Equine mesenchymal stem cell derived extracellular vesicle immunopathology biomarker discovery
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ABSTRACT:
SUBMITTER: Reynolds D
PROVIDER: S-EPMC11080797 | biostudies-literature | 2023 May
REPOSITORIES: biostudies-literature
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Project description:We developed an extracellular vesicle (EV) bioprocessing platform for the scalable production of human Wharton's jelly mesenchymal stem cell (MSC)-derived EVs. The effects of clinical-scale MSC-EV products on wound healing were tested in two different wound models: subcutaneous injection of EVs in a conventional full-thickness rat model and topical application of EVs using a sterile re-absorbable gelatin sponge in the chamber mouse model that was developed to prevent the contraction of wound areas. In vivo efficacy tests showed that treatment with MSC-EVs improved the recovery following wound injury, regardless of the type of wound model or mode of treatment. In vitro mechanistic studies using multiple cell lines involved in wound healing showed that EV therapy contributed to all stages of wound healing, such as anti-inflammation and proliferation/migration of keratinocytes, fibroblasts, and endothelial cells, to enhance wound re-epithelialization, extracellular matrix remodeling, and angiogenesis.
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Project description:Wound healing is a dynamic process that involves a series of molecular and cellular events aimed at replacing devitalized and missing cellular components and/or tissue layers. Recently, extracellular vesicles (EVs), naturally cell-secreted lipid membrane-bound vesicles laden with biological cargos including proteins, lipids, and nucleic acids, have drawn wide attention due to their ability to promote wound healing and tissue regeneration. However, current exploitation of EVs as therapeutic agents is limited by their low isolation yields and tedious isolation processes. To circumvent these challenges, bioinspired cell-derived nanovesicles (CDNs) that mimic EVs were obtained by shearing mesenchymal stem cells (MSCs) through membranes with different pore sizes. Physical characterisations and high-throughput proteomics confirmed that MSC-CDNs mimicked MSC-EVs. Moreover, these MSC-CDNs were efficiently uptaken by human dermal fibroblasts and demonstrated a dose-dependent activation of MAPK signalling pathway, resulting in enhancement of cell proliferation, cell migration, secretion of growth factors and extracellular matrix proteins, which all promoted tissue regeneration. Of note, MSC-CDNs enhanced angiogenesis in human dermal microvascular endothelial cells in a 3D PEG-fibrin scaffold and animal model, accelerating wound healing in vitro and in vivo. These findings suggest that MSC-CDNs could replace both whole cells and EVs in promoting wound healing and tissue regeneration.
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Project description:Alzheimer's disease (AD), as a neurodegenerative disorder, is characterized by mass neuronal and synaptic loss and, currently, there are no successful curative therapies. Extracellular vesicles (EVs) are an emerging approach to intercellular communication via transferring cellular materials such as proteins, lipids, mRNAs, and miRNAs from parental cells to recipient cells, leading to the reprogramming of the molecular machinery. Numerous studies have suggested the therapeutic potential of EVs derived from mesenchymal stem cells (MSCs) in the treatment of AD, based on the neuroprotective, regenerative and immunomodulatory effects as effective as MSCs. In this review, we focus on the biology and function of EVs, the potential of MSC-derived EVs for AD therapy in preclinical and clinical studies, as well as the potent mechanisms of MSC-derived EVs actions. Finally, we highlight the modification strategies and diagnosis utilities in order to make advance in this field.
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Project description:Mesenchymal stem cell (MSC)-based therapies have emerged as promising methods for regenerative medicine; however, how to precisely enhance their tissue repair effects is still a major question in the field. Circulating extracellular vesicles (EVs) from diseased states carry diverse pathological information and affect the functions of recipient cells. Based on this unique property, we report that disease-derived circulating EV (disease-EV) preconditioning is a potent strategy for precisely enhancing the tissue repair potency of MSCs in diverse disease models. Briefly, plasma EVs from lung or kidney tissue injuries were shown to contain distinctly enriched molecules and were shown to induce tissue injury-specific gene expression responses in cultured MSCs. Disease-EV preconditioning improved the performance (including proliferation, migration, and growth factor production) of MSCs through metabolic reprogramming (such as via enhanced oxidative phosphorylation and lipid metabolism) without inducing an adverse immune response. Consequently, compared with normal MSCs, disease-EV-preconditioned MSCs exhibited superior tissue repair effects (including anti-inflammatory and antiapoptotic effects) in diverse types of tissue injury (such as acute lung or kidney injury). Disease-derived EVs may serve as a type of "off-the-shelf" product due to multiple advantages, such as flexibility, stability, long-term storage, and ease of shipment and use. This study highlights the idea that disease-EV preconditioning is a robust strategy for precisely enhancing the regenerative capacity of MSC-based therapies.
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Project description:It is currently thought that extracellular vesicles (EVs), such as exosomes and microvesicles, play an important autocrine/paracrine role in intercellular communication. EVs package proteins, mRNA and microRNA (miRNA), which have the ability to transfer biological information to recipient cells in the lungs. Depending on their origin, EVs fulfil different functions. EVs derived from mesenchymal stem cells (MSCs) have been found to promote therapeutic activities that are comparable to MSCs themselves. Recent animal model-based studies suggest that MSC-derived EVs have significant potential as a novel alternative to whole-cell therapies. Compared to their parent cells, EVs may have a superior safety profile and can be stored without losing function. It has been observed that MSC-derived EVs suppress pro-inflammatory processes and reduce oxidative stress, pulmonary fibrosis and remodeling in a variety of in vivo inflammatory lung disease models by transferring their components. However, there remain significant challenges to translate this therapy to the clinic. From this view point, we will summarize recent studies on EVs produced by MSCs in preclinical experimental models of inflammatory lung diseases. We will also discuss the most relevant issues in bringing MSC-derived EV-based therapeutics to the clinic for the treatment of inflammatory lung diseases.
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Project description:Cell therapy limits ischemic injury following myocardial infarction (MI) by preventing cell death, modulating the immune response, and promoting tissue regeneration. The therapeutic efficacy of cardiosphere-derived cells (CDCs) and mesenchymal stem cells (MSCs) is associated with extracellular vesicle (EV) release. Prior head-to-head comparisons have shown CDCs to be more effective than MSCs in MI models. Despite differences in cell origin, it is unclear why EVs from different adult stem cell populations elicit differences in therapeutic efficacy. Here, we compare EVs derived from multiple human MSC and CDC donors using diverse in vitro and in vivo assays. EV membrane protein and non-coding RNA composition are highly specific to the parent cell type; for example, miR-10b is enriched in MSC-EVs relative to CDC-EVs, while Y RNA fragments follow the opposite pattern. CDC-EVs enhance the Arg1/Nos2 ratio in macrophages in vitro and reduce MI size more than MSC-EVs and suppress inflammation during acute peritonitis in vivo. Thus, CDC-EVs are distinct from MSC-EVs, confer immunomodulation, and protect the host against ischemic myocardial injury and acute inflammation.
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Project description:Extracellular vesicles (EVs) are being widely investigated as acellular therapeutics in regenerative medicine applications. EVs isolated from mesenchymal stromal cells (MSCs) are by far the most frequently used in preclinical models for diverse therapeutic applications, including inflammatory, degenerative, or acute diseases. Although they represent promising tools as cell-free therapeutic agents, one limitation to their use is related to the batch-to-batch unreliability that may arise from the heterogeneity between MSC donors. Isolating EVs from MSCs derived from induced pluripotent stem cells (iMSCs) might allow unlimited access to cells with a more stable phenotype and function. In the present review, we first present the latest findings regarding the functional aspects of EVs isolated from iMSCs and their interest in regenerative medicine for the treatment of various diseases. We will then discuss future directions for their translation to clinics with good manufacturing practice implementation.
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Project description:IntroductionEquine osteoarthritis (OA) is a heterogeneous, degenerative disease of the musculoskeletal system with multifactorial causation, characterized by a joint metabolic imbalance. Extracellular vesicles are nanoparticles involved in intracellular communication. Mesenchymal stem cell (MSC) therapy is a form of regenerative medicine that utilizes their properties to repair damaged tissues. Despite its wide use in veterinary practice, the exact mechanism of action of MSCs is not fully understood. The aim of this study was to determine the synovial fluid extracellular vesicle protein cargo following integrin α10β1-selected mesenchymal stem cell (integrin α10-MSC) treatment in an experimental model of equine osteoarthritis with longitudinal sampling.MethodsAdipose tissue derived, integrin α10-MSCs were injected intraarticularly in six horses 18 days after experimental induction of OA. Synovial fluid samples were collected at day 0, 18, 21, 28, 35, and 70. Synovial fluid was processed and extracellular vesicles were isolated and characterized. Extracellular vesicle cargo was then analyzed using data independent acquisition mass spectrometry proteomics.ResultsA total of 442 proteins were identified across all samples, with 48 proteins differentially expressed (FDR ≤ 0.05) between sham-operated control joint without MSC treatment and OA joint treated with MSCs. The most significant pathways following functional enrichment analysis of the differentially abundant protein dataset were serine endopeptidase activity (p = 0.023), complement activation (classical pathway) (p = 0.023), and collagen containing extracellular matrix (p = 0.034). Due to the lack of an OA group without MSC treatment, findings cannot be directly correlated to only MSCs.DiscussionTo date this is the first study to quantify the global extracellular vesicle proteome in synovial fluid following MSC treatment of osteoarthritis. Changes in the proteome of the synovial fluid-derived EVs following MSC injection suggest EVs may play a role in mediating the effect of cell therapy through altered joint homeostasis. This is an important step toward understanding the potential therapeutic mechanisms of MSC therapy, ultimately enabling the improvement of therapeutic efficacy.
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Project description:Aging is associated with high prevalence of chronic degenerative diseases that take a large part of the increasing burden of morbidities in a growing demographic of elderly people. Aging is a complex process that involves cell autonomous and cell non-autonomous mechanisms where senescence plays an important role. Senescence is characterized by the loss of proliferative potential, resistance to cell death by apoptosis and expression of a senescence-associated secretory phenotype (SASP). SASP includes pro-inflammatory cytokines and chemokines, tissue-damaging proteases, growth factors; all contributing to tissue microenvironment alteration and loss of tissue homeostasis. Emerging evidence suggests that the changes in the number and composition of extracellular vesicles (EVs) released by senescent cells contribute to the adverse effects of senescence in aging. In addition, age-related alterations in mesenchymal stem/stromal cells (MSCs) have been associated to dysregulated functions. The loss of functional stem cells necessary to maintain tissue homeostasis likely directly contributes to aging. In this review, we will focus on the characteristics and role of EVs isolated from senescent MSCs, the potential effect of MSC-derived EVs in aging and discuss their therapeutic potential to improve age-related diseases.
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Project description:BackgroundExtracellular vesicles (EVs) and their mimics from mesenchymal stem cells (MSCs) are promising drug carriers to improve cancer treatment, but their application is hindered by donor variations and expansion limitations of conventional tissue-derived MSCs. To circumvent these issues, we made EV-mimicking nanovesicles from standardized MSCs derived from human induced pluripotent stem cells (iPSCs) with a theoretically limitless expandability, and examined the targeting capacity of these nanovesicles to prostate cancer.MethodsNanovesicles are made from intact iPSC-MSCs through serial extrusion. The selective uptake of fluorescently labeled nanovesicles by prostate cancer cells vs. non-tumor cells was examined with flow cytometry. For in vivo tracing, nanovesicles were labeled with fluorescent dye DiR or renilla luciferase. In mice carrying subcutaneous or bone metastatic PC3 prostate cancer, the biodistribution of systemically infused nanovesicles was examined with in vivo and ex vivo imaging of DiR and luminescent signals. A chemotherapeutic drug, docetaxel, was loaded into nanovesicles during extrusion. The cytotoxicities of nanovesicle-encapsulated docetaxel on docetaxel-sensitive and -resistant prostate cancer cells and non-tumor cells were examined in comparison with free docetaxel. Therapeutic effects of nanovesicle-encapsulated docetaxel were examined in mice carrying subcutaneous or bone metastatic prostate cancer by monitoring tumor growth in comparison with free docetaxel.ResultsiPSC-MSC nanovesicles are more selectively taken up by prostate cancer cells vs. non-tumor cells in vitro compared with EVs, membrane-only EV-mimetic nanoghosts and liposomes, which is not affected by storage for up to 6 weeks. In mouse models of subcutaneous and bone metastatic PC3 prostate cancer, systemically infused nanovesicles accumulate in tumor regions with significantly higher selectivity than liposomes. The loading of docetaxel into nanovesicles was efficient and did not affect the selective uptake of nanovesicles by prostate cancer cells. The cytotoxicities of nanovesicle-encapsulated docetaxel are significantly stronger on docetaxel-resistant prostate cancer cells and weaker on non-tumor cells than free docetaxel. In mouse models of subcutaneous and bone metastatic prostate cancer, nanovesicle-encapsulated docetaxel significantly decreased the tumor growth and toxicity to white blood cells compared with free docetaxel.ConclusionsOur data indicate that EV-mimicking iPSC-MSC nanovesicles are promising to improve the treatment of metastatic prostate cancer.
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