Exosomes and cardioprotection – A critical analysis

Davidson, Sean M.; Yellon, Derek M.

doi:10.1016/j.mam.2017.11.004

Cited by 84 publications

(91 citation statements)

References 102 publications

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“…To confirm the release of EV, hCPC culture supernatant (SN) was subjected to differential centrifugation and processed for NTA and TEM. NTA demonstrated 95% enrichment in nanovesicles with typical small‐EV/exosomes (Exs) size range (30–150 nm) and a 5%‐minute fraction of medium/large‐EV (≥200 nm) and/or apoptotic bodies . These results were consistent with TEM, which identified primarily particles of the size of small‐EV/Exs (30–100 nm).…”

Section: Resultssupporting

confidence: 79%

Extracellular Vesicles Released by Allogeneic Human Cardiac Stem/Progenitor Cells as Part of Their Therapeutic Benefit

Hocine

Brunel

Chen

et al. 2019

Stem Cells Translational Medicine

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The positive effects of therapeutic human allogeneic cardiac stem/progenitor cells (hCPC) in terms of cardiac repair/regeneration are very likely mediated by paracrine effects. Our previous studies revealed the advantageous immune interactions of allogeneic hCPC and proposed them as part of the positive paracrine effects occurring upon their application postmyocardial infarction (MI). Currently, extracellular vesicles/exosomes (EV/Exs) released by stem/progenitor cells are also proposed as major mediators of paracrine effects of therapeutic cells. Along this line, we evaluated contribution of EV/Exs released by therapeutic hCPC to the benefit of their successful allogeneic clinical application. Through tailored allogeneic in vitro human assay models mimicking the clinical setting, we demonstrate that hCPC‐released EV/Exs were rapidly and efficiently up‐taken by chief cellular actors of cardiac repair/regeneration. This promoted MAPK/Erk1/2 activation, migration, and proliferation of human leukocyte antigens (HLA)‐mismatched hCPC, mimicking endogenous progenitor cells and cardiomyocytes, and enhanced endothelial cell migration, growth, and organization into tube‐like structures through activation of several signaling pathways. EV/Exs also acted as pro‐survival stimuli for HLA‐mismatched monocytes tuning their phenotype toward an intermediate anti‐inflammatory pro‐angiogenic phenotype. Thus, while positively impacting the intrinsic regenerative and angiogenic programs, EV/Exs released by therapeutic allogeneic hCPC can also actively contribute to shaping MI‐inflammatory environment, which could strengthen the benefits of hCPC allogeneic interactions. Collectively, our data might forecast the application of allogeneic hCPC followed by their cell‐free EV/Exs as a strategy that will not only elicit the cell‐contact mediated reparative/regenerative immune response but also have the desired long‐lasting effects through the EV/Exs. stem cells translational medicine 2019;8:911&924

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Section: Resultssupporting

confidence: 79%

Extracellular Vesicles Released by Allogeneic Human Cardiac Stem/Progenitor Cells as Part of Their Therapeutic Benefit

Hocine

Brunel

Chen

et al. 2019

Stem Cells Translational Medicine

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“…Thus, the EV, secreted from both induced pluripotent stem cells (iPSC) and young MSC, reduce the cellular senescence associated to aging MSC cultures, by reducing the intracellular levels of reactive oxygen species (ROS) . On the other hand, the anti-fibrotic effect of EV can be applied to the treatment of fibrosis in organs such as the liver, heart, lung, and skin (Zhao et al, 2017;Davidson and Yellon, 2018;Mansouri et al, 2019;Rong et al, 2019).…”

Section: Properties and Therapeutic Potential Of Mscmentioning

confidence: 99%

Extracellular Vesicles Derived From Mesenchymal Stem Cells (MSC) in Regenerative Medicine: Applications in Skin Wound Healing

Casado-Díaz

Quesada‐Gómez

Dorado

2020

Front. Bioeng. Biotechnol.

221

183

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The cells secrete extracellular vesicles (EV) that may have an endosomal origin, or from evaginations of the plasma membrane. The former are usually called exosomes, with sizes ranging from 50 to 100 nm. These EV contain a lipid bilayer associated to membrane proteins. Molecules such as nucleic acids (DNA, mRNA, miRNA, lncRNA, etc.) and proteins may be stored inside. The EV composition depends on the producer cell type and its physiological conditions. Through them, the cells modify their microenvironment and the behavior of neighboring cells. That is accomplished by transferring factors that modulate different metabolic and signaling pathways. Due to their properties, EV can be applied as a diagnostic and therapeutic tool in medicine. The mesenchymal stromal cells (MSC) have immunomodulatory properties and a high regenerative capacity. These features are linked to their paracrine activity and EV secretion. Therefore, research on exosomes produced by MSC has been intensified for use in cell-free regenerative medicine. In this area, the use of EV for the treatment of chronic skin ulcers (CSU) has been proposed. Such sores occur when normal healing does not resolve properly. That is usually due to excessive prolongation of the inflammatory phase. These ulcers are associated with aging and diseases, such as diabetes, so their prevalence is increasing with the one of such latter disease, mainly in developed countries. This has very important socio-economic repercussions. In this review, we show that the application of MSC-derived EV for the treatment of CSU has positive effects, including accelerating healing and decreasing scar formation. This is because the EV have immunosuppressive and immunomodulatory properties. Likewise, they have the ability to activate the angiogenesis, proliferation, migration, and differentiation of the main cell types involved in skin regeneration. They include endothelial cells, fibroblasts, and keratinocytes. Most of the studies carried out so far are preclinical. Therefore, there is a need to advance more in the knowledge about the conditions of production, isolation, and action mechanisms of EV. Interestingly, their potential application in the treatment of CSU opens the door for the design of new highly effective therapeutic strategies.

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“…We, therefore, think that ATG treatment does not only differ with regards to the applicability to anti-CD3 treatment, but also regarding the mechanistic pathways by which the observed cardioprotective phenotypes were mediated. Therefore, furthermore, both quantitative and qualitative changes in exosomes, which are known to have cardioprotective capabilities, were assessed in this study [23]. Indeed, pronounced effects on several distinct miRNAs were observed.…”

Section: Discussionmentioning

confidence: 96%

Anti-CD3 Antibody Treatment Reduces Scar Formation in a Rat Model of Myocardial Infarction

Wernly

Paar

Aigner

et al. 2020

Cells

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Introduction: Antibody treatment with anti-thymocyte globulin (ATG) has been shown to be cardioprotective. We aimed to evaluate which single anti-T-cell epitope antibody alters chemokine expression at a level similar to ATG and identified CD3, which is a T-cell co-receptor mediating T-cell activation. Based on these results, the effects of anti-CD3 antibody treatment on angiogenesis and cardioprotection were tested in vitro and in vivo. Methods: Concentrations of IL-8 and MCP-1 in supernatants of human peripheral blood mononuclear cell (PBMC) cultures following distinct antibody treatments were evaluated by Enzyme-linked Immunosorbent Assay (ELISA). In vivo, anti-CD3 antibodies or vehicle were injected intravenously in rats subjected to acute myocardial infarction (AMI). Chemotaxis and angiogenesis were evaluated using tube and migration assays. Intracellular pathways were assessed using Western blot. Extracellular vesicles (EVs) were quantitatively evaluated using fluorescence-activated cell scanning, exoELISA, and nanoparticle tracking analysis. Also, microRNA profiles were determined by next-generation sequencing. Results: Only PBMC stimulation with anti-CD3 antibody led to IL-8 and MCP-1 changes in secretion, similar to ATG. In a rat model of AMI, systemic treatment with an anti-CD3 antibody markedly reduced infarct scar size (27.8% (Inter-quartile range; IQR 16.2-34.9) vs. 12.6% (IQR 8.3-27.2); p < 0.01). The secretomes of anti-CD3 treated PBMC neither induced cardioprotective pathways in cardiomyocytes nor pro-angiogenic mechanisms in human umbilical vein endothelial cell (HUVECs) in vitro. While EVs quantities remained unchanged, PBMC incubation with an anti-CD3 antibody led to alterations in EVs miRNA expression. Conclusion: Treatment with an anti-CD3 antibody led to decreased scar Cells 2020, 9, 295 2 of 19 size in a rat model of AMI. Whereas cardioprotective and pro-angiogenetic pathways were unaltered by anti-CD3 treatment, qualitative changes in the EVs miRNA expression could be observed, which might be causal for the observed cardioprotective phenotype. We provide evidence that EVs are a potential cardioprotective treatment target. Our findings will also provide the basis for a more detailed analysis of putatively relevant miRNA candidates.

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Exosomes and cardioprotection – A critical analysis

Cited by 84 publications

References 102 publications

Extracellular Vesicles Released by Allogeneic Human Cardiac Stem/Progenitor Cells as Part of Their Therapeutic Benefit

Extracellular Vesicles Released by Allogeneic Human Cardiac Stem/Progenitor Cells as Part of Their Therapeutic Benefit

Extracellular Vesicles Derived From Mesenchymal Stem Cells (MSC) in Regenerative Medicine: Applications in Skin Wound Healing

Anti-CD3 Antibody Treatment Reduces Scar Formation in a Rat Model of Myocardial Infarction

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