Exosomes derived from SDF1‐overexpressing mesenchymal stem cells inhibit ischemic myocardial cell apoptosis and promote cardiac endothelial microvascular regeneration in mice with myocardial infarction

Gong, Xuhe; Liu, Hui; Wang, Sijia; Liang, Siwen; Wang, Guogan

doi:10.1002/jcp.28070

Cited by 109 publications

(82 citation statements)

References 39 publications

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“…Currently, several strategies are under exploration that aim to enhance the exosomes released from MSCs. Hypoxia can facilitate MSCs to release exosomes, thus improving repair of cardiac tissues in a mouse model of myocardial infarction [274]. Compared with MSCs, exosomes derived from SDF1-overexpressing MSCs show enhanced therapeutic effects in myocardial infarction by increasing cardiac endothelial microvascular regeneration and inhibiting cardiomyocyte apoptosis in mice [275].…”

Section: Extracellular Vesicles (Exosomes)mentioning

confidence: 99%

Mechanisms underlying the protective effects of mesenchymal stem cell-based therapy

Fan

Zhang

et al. 2020

Cell. Mol. Life Sci.

364

282

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Mesenchymal stem cells (MSCs) have been extensively investigated for the treatment of various diseases. The therapeutic potential of MSCs is attributed to complex cellular and molecular mechanisms of action including differentiation into multiple cell lineages and regulation of immune responses via immunomodulation. The plasticity of MSCs in immunomodulation allow these cells to exert different immune effects depending on different diseases. Understanding the biology of MSCs and their role in treatment is critical to determine their potential for various therapeutic applications and for the development of MSC-based regenerative medicine. This review summarizes the recent progress of particular mechanisms underlying the tissue regenerative properties and immunomodulatory effects of MSCs. We focused on discussing the functional roles of paracrine activities, direct cell-cell contact, mitochondrial transfer, and extracellular vesicles related to MSC-mediated effects on immune cell responses, cell survival, and regeneration. This will provide an overview of the current research on the rapid development of MSC-based therapies. Keywords Regenerative potential • Integration of MSCs • Immunomodulation • Soluble factors • Cell-cell contact • Mitochondrial transfer • Extracellular vesicles Abbreviations AHR Airway hyper-responsiveness Alix ALG-2-interacting protein X Ang-1 Angiopoietin-1 ASCs Adipose-derived stem cells BAX BCL-2-associated X protein BCL-2 B-cell lymphoma 2 CASP3 Caspase 3 CX43 Connexin 43 CXCR4 Chemokine receptor type 4 DC Dendritic cell Cellular and Molecular Life Sciences

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Section: Extracellular Vesicles (Exosomes)mentioning

confidence: 99%

Mechanisms underlying the protective effects of mesenchymal stem cell-based therapy

Fan

Zhang

et al. 2020

Cell. Mol. Life Sci.

364

282

View full text Add to dashboard Cite

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“…Human UC-MSC-EVs overexpressing the pro-survival Akt kinase was shown to modulate local angiogenesis in a preclinical rat model of MI, via PDGF-D as pro-angiogenic mediator [199]. Likewise, EVs from UC-MSCs overexpressing the tissue matrix metalloproteinase inhibitor 2 (TIMP2) or the cardioprotective stromal-derived factor 1 alpha (SFD1a) have been shown to limit detrimental ventricular remodelling via the pro-survival Akt/Sfrp2 pathway and to inhibit apoptosis and autophagy of myocardial cells while sustaining local angiogenesis in preclinical rodent models of MI [200,201]. MSCs derived from human term placenta, also referred to as amniotic mesenchymal stromal cells (AMSCs), are well-known for their (immuno)modulatory properties [202,203]; EVs released by human term placenta-MSCs have been recently demonstrated exertion of relevant therapeutic effects as supporting new vessel development in vitro and in vivo [204], with nitric oxide (NO)-releasing polymer stimulation as a functional trigger of exosomal enrichment of pro-angiogenic VEGF and miR-126 [205].…”

Section: Contribution Of Exogenous Stem/progenitor Cell-evsmentioning

confidence: 99%

Message in a Bottle: Upgrading Cardiac Repair into Rejuvenation

Balbi

Costa

Barile

2020

Cells

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Ischaemic cardiac disease is associated with a loss of cardiomyocytes and an intrinsic lack of myocardial renewal. Recent work has shown that the heart retains limited cardiomyocyte proliferation, which remains inefficient when facing pathological conditions. While broadly active in the neonatal mammalian heart, this mechanism becomes quiescent soon after birth, suggesting loss of regenerative potential with maturation into adulthood. A key question is whether this temporary regenerative window can be enhanced via appropriate stimulation and further extended. Recently the search for novel therapeutic approaches for heart disease has centred on stem cell biology. The "paracrine effect" has been proposed as a promising strategy to boost endogenous reparative and regenerative mechanisms from within the cardiac tissue by exploiting the modulatory potential of soluble stem cell-secreted factors. As such, growing interest has been specifically addressed towards stem/progenitor cell-secreted extracellular vesicles (EVs), which can be easily isolated in vitro from cell-conditioned medium. This review will provide a comprehensive overview of the current paradigm on cardiac repair and regeneration, with a specific focus on the role and mechanism(s) of paracrine action of EVs from cardiac stromal progenitors as compared to exogenous stem cells in order to discuss the optimal choice for future therapy. In addition, the challenges to overcoming translational EV biology from bench to bedside for future cardiac regenerative medicine will be discussed.

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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]. Exosomes exert their therapeutic effect by transferring lipids, proteins, and a variety of RNAs to recipient cardiac cells.…”

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

124

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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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Exosomes derived from SDF1‐overexpressing mesenchymal stem cells inhibit ischemic myocardial cell apoptosis and promote cardiac endothelial microvascular regeneration in mice with myocardial infarction

Cited by 109 publications

References 39 publications

Mechanisms underlying the protective effects of mesenchymal stem cell-based therapy

Mechanisms underlying the protective effects of mesenchymal stem cell-based therapy

Message in a Bottle: Upgrading Cardiac Repair into Rejuvenation

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

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