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Potential of Mesenchymal Stromal Cell-Derived Extracellular Vesicles as Natural Nanocarriers: Concise Review.

ABSTRACT: Intercellular communication, through direct and indirect cell contact, is mandatory in multicellular organisms. These last years, the microenvironment, and in particular, transfer by extracellular vesicles (EVs), has emerged as a new communication mechanism. Different biological fluids and cell types are common sources of EVs. EVs play different roles, acting as signalosomes, biomarkers, and therapeutic agents. As therapeutic agents, MSC-derived EVs display numerous advantages: they are biocompatible, non-immunogenic, and stable in circulation, and they are able to cross biological barriers. Furthermore, EVs have a great potential for drug delivery. Different EV isolation protocols and loading methods have been tested and compared. Published and ongoing clinical trials, and numerous preclinical studies indicate that EVs are safe and well tolerated. Moreover, the latest studies suggest their applications as nanocarriers. The current review will describe the potential for MSC-derived EVs as drug delivery systems (DDS) in disease treatment, and their advantages. Thereafter, we will outline the different EV isolation methods and loading techniques, and analyze relevant preclinical studies. Finally, we will describe ongoing and published clinical studies. These elements will outline the benefits of MSC-derived EV DDS over several aspects.

SUBMITTER: Draguet F

PROVIDER: S-EPMC9964668 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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Potential of Mesenchymal Stromal Cell-Derived Extracellular Vesicles as Natural Nanocarriers: Concise Review.

Draguet Florian F Bouland Cyril C Dubois Nathan N Bron Dominique D Meuleman Nathalie N Stamatopoulos Basile B Lagneaux Laurence L

Pharmaceutics 20230207 2

Intercellular communication, through direct and indirect cell contact, is mandatory in multicellular organisms. These last years, the microenvironment, and in particular, transfer by extracellular vesicles (EVs), has emerged as a new communication mechanism. Different biological fluids and cell types are common sources of EVs. EVs play different roles, acting as signalosomes, biomarkers, and therapeutic agents. As therapeutic agents, MSC-derived EVs display numerous advantages: they are biocompa ...[more]

PMID: 36839879

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Project description:IntroductionOsteoarthritis (OA) affects a large percentage of the population worldwide. Current surgical and nonsurgical concepts for treating OA only result in symptom-modifying effects. However, there is no disease-modifying therapy available. Extracellular vesicles released by mesenchymal stem/stromal cells (MSC-EV) are promising agents to positively influence joint homeostasis in the osteoarthritic surroundings. This pilot study aimed to investigate the effect of characterized MSC-EVs on chondrogenesis in a 3D chondrocyte inflammation model with the pro-inflammatory cytokine TNFα.MethodsBovine articular chondrocytes were expanded and transferred into pellet culture at passage 3. TNFα, human MSC-EV preparations (MSC-EV batches 41.5-EVi1 and 84-EVi), EVs from human platelet lysate (hPL4-EV), or the combination of TNFα and EVs were supplemented. To assess the effect of MSC-EVs in the chondrocyte inflammation model after 14 days, DNA, glycosaminoglycan (GAG), total collagen, IL-6, and NO release were quantified, and gene expression of anabolic (COL-II, aggrecan, COMP, and PRG-4), catabolic (MMP-3, MMP-13, ADAMTS-4 and ADAMTS-5), dedifferentiation (COL-I), hypertrophy (COL-X, VEGF), and inflammatory (IL-8) markers were analyzed; histological evaluation was performed using safranin O/Fast Green staining and immunohistochemistry of COL I and II. For statistical evaluation, nonparametric tests were chosen with a significance level of p < 0.05.ResultsTNFα supplementation resulted in catabolic stimulation with increased levels of NO and IL-6, upregulation of catabolic gene expression, and downregulation of anabolic markers. These findings were supported by a decrease in matrix differentiation (COL-II). Supplementation of EVs resulted in an upregulation of the chondrogenic marker PRG-4. All MSC-EV preparations significantly increased GAG retention per pellet. In contrast, catabolic markers and IL-8 expression were upregulated by 41.5-EVi1. Regarding protein levels, IL-6 and NO release were increased by 41.5-EVi1. Histologic and immunohistochemical evaluations indicated a higher differentiation potential of chondrocytes treated with 84-EVi.DiscussionMSC-EVs can positively influence chondrocyte matrix production in pro-inflammatory surroundings, but can also stimulate inflammation. In this study MSC-EV 41.5-EVi1 supplementation increased chondrocyte inflammation, whereas MSC-84-EVi supplementation resulted a higher chondrogenic potential of chondrocytes in 3D pellet culture. In summary, the selected MSC-EVs exhibited promising chondrogenic effects indicating their significant potential for the treatment of OA; however, the functional heterogeneity in MSC-EV preparations has to be solved.

Project description:BackgroundArticular cartilage injuries can lead to pain, stiffness, and reduced mobility, and may eventually progress to osteoarthritis (OA). Despite substantial research efforts, effective therapies capable of regenerating cartilage are still lacking. Mesenchymal stromal cells (MSCs) are known for their differentiation and immunomodulatory capabilities, yet challenges such as limited survival post-injection and inconsistent therapeutic outcomes hinder their clinical application. Recent evidence suggests that the beneficial effects of MSCs are largely mediated by their secreted small extracellular vesicles (sEVs), which have been shown to promote tissue repair and reduce inflammation. MSC-derived sEVs have shown promise in mitigating cartilage degradation and chondrocyte apoptosis, positioning them as a promising alternative to MSC-based therapies for OA treatment. This review explores the potential and limitations of MSC-derived sEVs in cartilage regeneration.Main textThis systematic review was conducted following PRISMA guidelines, with a comprehensive search of the Web of Science and Scopus databases for studies published between 2019 and 2024. A total of 223 records were identified, of which 132 articles were assessed for eligibility based on general selection criteria. After full-text screening, 60 articles were initially selected, comprising 58 in vitro studies and 40 in vivo studies. Following further exclusion based on specific criteria, 33 in vitro and 28 in vivo studies from a total of 47 scientific papers were included in the final qualitative synthesis. Most studies indicate that MSC-derived sEVs enhance chondrocyte proliferation, improve cartilage extracellular matrix composition, and reduce matrix-degrading enzymes and inflammation, thereby delaying OA progression.ConclusionA growing body of evidence supports the use of MSC-derived sEVs as a therapeutic tool for preventing OA progression, with most studies reporting beneficial effects on cartilage structure and function. However, challenges remain in optimizing and standardizing sEVs isolation, dosage, and delivery methods for clinical application. Further research is necessary to elucidate the mechanisms underlying sEVs-mediated cartilage regeneration and to facilitate their translation into effective OA therapies.

Dataset Information

Potential of Mesenchymal Stromal Cell-Derived Extracellular Vesicles as Natural Nanocarriers: Concise Review.

Publications

Potential of Mesenchymal Stromal Cell-Derived Extracellular Vesicles as Natural Nanocarriers: Concise Review.

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