenchymal stromal cells (MSCs). Case presentation: The patient was a 36-year-old woman with a history of invasive ductal carcinoma, underwent six courses of chemotherapy with paclitaxel and adriamycin. Following this treatment and for almost 18 months, she, unfortunately, had no regrowth of hair except some light vellus hairs on the scalp. She then received MSC-derived EVs with scalp injection (subcutaneous) every 4 weeks for 3 continuous months at which point she presented complete regrowth of terminal hair on her scalp. Conclusion: This report demonstrates that MSC-derived EVs could be a possible treatment for permanent chemotherapy-induced alopecia; however, further studies and trials are necessary.
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Systemic steroid exposure, while useful for the treatment of acute flares in inflammatory bowel disease (IBD), is associated with an array of side effects that are particularly significant in children. Technical advancements have enabled locoregional intraarterial steroid delivery directly into specific segments of the gastrointestinal tract, thereby maximizing tissue concentration while limiting systemic exposure. We investigated the feasibility of intraarterial steroid administration into the bowel in a cohort of nine pediatric patients who had IBD. This treatment approach provided symptom relief in all patients, with sustained relief (>2 weeks) in seven out of nine; no serious adverse effects occurred in any patient. In addition, we identified patterns of vascular morphologic changes indicative of a vasculopathy within the mesenteric circulation of inflamed segments of the bowel in pediatric patients with Crohn's disease, which correlated with disease activity. An analysis of publicly available transcriptomic studies identified vasculitis-associated molecular pathways activated in the endothelial cells of patients with active Crohn's disease, suggesting a possible shared transcriptional program between vasculitis and IBD. Intraarterial corticosteroid treatment is safe and has the potential to be widely accepted as a locoregional approach for therapy delivery directly into the bowel; however, this approach still warrants further consideration as a short-term "bridge" between therapy transitions for symptomatic IBD patients with refractory disease, as part of a broader steroid-minimizing treatment strategy.
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The International Society for Cell & Gene Therapy Scientific Signature Series event "Therapeutic Advances With Native and Engineered Human EVs" took place as part of the International Society for Cell & Gene Therapy 2022 Annual Meeting, held from May 4 to 7, 2022, in San Francisco, California, USA. This was the first signature series event on extracellular vesicles (EVs) and a timely reflection of the growing interest in EVs, including both native and engineered human EVs, for therapeutic applications. The event successfully gathered academic and industrial key opinion leaders to discuss the current state of the art in developing and understanding native and engineered EVs and applying our knowledge toward advancing EV therapeutics. Latest advancements in understanding the mechanisms by which native and engineered EVs exert their therapeutic effects against different diseases in animal models were presented, with some diseases such as psoriasis and osteoarthritis already reaching clinical testing of EVs. The discussion also covered various aspects relevant to advancing the clinical translation of EV therapies, including EV preparation, manufacturing, consistency, site(s) of action, route(s) of administration, and luminal cargo delivery of RNA and other compounds.
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Vesículas Extracelulares , Animais , Humanos , Terapia Baseada em Transplante de Células e Tecidos , Terapia GenéticaRESUMO
In this Committee Proceedings, representatives from the Early Stage Professional (ESP) committee highlight the innovative discoveries and key take-aways from oral presentations at the 2022 International Society for Cell and Gene Therapy (ISCT) Annual Meeting that cover the following subject categories: Immunotherapy, Exosomes and Extracellular Vesicles, HSC/Progenitor Cells and Engineering, Mesenchymal Stromal Cells, and ISCT Late-Breaking Abstracts.
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Terapia Baseada em Transplante de Células e Tecidos , Células-Tronco Mesenquimais , Humanos , Terapia Genética , Imunoterapia , Sociedades MédicasRESUMO
Mesenchymal stem cells (MSCs) are gaining increasing prominence as an effective regenerative cellular therapy. However, ensuring consistent and reliable effects across clinical populations has proved to be challenging. In part, this can be attributed to heterogeneity in the intrinsic molecular and regenerative signature of MSCs, which is dependent on their source of origin. The present work uses integrated omics-based profiling, at different functional levels, to compare the anti-inflammatory, immunomodulatory, and angiogenic properties between MSCs from neonatal (umbilical cord MSC [UC-MSC]) and adult (adipose tissue MSC [AD-MSC], and bone marrow MSC [BM-MSC]) sources. Using multi-parametric analyses, we identified that UC-MSCs promote a more robust host innate immune response; in contrast, adult-MSCs appear to facilitate remodeling of the extracellular matrix (ECM) with stronger activation of angiogenic cascades. These data should help facilitate the standardization of source-specific MSCs, such that their regenerative signatures can be confidently used to target specific disease processes.
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Células-Tronco Adultas , Células-Tronco Mesenquimais , Recém-Nascido , Humanos , Proteoma , Transcriptoma , Perfilação da Expressão Gênica , Células da Medula ÓsseaRESUMO
Purpose: In this systematic review and meta-analysis, we investigated the effect and side effects of Citrullus colocynthis on glycemic factors and lipid profile in diabetic patients. Methods: We systematically searched English and Persian databases from inception till August 2021 using Medical Subject Headings (MeSH). Two authors independently extracted data and assessed the quality of studies. The standardized mean differences were pooled using fixed-effect models, and statistical heterogeneity was assessed using the I squared (I²) index. Results: Of the 321 articles searched in the databases, 136 related articles were screened, 14 relevant full-text articles were assessed for eligibility; finally, four articles were included in the study, three articles were entered into the meta-analysis. The results of the meta-analysis indicated that Citrullus colocynthis does not have a significant effect on fasting blood sugar (FBS), hemoglobin A1c (HBA1c), low-density lipoprotein (LDL), total cholesterol, and triglyceride indices but increases high-density lipoprotein (HDL) (Mean Difference: 5.76; 95% CI: 1.69 to 9.84; P = 0.006; I2 = 0%). Conclusions: The meta-analysis results showed that Citrullus colocynthis has no significant effect on glycemic and metabolic indices of diabetes - except HDL. Due to the relatively low quality and the small number of included trials, conducting further large scale well-designed randomized clinical trials to determine the effect of Citrullus colocynthis on glycemic and metabolic indices seems essential. Supplementary information: The online version contains supplementary material available at 10.1007/s40200-022-01045-9.
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BACKGROUND: Exosomes are the smallest group of extracellular vesicles in size from 30 to 150 nm, surrounded by a lipid bilayer membrane, and originate from multivesicular bodies secreted by different types of cells, such as virus-infected cells. The critical role of exosomes is information transfer among cells, representing a unique way for intercellular communication via a load of many kinds of molecules, including various signaling proteins and nucleic acids. In this review, we aimed to comprehensively investigate the role of exosomes in promoting human oncogenic viruses-associated cancers. METHODS: Our search was conducted for published researches between 2000 and 2022 by using several international databases includeing Scopus, PubMed, and Web of Science as well as Google scholar. We also reviewed additional evidence from relevant published articles. RESULTS: It has been shown that exosomes can create the conditions for viral spread in viral infections. Exosome secretion in a human tumor virus can switch on the cell signaling pathways by transferring exosome-encapsulated molecules, including viral oncoproteins, signal transduction molecules, and virus-encoded miRNAs, into various cells. CONCLUSION: Given the role of exosomes in viruses-associated cancers, they can also be considered as molecular targets in diagnosis and treatment.
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In recent years, mesenchymal stromal cells (MSCs) have generated a lot of attention due to their paracrine and immuno-modulatory properties. mesenchymal stromal cells derived from the umbilical cord (UC) are becoming increasingly recognized as having increased therapeutic potential when compared to mesenchymal stromal cells from other sources. The purpose of this review is to provide an overview of the various compartments of umbilical cord tissue from which mesenchymal stromal cells can be isolated, the differences and similarities with respect to their regenerative and immuno-modulatory properties, as well as the single cell transcriptomic profiles of in vitro expanded and freshly isolated umbilical cord-mesenchymal stromal cells. In addition, we discuss the therapeutic potential and biodistribution of umbilical cord-mesenchymal stromal cells following systemic administration while providing an overview of pre-clinical and clinical trials involving umbilical cord-mesenchymal stromal cells and their associated secretome and extracellular vesicles (EVs). The clinical applications of umbilical cord-mesenchymal stromal cells are also discussed, especially in relation to obstacles and potential solutions for their effective translation from bench to bedside.
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Alzheimer's disease (AD) is a major cause of age-related dementia and is characterized by progressive brain damage that gradually destroys memory and the ability to learn, which ultimately leads to the decline of a patient's ability to perform daily activities. Although some of the pharmacological treatments of AD are available for symptomatic relief, they are not able to limit the progression of AD and have several side effects. Mesenchymal stem/stromal cells (MSCs) could be a potential therapeutic option for treating AD due to their immunomodulatory, anti-inflammatory, regenerative, antioxidant, anti-apoptotic, and neuroprotective effects. MSCs not only secret neuroprotective and anti-inflammatory factors to promote the survival of neurons, but they also transfer functional mitochondria and miRNAs to boost their bioenergetic profile as well as improve microglial clearance of accumulated protein aggregates. This review focuses on different clinical and preclinical studies using MSC as a therapy for treating AD, their outcomes, limitations and the strategies to potentiate their clinical translation.
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Circular RNAs (circRNAs) have recently been implicated in impaired ß-cell function in diabetes. Using microarray-based profiling of circRNAs in human EndoC-ßH1 cells treated with pro-inflammatory cytokines, this study aimed to investigate the expression and possible regulatory roles of circRNAs in human ß cells. We identified ~5000 ß-cell-expressed circRNAs, of which 84 were differentially expressed (DE) after cytokine exposure. Pathway analysis of the host genes of the DE circRNAs revealed the enrichment of cytokine signaling pathways, indicative of circRNA transcription from inflammatory genes in response to cytokines. Multiple binding sites for ß-cell-enriched microRNAs and RNA-binding proteins were observed for the highly upregulated circRNAs, supporting their function as 'sponges' or 'decoys'. We also present evidence for circRNA sequence conservation in multiple species, the presence of cytokine-induced regulatory elements, and putative protein-coding potential for the DE circRNAs. This study highlights the complex regulatory potential of circRNAs, which may play a crucial role during immune-mediated ß-cell destruction in type 1 diabetes.
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Anti-angiogenic therapy is a practical approach to managing diseases with increased angiogenesis, such as cancer, maculopathies, and retinopathies. Considering the fundamental gaps in the knowledge of the vital pathways involved in angiogenesis and its inhibition and the insufficient efficiency of existing angiogenesis inhibitors, there is an increasing focus on the emergence of new therapeutic strategies aimed at inhibiting pathological angiogenesis. Angiogenesis is forming a new vascular network from existing vessels; endothelial cells (ECs), vascular lining cells, are the main actors of angiogenesis in physiological or pathological conditions. Switching from a quiescent state to a highly migratory and proliferative state during new vessel formation called "angiogenic switch" is driven by a "metabolic switch" in ECs, angiogenic growth factors, and other signals. As the characteristics of ECs change by altering the surrounding environment, they appear to have a different metabolism in a tumor microenvironment (TME). Therefore, pathological angiogenesis can be inhibited by targeting metabolic pathways. In the current review, we aim to discuss the EC metabolic pathways under normal and TME conditions to verify the suitability of targeting them with novel therapies.