Mesenchymal stem cell-derived extracellular vesicles in the failing heart: past, present, and future.

Cardiovascular disease (CVD) is the leading cause of death globally. Current treatment options include lifestyle changes, medication, and surgical intervention. However, many patients are unsuitable candidates for surgeries due to comorbidities, diffuse coronary artery disease or advanced stages of heart failure. The search for new treatment options has recently transitioned from cell-based therapies to stem-cell derived extracellular vesicles (EVs). A number of challenges remain in the EV field, including the effect of comorbidities, characterization, and delivery, However, recent revolutionary developments and insight into the potential of 'personalizing' EV contents by bioengineering methods to alter specific signaling pathways in the ischemic myocardium hold promise. Here, we discuss the past limitations of cell-based therapies, and recent EV studies involving in vivo, in vitro, and omics, and future challenges and opportunities in EV-based treatments in CVD.

• Publication year

  2021

• Venue

  American Journal of Physiology. Heart and Circulatory Physiology

• Publication date

  2021-04-16

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1152/ajpheart.00951.2020PMID 33861149PMCID PMC8163643
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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• Prevalence of Obesity and Severe Obesity Among Adults: United States, 2017-2018.

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• Quantification of extracellular vesicles in vitro and in vivo using sensitive bioluminescence imaging

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• Mesenchymal stem cell secretions improve donor heart function following ex vivo cold storage.

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• Adiponectin Stimulates Exosome Release to Enhance Mesenchymal Stem-Cell-Driven Therapy of Heart Failure in Mice

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• Selective intrarenal delivery of mesenchymal stem cell-derived extracellular vesicles attenuates myocardial injury in experimental metabolic renovascular disease

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• Reassessment of Exosome Composition.

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• Therapeutic Application of Mesenchymal Stem Cells Derived Extracellular Vesicles for Immunomodulation

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• Heart Disease and Stroke Statistics—2019 Update: A Report From the American Heart Association

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• Enhanced Therapeutic Effects of Mesenchymal Stem Cell-Derived Exosomes with an Injectable Hydrogel for Hindlimb Ischemia Treatment.

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• The microRNA regulatory landscape of MSC-derived exosomes: a systems view

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• Minimal information for studies of extracellular vesicles 2018 (MISEV2018): a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines

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• Stem Cell Therapy in Heart Diseases – Cell Types, Mechanisms and Improvement Strategies

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• Emerging roles of extracellular vesicles in cardiac repair and rejuvenation.

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• GATA-4-expressing mouse bone marrow mesenchymal stem cells improve cardiac function after myocardial infarction via secreted exosomes

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• The Expressed Genome in Cardiovascular Diseases and Stroke: Refinement, Diagnosis, and Prediction A Scientific Statement From the American Heart Association

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• Endothelial Cell Metabolism in Health and Disease.

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• Comparative Efficacy of Intracoronary Allogeneic Mesenchymal Stem Cells and Cardiosphere-Derived Cells in Swine with Hibernating Myocardium.

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• Minimal experimental requirements for definition of extracellular vesicles and their functions: a position statement from the International Society for Extracellular Vesicles

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• Identification of targeting peptides for ischemic myocardium by in vivo phage display.

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• Mechanism of Ca(2+) overload in endothelial cells exposed to simulated ischemia.

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• Toll4 (TLR4) expression in cardiac myocytes in normal and failing myocardium.

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• A calcineurin-dependent transcriptional pathway for cardiac hypertrophy.

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• Mitochondrial electron transport can become a significant source of oxidative injury in cardiomyocytes.

  1997cited by this paper
• Significant levels of oxidants are generated by isolated cardiomyocytes during ischemia prior to reperfusion.

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• Transport of lactate and other monocarboxylates across mammalian plasma membranes.

  1993cited by this paper
• The Biology of Myocardial Infarction

  1968cited by this paper

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• Commentary: Reversing the irreversible ischemic fibrosis with extracellular vesicle therapy.

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• Current Status of Myocardial Restoration via the Paracrine Function of Mesenchymal Stromal Cells.

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