Aims Mesenchymal stromal cells (MSCs) gradually become attractive candidates for cardiac inflammation modulation, yet understanding of the mechanism remains elusive. Strikingly, recent studies indicated that exosomes secreted by MSCs might be a novel mechanism for the beneficial effect of MSCs transplantation after myocardial infarction. We therefore explored the role of MSC-derived exosomes (MSC-Exo) in the immunomodulation of macrophages after myocardial ischaemia/reperfusion (I/R) and its implications in cardiac injury repair. Methods and results Exosomes were isolated from the supernatant of MSCs using gradient centrifugation method. Administration of MSC-Exo to mice through intramyocardial injection after myocardial I/R reduced infarct size and alleviated inflammation level in heart and serum. Systemic depletion of macrophages with clodronate liposomes abolished the curative effects of MSC-Exo. MSC-Exo modified the polarization of M1 macrophages to M2 macrophages both in vivo and in vitro. miRNA sequencing of MSC-Exo and bioinformatics analysis implicated miR-182 as a potent candidate mediator of macrophage polarization and toll-like receptor 4 (TLR4) as a downstream target. Diminishing miR-182 in MSC-Exo partially attenuated its modulation of macrophage polarization. Likewise, knock down of TLR4 also conferred cardioprotective efficacy and reduced inflammation level in a mouse model of myocardial I/R. Conclusion Our data indicate that MSC-Exo attenuates myocardial I/R injury in mice via shuttling miR-182 that modifies the polarization status of macrophages. This study sheds new light on the application of MSC-Exo as a potential therapeutic tool for myocardial I/R injury.

Mesenchymal stromal cell-derived exosomes attenuate myocardial ischaemia-reperfusion injury through miR-182-regulated macrophage polarization

Exosomes are nano-sized vesicles that serve as mediators for cell-to-cell communication. With their unique nucleic acids, proteins, and lipids cargo compositions that reflect the characteristics of producer cells, exosomes can be utilized as cell-free therapeutics. Among exosomes derived from various cellular origins, mesenchymal stem cell-derived exosomes (MSC-exosomes) have gained great attention due to their immunomodulatory and regenerative functions. Indeed, many studies have shown anti-inflammatory, anti-aging and wound healing effects of MSC-exosomes in various in vitro and in vivo models. In addition, recent advances in the field of exosome biology have enabled development of specific guidelines and quality control methods, which will ultimately lead to clinical application of exosomes. This review highlights recent studies that investigate therapeutic potential of MSC-exosomes and relevant mode of actions for skin diseases, as well as quality control measures required for development of exosome-derived therapeutics.

Mesenchymal Stem/Stromal Cell-Derived Exosomes for Immunomodulatory Therapeutics and Skin Regeneration.

Extracellular vesicles (EVs), such as exosomes and microvesicles, have been identified as mediators of a newly-discovered intercellular communication system. They are essential signaling mediators in various physiological and pathophysiological processes. Depending on their origin, they fulfill different functions. EVs of mesenchymal stem/stromal cells (MSCs) have been found to promote comparable therapeutic activities as MSCs themselves. In a variety of in vivo models, it has been observed that they suppress pro-inflammatory processes and reduce oxidative stress and fibrosis. By switching pro-inflammatory into tolerogenic immune responses, MSC-EVs very likely promote tissue regeneration by creating a pro-regenerative environment allowing endogenous stem and progenitor cells to successfully repair affected tissues. Accordingly, MSC-EVs provide a novel, very promising therapeutic agent, which has already been successfully applied to humans. However, the MSC-EV production process has not been standardized, yet. Indeed, a collection of different protocols has been used for the MSC-EV production, characterization and application. By focusing on kidney, heart, liver and brain injuries, we have reviewed the major outcomes of published MSC-EV in vivo studies.

Mesenchymal Stem/Stromal Cell-Derived Extracellular Vesicles and Their Potential as Novel Immunomodulatory Therapeutic Agents

Exosomes are a type of extracellular vesicles, produced within multivesicular bodies, that are then released into the extracellular space through a merging of the multivesicular body with the plasma membrane. These vesicles are secreted by almost all cell types to aid in a vast array of cellular functions, including intercellular communication, cell differentiation and proliferation, angiogenesis, stress response, and immune signaling. This ability to contribute to several distinct processes is due to the complexity of exosomes, as they carry a multitude of signaling moieties, including proteins, lipids, cell surface receptors, enzymes, cytokines, transcription factors, and nucleic acids. The favorable biological properties of exosomes including biocompatibility, stability, low toxicity, and proficient exchange of molecular cargos make exosomes prime candidates for tissue engineering and regenerative medicine. Exploring the functions and molecular payloads of exosomes can facilitate tissue regeneration therapies and provide mechanistic insight into paracrine modulation of cellular activities. In this review, we summarize the current knowledge of exosome biogenesis, composition, and isolation methods. We also discuss emerging healing properties of exosomes and exosomal cargos, such as microRNAs, in brain injuries, cardiovascular disease, and COVID-19 amongst others. Overall, this review highlights the burgeoning roles and potential applications of exosomes in regenerative medicine.

https://www.mdpi.com/2073-4409/10/8/1959/pdf

Mesenchymal Stem Cell-Derived Exosomes: Applications in Regenerative Medicine.

Stem cell therapy has garnered much attention and application in the past decades for the treatment of diseases and injuries. Mesenchymal stem cells (MSCs) are studied most extensively for their therapeutic roles, which appear to be derived from their paracrine activity. Recent studies suggest a critical therapeutic role for extracellular vesicles (EV) secreted by MSCs. EV are nano-sized membrane-bound vesicles that shuttle important biomolecules between cells to maintain physiological homeostasis. Studies show that EV from MSCs (MSC-EV) have regenerative and anti-inflammatory properties. The use of MSC-EV, as an alternative to MSCs, confers several advantages, such as higher safety profile, lower immunogenicity, and the ability to cross biological barriers, and avoids complications that arise from stem cell-induced ectopic tumor formation, entrapment in lung microvasculature, and immune rejection. These advantages and the growing body of evidence suggesting that MSC-EV display therapeutic roles contribute to the strong rationale for developing EV as an alternative therapeutic option. Despite the success in preclinical studies, use of MSC-EV in clinical settings will require careful consideration; specifically, several critical issues such as (i) production methods, (ii) quantification and characterization, (iii) pharmacokinetics, targeting and transfer to the target sites, and (iv) safety profile assessments need to be resolved. Keeping these issues in mind, the aim of this mini-review is to shed light on the challenges faced in MSC-EV research in translating successful preclinical studies to clinical platforms.

/pdf/mesenchymal-stem-cell-derived-extracellular-vesicles-5e9o9dwxpy.pdf

Mesenchymal Stem Cell-Derived Extracellular Vesicles: Challenges in Clinical Applications

Mesenchymal stem cells (MSCs) repair infarcted heart through paracrine mechanism. We sought to compare the effectiveness of MSCs and MSC-derived exosomes (MSC-Exo) in repairing infarcted hearts and to identify how MSC-Exo mediated cardiac repair is regulated. In a rat myocardial infarction model, we found that MSC-Exo inhibited cardiac fibrosis, inflammation, and improved cardiac function. The beneficial effects of MSC-Exo were significantly superior compared to that of MSCs. To explore the potential mechanisms underlying MSC-Exo's effects, we performed several in vitro experiments and miRNA-sequence analysis. MSC-Exo stimulated cardiomyocyte H9C2 cell proliferation, inhibited apoptosis induced by H2O2, and inhibited TGF-β induced transformation of fibroblast cell into myofibroblast. Importantly, novel miRNA sequencing results indicated that MSC-Exo and MSCs have similar miRNA expression profile, which could be one of the reasons that MSC-Exo can replace MSCs for cardiac repair. In addition, the expression of several miRNAs from MSC-Exo was significantly different from that of MSCs, which may explain why MSC-Exo has better therapeutic effect than MSCs. In conclusion, this study demonstrates that MSC-Exo could be used alone to promote cardiac repair and are superior to MSCs in repairing injured myocardium.

/pdf/mirna-sequence-indicates-that-mesenchymal-stem-cells-and-48hdzp97s3.pdf

MiRNA-Sequence Indicates That Mesenchymal Stem Cells and Exosomes Have Similar Mechanism to Enhance Cardiac Repair

Introduction: Mesenchymal stem cell (MSC) repairs infarcted heart through paracrine mechanism We sought to determine whether MSC - derived exosomes could enhance myocardial repair and how exosome 

Abstract 17615: MSC Exosome Mediated Myocardial Repair is Inhibited by Knockdown of Igf-1 Signaling Pathway Through CRISPR/Cas9 Genome Editing

Introduction: Allogeneic mesenchymal stem cells (allo-MSC) are convenient cell source for stem cell based therapy. However, immune rejection is a major obstacle for clinical application of allo-MSC...

Abstract 17501: Enhancing Cardiac Repair by Allogeneic MSC via Downregulation of B2M by CRISPR/Cas9 Technology

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MiRNA-Sequence Indicates That Mesenchymal Stem Cells and Exosomes Have Similar Mechanism to Enhance Cardiac Repair

Abstract 17615: MSC Exosome Mediated Myocardial Repair is Inhibited by Knockdown of Igf-1 Signaling Pathway Through CRISPR/Cas9 Genome Editing

Abstract 17501: Enhancing Cardiac Repair by Allogeneic MSC via Downregulation of B2M by CRISPR/Cas9 Technology