Hypoxic BMSC-derived exosomal miRNAs promote metastasis of lung cancer cells via STAT3-induced EMT

Molecular Cancer, Journal Year: 2019, Volume and Issue: 18(1)

Published: March 13, 2019

Metastasis is the main cause of lung cancer mortality. Bone marrow-derived mesenchymal stem cells (BMSCs) are a component microenvironment and contribute to progression. Intratumoral hypoxia affects both stromal cells. Exosomes recognized as mediators intercellular communication. Here, we aim further elucidate communication between BMSC-derived exosomes in hypoxic niche. Exosomal miRNA profiling was performed using microRNA array. Lung an vivo mouse syngeneic tumor model were used evaluate effects select exosomal microRNAs. Hypoxic plasma miRNAs assessed for their capacity discriminate patients non-cancerous controls with or without metastasis. We demonstrate that derived from BMSCs taken by neighboring promote cell invasion EMT. Exosome-mediated transfer microRNAs, including miR-193a-3p, miR-210-3p miR-5100, epithelial activates STAT3 signaling increases expression related molecules. The diagnostic accuracy individual showed miR-193a-3p can controls. A panel these three microRNAs better metastasis than microRNA. could activating signalling-induced These may be promising noninvasive biomarkers

Language: Английский

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Exosome-shuttled miR-216a-5p from hypoxic preconditioned mesenchymal stem cells repair traumatic spinal cord injury by shifting microglial M1/M2 polarization

Journal of Neuroinflammation, Journal Year: 2020, Volume and Issue: 17(1)

Published: Feb. 4, 2020

Spinal cord injury (SCI) can lead to severe motor and sensory dysfunction with high disability mortality. In recent years, mesenchymal stem cell (MSC)-secreted nano-sized exosomes have shown great potential for promoting functional behavioral recovery following SCI. However, MSCs are usually exposed normoxia in vitro, which differs greatly from the hypoxic micro-environment vivo. Thus, main purpose of this study was determine whether derived under hypoxia (HExos) exhibit greater effects on than those (Exos) SCI mice seek underlying mechanism.Electron microscope, nanoparticle tracking analysis (NTA), western blot were applied characterize differences between Exos HExos group. A model vivo a series vitro experiments performed compare therapeutic two groups. Next, miRNA microarray rescue conducted verify role exosomal Western blot, luciferase activity, RNA-ChIP used investigate mechanisms.Our results indicate that promote by shifting microglial polarization M1 M2 phenotype vitro. array showed miR-216a-5p be most enriched potentially involved HExos-mediated polarization. TLR4 identified as target downstream gene miR-216a-5p/TLR4 axis confirmed gain- loss-of-function experiments. Finally, we found TLR4/NF-κB/PI3K/AKT signaling cascades may modulation miR-216a-5p.Hypoxia preconditioning represents promising effective approach optimize actions MSC-derived combination miRNAs present minimally invasive method treating

Language: Английский

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Molecular Mechanisms Responsible for Therapeutic Potential of Mesenchymal Stem Cell-Derived Secretome

Cells, Journal Year: 2019, Volume and Issue: 8(5), P. 467 - 467

Published: May 16, 2019

Mesenchymal stem cell (MSC)-sourced secretome, defined as the set of MSC-derived bioactive factors (soluble proteins, nucleic acids, lipids and extracellular vesicles), showed therapeutic effects similar to those observed after transplantation MSCs. secretome may bypass many side MSC-based therapy, including unwanted differentiation engrafted In contrast MSCs which had be expanded in culture reach optimal number for transplantation, MSC-sourced is immediately available treatment acute conditions, fulminant hepatitis, cerebral ischemia myocardial infarction. Additionally, could massively produced from commercially lines avoiding invasive collection procedure. this review article we emphasized molecular cellular mechanisms that were responsible beneficial secretomes degenerative inflammatory diseases hepatobiliary, respiratory, musculoskeletal, gastrointestinal, cardiovascular nervous system. Results obtained a large studies suggested administration represents new, cell-free approach attenuation diseases. Therapeutic relied on their capacity deliver genetic material, growth immunomodulatory target cells enabling activation anti-apoptotic pro-survival pathways resulted tissue repair regeneration.

Language: Английский

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Context-specific regulation of extracellular vesicle biogenesis and cargo selection

Nature Reviews Molecular Cell Biology, Journal Year: 2023, Volume and Issue: 24(7), P. 454 - 476

Published: Feb. 10, 2023

Language: Английский

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Design strategies and application progress of therapeutic exosomes

Theranostics, Journal Year: 2019, Volume and Issue: 9(4), P. 1015 - 1028

Published: Jan. 1, 2019

Exosomes have great potential to be drug delivery vehicles due their natural material transportation properties, intrinsic long-term circulatory capability, and excellent biocompatibility, which are suitable for delivering a variety of chemicals, proteins, nucleic acids, gene therapeutic agents.However, an effective method loading specific protein agents into exosomes absorption by target cells is still lacking.The application exosome limited.In this review, we discussed the methods treating molecules (proteins, acids small chemicals) exosomes, design strategies cell tissue targeting, factors formation.This review can used as reference further research well development exosomes.

Language: Английский

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Hypoxic mesenchymal stem cell-derived exosomes promote bone fracture healing by the transfer of miR-126

Acta Biomaterialia, Journal Year: 2019, Volume and Issue: 103, P. 196 - 212

Published: Dec. 17, 2019

Language: Английский

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Biomaterials Functionalized with MSC Secreted Extracellular Vesicles and Soluble Factors for Tissue Regeneration

Advanced Functional Materials, Journal Year: 2020, Volume and Issue: 30(37)

Published: March 11, 2020

The therapeutic benefits of mesenchymal stromal cell (MSC) transplantation have been attributed to their secreted factors, including extracellular vesicles (EVs) and soluble factors. potential employing the MSC secretome as an alternative acellular approach therapy is being investigated in various tissue injury indications, but EVs administered via bolus injections are rapidly sequestered cleared. However, biomaterials offer delivery platforms enhance EV retention rates healing efficacy. In this review, we highlight mechanisms underpinning effects MSC-EVs factors effectors immunomodulation regeneration, conferred primarily nucleic acid protein contents. We discuss how manipulating culture microenvironment or genetic modification MSCs can further augment potency secretions. most recent advances development EV-functionalized that mediate enhanced angiogenesis survival, while attenuating inflammation fibrosis, presented. Finally, some technical challenges be considered for clinical translation carrying MSC-secreted bioactive cargo discussed.

Language: Английский

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Atorvastatin enhances the therapeutic efficacy of mesenchymal stem cells-derived exosomes in acute myocardial infarction via up-regulating long non-coding RNA H19

Cardiovascular Research, Journal Year: 2019, Volume and Issue: 116(2), P. 353 - 367

Published: May 16, 2019

Abstract Aims Naturally secreted nanovesicles, known as exosomes, play important roles in stem cell-mediated cardioprotection. We have previously demonstrated that atorvastatin (ATV) pretreatment improved the cardioprotective effects of mesenchymal cells (MSCs) a rat model acute myocardial infarction (AMI). The aim this study was to investigate if exosomes derived from ATV-pretreated MSCs exhibit more potent function AMI and so explore underlying mechanisms. Methods results Exosomes were isolated control (MSC-Exo) (MSCATV-Exo) then delivered endothelial cardiomyocytes vitro under hypoxia serum deprivation (H/SD) condition or vivo an acutely infarcted Sprague-Dawley heart. Regulatory genes pathways activated by ATV explored using genomics approaches functional studies. In vitro, MSCATV-Exo accelerated migration, tube-like structure formation, increased survival but not cardiomyocytes, whereas MSCATV-Exo-treated prevented H/SD-induced apoptosis. model, resulted recovery cardiac function, further reduction infarct size reduced cardiomyocyte apoptosis compared MSC-Exo. addition, promoted angiogenesis inhibited elevation IL-6 TNF-α peri-infarct region. Mechanistically, we identified lncRNA H19 mediator role regulating expression miR-675 activation proangiogenic factor VEGF intercellular adhesion molecule-1. Consistently, abrogated when depleted mimicked overexpression H19. Conclusion obtained significantly enhanced therapeutic efficacy for treatment possibly through promoting cell function. LncRNA mediates, at least partially, angiogenesis.

Language: Английский

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Extracellular vesicles secreted by hypoxia pre-challenged mesenchymal stem cells promote non-small cell lung cancer cell growth and mobility as well as macrophage M2 polarization via miR-21-5p delivery

Journal of Experimental & Clinical Cancer Research, Journal Year: 2019, Volume and Issue: 38(1)

Published: Feb. 8, 2019

To investigate the lung cancer-promoting mechanism of mesenchymal stem cell-secreted extracellular vesicles (MSC-EV).EV were isolated from culture media human bone marrow-derived MSCs that pre-challenged with or without hypoxia (referred to as H-EV and N-EV, respectively). After treatment N-EV H-EV, A549 H23 cell proliferation, apoptosis, trans-well invasion epithelial-to-mesenchymal transition (EMT) examined. Polarization primary monocytes-derived macrophages induction analyzed by flow cytometry ELISA. PTEN, PDCD4 RECK gene was overexpressed in cells, while miR-21-5p knocked down MSCs, cancer cells monocytes inhibitor transfection. Protein level PDCD4, RECK, AKT STAT3 well phosphorylation protein assayed western blot. Tumorigenicity MSC-EV co-injection on immunocompromised mice. The xenograft tumor examined for angiogenesis, apoptosis intra-tumoral M1/M2 macrophage polarization.Comparing significantly increased survival, invasiveness EMT M2 polarization. MiR-21-5p abrogated polarizing effects treatment. downregulated expression largely through miR-21-5p. Overexpressing reduced miR-21-5p-mediated anti-apoptotic pro-metastatic effect overexpressing PTEN polarization after presence H-EV. growth, angiogenesis vivo partially miR-21-5p.Increased delivery pre-challenge can promote development reducing promoting

Language: Английский

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Mesenchymal Stem Cell Derived Extracellular Vesicles for Tissue Engineering and Regenerative Medicine Applications

Cells, Journal Year: 2020, Volume and Issue: 9(4), P. 991 - 991

Published: April 16, 2020

Mesenchymal stem cells (MSCs) are being extensively investigated for their potential in tissue engineering and regenerative medicine. However, recent evidence suggests that the beneficial effects of MSCs may be manifest by released extracellular vesicles (EVs); typically not requiring administration MSCs. This evidence, predominantly from pre-clinical vitro vivo studies, MSC-EVs exhibit substantial therapeutic properties many pathophysiological conditions, potentially restoring an extensive range damaged or diseased tissues organs. These benefits MSC EVs apparently found, regardless anatomical body fluid origin (and include e.g., bone marrow, adipose tissue, umbilical cord, urine, etc). Furthermore, early indications suggest favourable could further enhanced modifying way which donor cultured (for example, hypoxic compared to normoxic 3D 2D culture formats) and/or if subsequently bio-engineered loaded with specific cargo). So far, few human clinical trials have been conducted questions remain unanswered on whether heterogeneous population is some sub-populations, how best we can scale-up MSC-EV production isolation utility, what format they should administered. as reviewed here, there now supporting use medicine research establish exploit this approach societal economic benefit warranted.

Language: Английский

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