Exosomes derived from pro‐inflammatory bone marrow‐derived mesenchymal stem cells reduce inflammation and myocardial injury via mediating macrophage polarization

Xu, Ruqin; Zhang, Fangcheng; Chai, Renjie; Zhou, Wenyi; Hu, Ming; Liu, Bin; Chen, Xuke; Liu, Mingke; Xu, Qiong; Liu, Ningning; Liu, Shiming

doi:10.1111/jcmm.14635

Cited by 186 publications

(163 citation statements)

References 61 publications

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“…Compared with MSC-EVs, LPS-primed MSC-EVs elevated phosphorylation activation of AKT1 and M2 polarization in vitro, while inhibiting phosphorylation of AKT2 and M1 polarization. The effect of LPS-primed MSC-EVs on macrophage polarization was partially abolished with either knocking down of AKT1 and AKT2, indicating the role of AKT1/AKT2 signaling pathway on macrophage polarization [78]. In a doxorubicin-induced dilated cardiomyopathy model, mice received bone marrow-derived MSC-EVs improved cardiac function, alleviated cardiac dilation, and attenuated cardiomyocytes apoptosis.…”

Section: Msc-ev-mediated Macrophage Polarization In Cardiovascular DImentioning

confidence: 97%

Mesenchymal stem cell-derived extracellular vesicles alter disease outcomes via endorsement of macrophage polarization

et al. 2020

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Mesenchymal stem cells (MSCs) are adult stromal cells that reside in virtually all postnatal tissues. Due to their regenerative and immunomodulatory capacities, MSCs have attracted growing attention during the past two decades. MSC-derived extracellular vesicles (MSC-EVs) are able to duplicate the effects of their parental cells by transferring functional proteins and genetic materials to recipient cells without cell-to-cell contact. MSC-EVs also target macrophages, which play an essential role in innate immunity, adaptive immunity, and homeostasis. Recent studies have demonstrated that MSC-EVs reduce M1 polarization and/or promote M2 polarization in a variety of settings. In this review, we discuss the mechanisms of macrophage polarization and roles of MSC-EV-induced macrophage polarization in the outcomes of cardiovascular, pulmonary, digestive, renal, and central nervous system diseases. In conclusion, MSC-EVs may become a viable alternative to MSCs for the treatment of diseases in which inflammation and immunity play a critical role.

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Section: Msc-ev-mediated Macrophage Polarization In Cardiovascular DImentioning

confidence: 97%

Mesenchymal stem cell-derived extracellular vesicles alter disease outcomes via endorsement of macrophage polarization

et al. 2020

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“…Recent studies have shown that MSC-based treatment of ischemia-induced cardiac damage can be mediated through the secretion of exosomes [5][6][7][8][9]. MSC-secreted exosomes have been reported to exert an anti-apoptotic effect on CMCs both in vivo and in vitro [5][6][7]10].…”

Section: Introductionmentioning

confidence: 99%

Mesenchymal stem cell-derived exosomes ameliorate cardiomyocyte apoptosis in hypoxic conditions through microRNA144 by targeting the PTEN/AKT pathway

Wen¹,

Mai²,

Zhu³

et al. 2020

Stem Cell Res Ther

126

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Background: A growing body of evidence suggests that stem cell-derived exosomal microRNAs (miRNAs) could be a promising cardioprotective therapy in the context of hypoxic conditions. The present study aims to explore how miRNA-144 (miR-144), a miRNA contained in bone marrow mesenchymal stem cell (MSC)-derived exosomes, exerts a cardioprotective effect on cardiomyocyte apoptosis in the context of hypoxic conditions and identify the underlying mechanisms. Methods: MSCs were cultured using the whole bone marrow adherent method. MSC-derived exosomes were isolated using the total exosome isolation reagent and confirmed by nanoparticle trafficking analysis as well as western blotting using TSG101 and CD63 as markers. The hypoxic growth conditions for the H9C2 cells were established using the AnaeroPack method. Treatment conditions tested included H9C2 cells pre-incubated with exosomes, transfected with miR-144 mimics or inhibitor, or treated with the PTEN inhibitor SF1670, all under hypoxic growth conditions. Cell apoptosis was determined by flow cytometry using 7-ADD and Annexin V together. The expression levels of the miRNAs were detected by real-time PCR, and the expression levels of AKT/p-AKT, Bcl-2, caspase-3, HIF-1α, PTEN, and Rac-1 were measured by both real-time PCR and western blotting. Results: Exosomes were readily internalized by H9C2 cells after co-incubation for 12 h. Exosome-mediated protection of H9C2 cells from apoptosis was accompanied by increasing levels of p-AKT. MiR-144 was found to be highly enriched in MSC-derived exosomes. Transfection of cells with a miR-144 inhibitor weakened exosomemediated protection from apoptosis. Furthermore, treatment of cells grown in hypoxic conditions with miR-144 mimics resulted in decreased PTEN expression, increased p-AKT expression, and prevented H9C2 cell apoptosis, whereas treatment with a miR-144 inhibitor resulted in increased PTEN expression, decreased p-AKT expression, and enhanced H9C2 cell apoptosis in hypoxic conditions. We also validated that PTEN was a target of miR-144 by using luciferase reporter assay. Additionally, cells treated with SF1670, a PTEN-specific inhibitor, resulted in increased p-AKT expression and decreased H9C2 cell apoptosis. Conclusions: These findings demonstrate that MSC-derived exosomes inhibit cell apoptotic injury in hypoxic conditions by delivering miR-144 to cells, where it targets the PTEN/AKT pathway. MSC-derived exosomes could be a promising therapeutic vehicle to facilitate delivery of miRNA therapies to ameliorate ischemic conditions.

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“…A recent study has also shown that culturing macrophages with exosomes from LPS-primed MSCs increases STAT3 gene expression, secretion of cytokines (IL-10 and IL-15), and expression of growth factors (FLT-3L); such macrophages also extend survival in a mouse model of acute radiation syndrome [122]. A different study showed that exosomes from LPS-primed MSCs increased M2 macrophage polarization, resulting in the attenuation of post-infarction inflammation and cardiomyocyte apoptosis in a mouse model of MI [123].…”

Section: Pre-conditioning Of Mscs With Biomolecules or Chemicalsmentioning

confidence: 99%

Current Knowledge and Future Perspectives on Mesenchymal Stem Cell-Derived Exosomes as a New Therapeutic Agent

Joo

Suh

Lee

et al. 2020

IJMS

195

151

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Mesenchymal stem cells (MSCs) are on the cusp of regenerative medicine due to their differentiation capacity, favorable culture conditions, ability to be manipulated in vitro, and strong immunomodulatory activity. Recent studies indicate that the pleiotropic effects of MSCs, especially their immunomodulatory potential, can be largely attributed to paracrine factors. Exosomes, vesicles that are 30-150 nanometers in diameter that function in cell-cell communication, are one of the key paracrine effectors. MSC-derived exosomes are enriched with therapeutic miRNAs, mRNAs, cytokines, lipids, and growth factors. Emerging evidences support the compelling possibility of using MSC-derived exosomes as a new form of therapy for treating several different kinds of disease such as heart, kidney, immune diseases, neural injuries, and neurodegenerative disease. This review provides a summary of current knowledge and discusses engineering of MSC-derived exosomes for their use in translational medicine.

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Exosomes derived from pro‐inflammatory bone marrow‐derived mesenchymal stem cells reduce inflammation and myocardial injury via mediating macrophage polarization

Cited by 186 publications

References 61 publications

Mesenchymal stem cell-derived extracellular vesicles alter disease outcomes via endorsement of macrophage polarization

Mesenchymal stem cell-derived extracellular vesicles alter disease outcomes via endorsement of macrophage polarization

Mesenchymal stem cell-derived exosomes ameliorate cardiomyocyte apoptosis in hypoxic conditions through microRNA144 by targeting the PTEN/AKT pathway

Current Knowledge and Future Perspectives on Mesenchymal Stem Cell-Derived Exosomes as a New Therapeutic Agent

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