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

Hocine, Hocine R.; Brunel, Sylvie; Chen, Qian; Giustiniani, Jérôme; San-Roman, Mabel Jouve; Ferrat, Yann; Palacios, Itziar; Rosa, Olga de la; Lombardo, Eleuterio; Bensussan, Armand; Charron, Dominique; Jabrane‐Ferrat, Nabila; Al-Daccak, Reem

doi:10.1002/sctm.18-0256

Cited by 13 publications

(16 citation statements)

References 64 publications

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“…In the current study we were not able to confirm blood vessel stimulation as we did not collect tissue samples for histology from all pigs (only a subset of four from each group). Other mechanisms whereby exosomes likely exert their cardiac protection and repair effect are by reducing oxidative stress ( 11 ) and modulating the local inflammatory response and environment ( 11 , 39 ). Taken together, it is likely that multiple mechanisms contribute to exosomes ability to protect, repair, and regenerate myocardium following a prolonged cardiac ischemia and MI.…”

Section: Discussionmentioning

confidence: 99%

Systemic Mesenchymal Stem Cell-Derived Exosomes Reduce Myocardial Infarct Size: Characterization With MRI in a Porcine Model

Charles

Yeung

et al. 2020

Front. Cardiovasc. Med.

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The observations that mesenchymal stem cells (MSCs) exert cardiac protection and repair via their secretome with the active component(s) identified as exosomes underpinned our test of the efficacy of MSC exosomes in a porcine model of myocardial infarction (MI) when administered systemically by the convenient method of intravenous (IV) bolus injection. Results show that 7 days of IV exosomes results in clear reduction (30–40%) of infarct size measured at both 7 and 28 days post-MI, despite near identical release of hs Troponin T. Together with reduced infarct size, exosome treatment reduced transmurality and lessened wall thinning in the infarct zone. Exosome treated pigs showed relative preservation of LV function with significant amelioration of falls in fractional wall thickening compared with control. However, global measures of LV function were less protected by exosome treatment. It is possible that greater preservation of global LV function may have been attenuated by increased cardiac fibrosis, as T1 values showed significant increase in the exosome pigs compared to control particularly in the infarct related segments. Taken together, these results show clear effects of IV exosomes administered over 7 days to reduce infarct size with relatively preserved cardiac function compared to control treated infarct pigs.

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Section: Discussionmentioning

confidence: 99%

Systemic Mesenchymal Stem Cell-Derived Exosomes Reduce Myocardial Infarct Size: Characterization With MRI in a Porcine Model

Charles

Yeung

et al. 2020

Front. Cardiovasc. Med.

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“…Although a consensus has not yet been reached on specific markers of EV subtypes, EV can be characterized by the expression of proteins like the tetraspanins (CD9, CD63 and CD81) and integrins while additional features of their profile depend on the phenotype of the parent cell [17][18][19][20] . Furthermore, while the molecular mechanisms underpinning the cardio-protective effects of EV are still under investigation, the therapeutic potential of EV likely relies on pleiotropic effects including angiogenesis, modulation of the inflammatory environment and, possibly, activation of cardiac intrinsic regenerative pathways 5,6,[21][22][23][24] .…”

Section: Introductionmentioning

confidence: 99%

Extracellular vesicles from human cardiovascular progenitors trigger a reparative immune response in infarcted hearts

Correa

Harane

Gomez

et al. 2020

Cardiovascular Research

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Aims The cardioprotective effects of human induced pluripotent stem cell-derived cardiovascular progenitor cells (CPC) are largely mediated by the paracrine release of extracellular vesicles (EV). We aimed to assess the immunological behaviour of EV-CPC, which is a prerequisite for their clinical translation. Methods and results Flow cytometry demonstrated that EV-CPC expressed very low levels of immune relevant molecules including HLA Class I, CD80, CD274 (PD-L1), and CD275 (ICOS-L); and moderate levels of ligands of the natural killer (NK) cell activating receptor, NKG2D. In mixed lymphocyte reactions, EV-CPC neither induced nor modulated adaptive allogeneic T cell immune responses. They also failed to induce NK cell degranulation, even at high concentrations. These in vitro effects were confirmed in vivo as repeated injections of EV-CPC did not stimulate production of immunoglobulins or affect the interferon (IFN)-γ responses from primed splenocytes. In a mouse model of chronic heart failure, intra-myocardial injections of EV-CPC, 3 weeks after myocardial infarction, decreased both the number of cardiac pro-inflammatory Ly6Chigh monocytes and circulating levels of pro-inflammatory cytokines (IL-1α, TNF-α, and IFN-γ). In a model of acute infarction, direct cardiac injection of EV-CPC 2 days after infarction reduced pro-inflammatory macrophages, Ly6Chigh monocytes, and neutrophils in heart tissue as compared to controls. EV-CPC also reduced levels of pro-inflammatory cytokines IL-1α, IL-2, and IL-6, and increased levels of the anti-inflammatory cytokine IL-10. These effects on human macrophages and monocytes were reproduced in vitro; EV-CPC reduced the number of pro-inflammatory monocytes and M1 macrophages, while increasing the number of anti-inflammatory M2 macrophages. Conclusions EV-CPC do not trigger an immune response either in in vitro human allogeneic models or in immunocompetent animal models. The capacity for orienting the response of monocyte/macrophages towards resolution of inflammation strengthens the clinical attractiveness of EV-CPC as an acellular therapy for cardiac repair.

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“…Recent studies and those from our labs suggest that EVs largely recapitulate the reparative activity of the stem/progenitor cell themselves in ischemic tissue repair and regeneration. Specifically, EPC-, CPC-, and CBSC-secreted EVs benefit cardiac repair and regeneration following ischemic injury [ 4 , 35 ]. However, EV cargo and biological properties differ depending on physiological condition of their parental cells [ 12 , 13 , 14 ].…”

Section: Discussionmentioning

confidence: 99%

Identification and Comparison of Hyperglycemia-Induced Extracellular Vesicle Transcriptome in Different Mouse Stem Cells

Huang

Garikipati

Zhou

et al. 2020

Cells

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Extracellular vesicles (EVs) derived from stem /progenitor cells harbor immense potential to promote cardiomyocyte survival and neovascularization, and to mitigate ischemic injury. However, EVs’ parental stem/progenitor cells showed modest benefits in clinical trials, suggesting autologous stem cell/EV quality might have been altered by stimuli associated with the co-morbidities such as hyperglycemia associated with diabetes. Hyperglycemia is a characteristic of diabetes and a major driving factor in cardiovascular disease. The functional role of stem/progenitor cell-derived EVs and the molecular signature of their secreted EV cargo under hyperglycemic conditions remain elusive. Therefore, we hypothesized that hyperglycemic stress causes transcriptome changes in stem/progenitor cell-derived EVs that may compromise their reparative function. In this study, we performed an unbiased analysis of EV transcriptome signatures from 3 different stem/progenitor cell types by RNA sequencing. The analysis revealed differential expression of a variety of RNA species in EVs. Specifically, we identified 241 common-dysregulated mRNAs, 21 ncRNAs, and 16 miRNAs in three stem cell-derived EVs. Gene Ontology revealed that potential function of common mRNAs mostly involved in metabolism and transcriptional regulation. This study provides potential candidates for preventing the adverse effects of hyperglycemia-induced stem/progenitor cell-derived EV dysfunction, and reference data for future biological studies and application of stem/progenitor cell-derived EVs.

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

Cited by 13 publications

References 64 publications

Systemic Mesenchymal Stem Cell-Derived Exosomes Reduce Myocardial Infarct Size: Characterization With MRI in a Porcine Model

Systemic Mesenchymal Stem Cell-Derived Exosomes Reduce Myocardial Infarct Size: Characterization With MRI in a Porcine Model

Extracellular vesicles from human cardiovascular progenitors trigger a reparative immune response in infarcted hearts

Identification and Comparison of Hyperglycemia-Induced Extracellular Vesicle Transcriptome in Different Mouse Stem Cells

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