• BMSCs
• TNF-α
• exosomes
• macrophage polarization
• myocardial infarction

• Animals
• Male
• Mice
• Bone Marrow Cells/cytology
• Disease Models, Animal
• Exosomes/metabolism
• Macrophages/metabolism
• Mesenchymal Stem Cells/cytology
• Mesenchymal Stem Cells/drug effects
• Mesenchymal Stem Cells/metabolism
• Mice, Inbred C57BL
• Myocardial Infarction/therapy
• Tumor Necrosis Factor-alpha/pharmacology

• Bibliometrics
• Cardiovascular diseases
• Myocardial fibrosis
• Stem cells
• VOSviewer

• EVs
• cardiac fibrosis
• cardiovascular diseases
• cell‐free therapy
• extracellular vesicles
• microRNA

• Myocytes, Cardiac/metabolism
• Humans
• Extracellular Vesicles/metabolism
• Fibrosis
• Fibroblasts/metabolism
• Animals
• MicroRNAs/metabolism
• Extracellular Matrix/metabolism
• Signal Transduction
• Transforming Growth Factor beta/metabolism
• Cells, Cultured
• Mice
• Adult

• 20F20112 Japan Society for the Promotion of Science
• JP21fk0108575 Japan Agency for Medical Research and Development
• Japan Society for the Promotion of Science
• Japan Agency for Medical Research and Development

• Acute myocardial infarction
• Exosomes
• Extracellular vesicles
• Large-animal studies

• Myocardial Infarction/therapy
• Extracellular Vesicles/transplantation
• Extracellular Vesicles/physiology
• Humans
• Animals

• R01 HL164588 NHLBI NIH HHS
• NIH

• cardiac diseases
• exosome
• mesenchymal stem cell (MSC)
• regeneration
• treatment

• BMSCs
• Exosome
• Gene delivery
• Myocardial infarction
• miR302

• Humans
• Myocytes, Cardiac/metabolism
• Exosomes/metabolism
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Myocardial Reperfusion Injury
• Myocardial Infarction/therapy
• Myocardial Infarction/genetics
• Myocardial Ischemia/therapy
• Myocardial Ischemia/metabolism
• Mesenchymal Stem Cells/metabolism
• Apoptosis
• Reperfusion

• 81800250 National Natural Science Foundation for Young Scholars of China
• 2022M711417 China Postdoctoral Science Foundation
• SSF2023000133 Tianjin Municipal Transportation Commission Science and Technology Development Plan Project

• exosomes
• mesenchymal stem cells
• miRNA
• myocardial infarction

• Humans
• Exosomes
• Mesenchymal Stem Cell Transplantation/methods
• Myocardial Infarction/therapy
• Myocytes, Cardiac
• Mesenchymal Stem Cells
• MicroRNAs/genetics

• National Natural Science Foundation of China

• Human bone mesenchymal stem cell-derived extracellular vesicles
• biodistribution
• intramyocardial injection
• intravenous injection
• myocardial infarction

• R01 HL046716 NHLBI NIH HHS
• T32 HL160517 NHLBI NIH HHS
• R56 HL133624 NHLBI NIH HHS
• T32 GM065085 NIGMS NIH HHS
• R01 HL133624 NHLBI NIH HHS
• R01 HL128831 NHLBI NIH HHS

• continuous perfusion
• ex vivo expansion
• extracellular vesicles
• fed-batch
• feeding regime
• mesenchymal stromal cells
• stirred tank reactor

• Humans
• Mesenchymal Stem Cells
• Batch Cell Culture Techniques
• Extracellular Vesicles/metabolism
• Regenerative Medicine
• Cell Proliferation

• endothelial cells
• large animal model
• miniature swine
• regenerative medicine
• vascular wall mesenchymal stem cells

• RFO 2021 RFO

• exosomes
• extracellular vesicles (EV)
• immunomodulation
• mesenchymal stromal cells (MSC)
• psoriasis

• Animals
• Mice
• Humans
• Exosomes/metabolism
• Interleukin-17
• Mice, Nude
• Reproducibility of Results
• Psoriasis/therapy
• Mesenchymal Stem Cells/metabolism

• Animals
• Swine
• Swine, Miniature
• Endoribonucleases
• Exosomes/pathology
• Quality of Life
• Protein Serine-Threonine Kinases
• Liver
• Mesenchymal Stem Cells
• Reperfusion Injury/therapy
• Reperfusion Injury/pathology
• Ischemia/pathology
• Reperfusion
• Endoplasmic Reticulum Stress

• atherosclerosis
• cardiovascular disease
• cholesterol
• exosome
• microRNA
• oligonucleotide

• Drug delivery system
• Exosomes
• Mesenchymal stem cells
• Non-coding RNA

• MicroRNAs/genetics
• Exosomes/metabolism
• Mesenchymal Stem Cells/metabolism

Background: Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) are important mediators of intercellular communication and participate in numerous physiological and pathological processes in the body. This study aims to introduce the research status, analyze the research hotspots, and predict the development trend through bibliometric analysis of MSC-EVs.

Methods: We searched all relevant literature on MSC-EVs from 2009 to 2021 in the Web of Science. R-bibliometrix, VOSviewer, and CiteSpace software were used to visualize the quantitative analysis of the published literature, including co-authorship, co-occurrence, citation, and co-citation, to provide objective presentation and predictions in the field.

Results: A total of 1595 articles and reviews on MSC-EVs published between 2009 and 2021 were identified. The annual publication outputs increased at an exponential rate, reaching as high as 555 publications in 2021. China contributed the most publications (n = 899, 56.36%) and had the most citations (n = 24,210). The United States had the strongest intensity of cooperation in this field. Shanghai Jiao Tong University had the maximum number of publications (n = 79). In terms of the number of publications and co-citations, the journal of Stem cell research & therapy ranked first. Camussi G was the most productive and most cited author. The top three themes in the research area were cell biology, research experimental medicine, and biochemistry molecular biology. Keyword co-occurrence and co-citation clustering analysis revealed that studies of MSC-EVs covered cellular origin (bone marrow mesenchymal stem cell, adipose-derived mesenchymal stem cell), injurious diseases (spinal cord injury, acute lung injury, ischemia/reperfusion injury, acute kidney injury, traumatic brain injury), tumor (breast cancer, tumor microenvironment), biological processes (drug delivery system, angiogenesis, inflammation, proliferation, differentiation, senescence), and molecular mechanisms (signaling pathway, signal transduction, oxidative stress, VEGF, TGF β).

Conclusions: Studies on MSC-EVs have shown a steep growth trend in recent years. Available studies mostly focused on the therapeutic effects and underlying mechanisms of MSC-EVs in aplastic diseases. Multidisciplinary integration is a development trend in this field, and senescence-related topics might be the focus of future research on MSC-EVs.

• National Natural Science Foundation of China

MSCs products as well as their derived extracellular vesicles, are currently being explored as advanced biologics in cell-based therapies with high expectations for their clinical use in the next few years. In recent years, various strategies designed for improving the therapeutic potential of mesenchymal stromal cells (MSCs), including pre-conditioning for enhanced cytokine production, improved cell homing and strengthening of immunomodulatory properties, have been developed but the manufacture and handling of these cells for their use as advanced therapy medicinal products (ATMPs) remains insufficiently studied, and available data are mainly related to non-industrial processes. In the present article, we will review this topic, analyzing current information on the specific regulations, the selection of living donors as well as MSCs from different sources (bone marrow, adipose tissue, umbilical cord, etc.), in-process quality controls for ensuring cell efficiency and safety during all stages of the manual and automatic (bioreactors) manufacturing process, including cryopreservation, the use of cell banks, handling medicines, transport systems of ATMPs, among other related aspects, according to European and US legislation. Our aim is to provide a guide for a better, homogeneous manufacturing of therapeutic cellular products with special reference to MSCs.

• Cell- and Tissue-Based Therapy
• Extracellular Vesicles
• Mesenchymal Stem Cells
• Treatment Outcome
• Umbilical Cord

• drug delivery
• exosomes
• extracellular vesicles
• lipid nanoparticle
• mesenchymal stem cell
• regenerative medicine

• cardiac fibrosis
• extracellular vesicles
• immunomodulation
• mesenchymal stromal/stem cells
• myocardial infarction
• swine/pig model
• ventricular remodeling

• Animals
• Disease Models, Animal
• Extracellular Vesicles
• Fibrosis
• Immunomodulation
• Leukocytes, Mononuclear
• Mesenchymal Stem Cells
• Myocardial Infarction/pathology
• Myocardium/pathology
• Swine
• Ventricular Remodeling

Exosomes (EXOs) derived from stem cells have become a potential new treatment for acute myocardial infarction (AMI). However, their impact is still not fully understood. Therefore, we performed this meta-analysis to systematically review the efficacy of EXOs on AMI in preclinical animal models.

We searched PubMed, EMBASE, and the Web of Science from September 1, 1980 to September 1, 2021, to retrieve the studies reporting the therapeutic effects of EXOs on AMI animal models. Secondary endpoints include the fractional shortening (FS), infarct size (IS), fibrosis area (FA), the TNF-α, IL-6 and IL-10 levels, the apoptosis rate and the number of autophagic vesicles. Two authors independently screened the articles based on inclusion and exclusion criteria. All statistical analyses were conducted using Stata14.0.

Ten studies satisfied the inclusion criteria. Pooled analyses demonstrated that the levels of LVEF (WMD = 3.67%; 95% CI 2.28–5.07%; P = 0.000), FS (WMD = 3.69%; 95% CI 2.06–5.33%; P = 0.000), IS (WMD = −4.52%, 95% CI − 7.14 to − 1.9%; P = 0.001), and FA (WMD = −7.04%, 95% CI − 8.74 to − 5.34%; P = 0.000), TNF-α (WMD = −3.09, 95% CI − 5.47 to − 0.72; P = 0.011), TL-6 (WMD = −6.34, 95% CI − 11.2 to − 1.49; P < 0.01), TL-10 (WMD = 6.37, 95% CI 1.53–11.21; P = 0.01), the apoptosis rate (WMD = −8.23, 95% CI − 15.29 to − 1.17; P = 0.000), and the number of autophagic vesicles (WMD = −4.52, 95% CI − 7.43 to − 1.62; P = 0.000). Subgroup analysis showed that the EXOs were derived from HMSCs. Subgroup analysis showed that the EXOs derived from HMSCs, and that exosome therapy immediately after myocardial infarction can better improve the LVEF. Conclusions: EXOs therapy has the potential to improve cardiac function, fibrogenesis, and inflammatory response, as well as reducing cell apoptosis and autophagy in preclinical AMI animal models. This can inform future human clinical trials of EXOs.

The online version contains supplementary material available at 10.1186/s13287-022-02833-z.

• Acute myocardial infarction
• Animal models
• Meta-analysis
• Stem cell-derived exosomes

• Angiogenesis
• Cardiac fibrosis
• Exosomes
• Inflammation
• Mesenchymal stromal cells

• EZH2
• HMGA2
• Mesenchymal stem cell-derived exosomes
• Myocardial fibrosis
• PI3K/AKT pathway

The importance of the biophysical characterization of mesenchymal stem cells (MSCs) was recently pointed out for supporting the development of MSC‐based therapies. Among others, tracking MSCs in vivo and a quantitative characterization of their regenerative impact by nuclear magnetic resonance (NMR) demands a full description of MSCs’ MR properties. In the work, Wharton Jelly MSCs are characterized in a low magnetic field (LF) in vitro by using different approaches. They encompass various settings: MSCs cultured in a Petri dish and cell suspensions; experiments‐ 1D‐T₁, 1D‐T₂, 1D diffusion, 2D T₁‐T₂ and D‐T₂; devices‐ with a bore aperture and single‐sided one. Complex NMR analysis with the aid of random walk simulations allows the determination of MSCs T₁ and T₂ relaxation times, cells and nuclei sizes, self‐diffusion coefficients of the nucleus and cytoplasm. In addition, the influence of a single layer of cells on the effective diffusion coefficient of water is detected with the application of a single‐sided NMR device. It also enables the identification of apoptotic and necrotic cell death and changed diffusional properties of cells suspension caused by compressing forces induced by the subsequent cell layers. The study delivers MSCs‐specific MR parameters that may help tracking MSCs in vivo.

• EVs
• Myocardial infarct
• Neuroinflammation
• Stroke
• miRNAs

• Animals
• Brain/immunology
• Brain/metabolism
• Humans
• Myocardial Infarction/genetics
• Myocardial Infarction/immunology
• Myocardial Infarction/metabolism
• Myocardium/immunology
• Myocardium/metabolism
• Signal Transduction

Background: Remote ischemic pre-conditioning (RIPC) alleviated the myocardial ischemia-reperfusion injury, yet the underlying mechanisms remain to be fully elucidated, especially at the late phase. Searching a key component as a transfer carrier may provide a novel insight into RIPC-mediated cardioprotection in the condition of myocardial ischemia-reperfusion.

Objective: To investigate the cardioprotective effect of plasma exosomes at the late phase of RIPC and its potential signaling pathways involved.

Methods and Results: Exosomes were isolated from the plasma of rats 48 h after the RIPC or control protocol. Although the total plasma exosomes level had no significant change at the late phase of RIPC (RIPC-exosome) compared with the control exosomes (Control-exosome), the RIPC-exosome afforded remarkable protection against myocardial ischemia-reperfusion (MI/R) injury in rats and hypoxia-reoxygenation (H/R) injury in cells. The miRNA array revealed significant enrichment of miR-126a-3p in RIPC-exosome. Importantly, both miR-126a-3p inhibitor and antagonist significantly blunted the cardioprotection of RIPC-exosome in H/R cells and MI/R rats, respectively, while miR-126a-3p mimic and agomir showed significant cardioprotection against H/R injury in cells and MI/R injury in rats. Mechanistically, RIPC-exosome, especially exosomal miR-126a-3p, activated the reperfusion injury salvage kinase (RISK) pathway by enhancing the phosphorylation of Akt and Erk1/2, and simultaneously inhibited Caspase-3 mediated apoptotic signaling.

Conclusions: Our findings reveal a novel myocardial protective mechanism that plasma exosomes at the late phase of RIPC attenuate myocardial ischemia-reperfusion injury via exosomal miR-126a-3p.

• cardiomyocyte apoptosis
• cardioprotection
• exosomes
• miR-126a-3p
• microRNA
• myocardial ischemia-reperfusion
• remote ischemic pre-conditioning

• articular cartilage
• bone marrow stimulation
• cartilage repair
• knee
• mesenchymal stem cells

• Animals
• Bone Marrow
• Cartilage, Articular/surgery
• Extracellular Vesicles
• Mesenchymal Stem Cells
• Swine
• Swine, Miniature
• X-Ray Microtomography

• Gigtforeningen

Excessive cardiac fibrosis plays a crucial role in almost all types of heart disease. Generally, cardiac fibrosis is a scarring process triggered in response to stress, injury, or aging and is characterized by the accumulation of activated myofibroblasts that deposit high levels of extracellular matrix proteins in the myocardium. While it is beneficial for cardiac repair in the short term, it can also result in pathological remodeling, tissue stiffening, and cardiac dysfunction, contributing to the progression of heart failure, arrhythmia, and sudden cardiac death. Despite its high prevalence, there is a lack of effective and safe therapies that specifically target myofibroblasts to inhibit or even reverse pathological cardiac fibrosis. In the past few decades, cell therapy has been under continuous evaluation as a potential treatment strategy, and several studies have shown that transplantation of mesenchymal stromal cells (MSCs) can reduce cardiac fibrosis and improve heart function. Mechanistically, it is believed that the heart benefits from MSC therapy by stimulating innate anti-fibrotic and regenerative reactions. The mechanisms of action include paracrine signaling and cell-to-cell interactions. In this review, we provide an overview of the anti-fibrotic properties of MSCs and approaches to enhance them and discuss future directions of MSCs for the treatment of cardiac fibrosis.

• anti-fibrosis
• cardiac fibrosis
• heart failure
• mesenchymal stromal cells
• therapy

Under vasculogenic conditioning, pro-inflammatory cell subsets of peripheral blood mononuclear cells (PBMCs) shift their phenotype to pro-regenerative cells such as vasculogenic endothelial progenitor cells, M2 macrophages, and regulatory T cells, collectively designated as regeneration-associated cells (RACs). In this study, we evaluated the therapeutic efficacy of RAC-derived extracellular vesicles (RACev) compared to mesenchymal stem cell-derived EVs (MSCev) in the context of myocardial ischemia reperfusion injury (M-IRI). Human PBMCs were cultured with defined growth factors for seven days to harvest RACs. RACev and MSCev were isolated via serial centrifugation and ultracentrifugation. EV quantity and size were characterized by nanoparticle tracking analysis. In vitro, RACev markedly enhanced the viability, and proliferation of human umbilical vein endothelial cells in a dose-dependent manner compared to MSCev. Notably, systemic injection of RACev improved cardiac functions at 4 weeks, such as fractional shortening, and protection from mitral regurgitation than the MSCev-treated group. Histologically, the RACev-transplanted group showed less interstitial fibrosis and enhanced capillary densities compared to the MSCev group. These beneficial effects were coupled with significant expression of angiogenesis, anti-fibrosis, anti-inflammatory, and cardiomyogenesis-related miRs in RACev, while modestly in MSCev. In vivo bioluminescence analysis showed preferential accumulation of RACev in the IR-injured myocardium, while MSCev accumulation was limited. Immune phenotyping analysis confirmed the immunomodulatory effect of MSCev and RACev. Overall, repetitive systemic transplantation of RACev is superior to MSCev in terms of cardiac function enhancements via crucial angiogenesis, anti-fibrosis, anti-inflammation miR delivery to the ischemic tissue.

• angiogenesis
• extracellular vesicles
• miR
• myocardial ischemia-reperfusion injury
• regeneration-associated cells

Objectives: Allicin is an allyl 2-propenethiosulfinate or diallyl thiosulfinate acid with cardioprotective effects in myocardial ischemia/reperfusion (MI/R) injury. This study aims to examine the underlying mechanism by which Allicin protects against MI/R.

Methods: C57BL6 mice were subjected to either sham or MI/R surgery, and mice in the Allicin group were injected with Allicin (5 mg/ml) before the induction of ischemia. The cardiac function and histopathology of experimental mice were evaluated by ultrasound quantification and Masson staining. We next measured the capillary angiogenesis of the peri-infarct area by Masson staining and immunohistochemical staining. The miRNA microarray was carried out to examine the expressed miRNAs in MI/R tissues and corresponding normal tissues. Real-time quantitative polymerase chain reaction (q-PCR) was performed to validate the selected miRNA-19α-3p gene expression. Besides, we evaluated the myocardial lactate dehydrogenase and COX-2 by immunofluorescence staining. The western blot analysis was used to evaluate the protein levels of p-AKT, p-PI3K, p-mTOR, COX-2, and VEGF protein in the Allicin and Model group. In vitro study, LPS stimulated Tie2 expressing macrophages were cultured in an ischemic buffer. We evaluated the accumulation of VEGF by fura-2/AM fluorescence. Besides, Western blotting was performed to examine the protein levels of p-PI3K, p-AKT, p-mTOR, VEGF, COX2, and MMP2. The PI3K inhibitor was applied to investigate whether Allicin-induced myocardial ischemia-reperfusion injury protection is mediated via the PI3K/AKT pathway. And the miR-19α-3p mimic/inhibitor were transfected to promote/inhibit the expression of miR-19a-3p for verifying the regulation of miR-19a-3p on PI3K pathway.

Results: Allicin pretreatment significantly improved I/R-induced cardiac function damage. Furthermore, Allicin could repress cardiac fibrosis, as evidenced by reduced areas of cardiac fibrosis. Allicin’s effect on the MI/R was associated with increased capillary angiogenesis. Microarray analysis exposed that miR-19a-3p down-regulated PIK3CA (PI3K) expression by directly targeting the PIK3CA gene. The regulation of the angiogenesis pathway and gene miRNA-19a-3p might affect the Allicin-induced MI/R protection. Immunofluorescence staining revealed that COX-2 and myocardial lactate dehydrogenase were significantly increased after Allicin treatment. Furthermore, western blot analysis demonstrated that p-AKT, p-PI3K, p-mTOR, COX-2, and VEGF protein levels were also increased in the Allicin group. In vitro study, the protein levels of p-PI3K, p-AKT, p-mTOR, VEGF, COX2, and MMP2 were significantly increased in the Allicin-treated Tie2 expressing macrophages. These effects were partially reversed by PI3K inhibitor (Wortmannin) treatment. MiR-19α-3p plays an important role in myocardial I/R injury. It could regulate the activity of the PI3K-AKT pathway. And inhibition of miR-19a-3p promoted angiogenesis by regulating PI3K/AKT pathway.

Conclusions: Allicin pretreatment protects against myocardial I/R and activating the miR-19a-3p/PI3K/AKT pathway.

• Allicin
• PI3K/AKT pathway
• angiogenesis
• miR-19a-3p
• myocardial I/R

Myocardial infarction (MI) is one of the most frequent cardiac emergencies, with significant potential for mortality. One of the major challenges of the post-MI healing response is that replacement fibrosis could lead to left ventricular remodeling (LVR) and heart failure (HF). This process involves canonical and non-canonical transforming growth factor-beta (TGF-β) signaling pathways translating into an intricate activation of cardiac fibroblasts and disproportionate collagen synthesis. Accumulating evidence has indicated that microRNAs (miRNAs) significantly contribute to the modulation of these signaling pathways. This review summarizes the recent updates regarding the molecular mechanisms underlying the role of the over 30 miRNAs involved in post-MI LVR. In addition, we compare the contradictory roles of several multifunctional miRNAs and highlight their potential use in pressure overload and ischemia-induced fibrosis. Finally, we discuss their attractive role as prognostic biomarkers for HF, highlighting the most relevant human trials involving these miRNAs.

• biomarker
• heart failure
• left ventricular remodeling
• miRNA
• myocardial infarction
• prognostic

• collagen
• exosome
• extracellular matrix
• extracellular vesicle
• fibrogenic
• fibrosis
• myofibroblast

• heart failure
• large animal models
• large animal surgery
• myocardial infarction
• preclinical
• review
• translational research

Exosomes transport biologically active cargo (e.g., proteins and microRNA) between cells, including many of the paracrine factors that mediate the beneficial effects associated with stem-cell therapy. Stem cell derived exosomes, in particular mesenchymal stem cells (MSCs), have been shown previously to largely replicate the therapeutic activity associated with the cells themselves, which suggests that exosomes may be a useful cell-free alternative for the treatment of cardiovascular disorders. However, the mechanisms that govern how exosomes home to damaged cells and tissues or the uptake and distribution of exosomal cargo are poorly characterized, because techniques for distinguishing between exosomal proteins and proteins in the targeted tissues are lacking. Here, we report the development of an in vivo model that enabled the visualization, tracking, and quantification of proteins from systemically administered MSC exosomes. The model uses bioorthogonal chemistry and cell-selective metabolic labeling to incorporate the non-canonical amino acid azidonorleucine (ANL) into the MSC proteome. ANL incorporation is facilitated via expression of a mutant (L274G) methionyl-tRNA-synthetase (MetRS^∗) and subsequent incubation with ANL-supplemented media; after which ANL can be covalently linked to alkyne-conjugated reagents (e.g., dyes and resins) via click chemistry. Our results demonstrate that when the exosomes produced by ANL-treated, MetRS^∗-expressing MSCs were systemically administered to mice, the ANL-labeled exosomal proteins could be accurately and reliably identified, isolated, and quantified from a variety of mouse organs, and that myocardial infarction (MI) both increased the abundance of exosomal proteins and redistributed a number of them from the membrane fraction of intact hearts to the cytosol of cells in infarcted hearts. Additionally, we found that Desmoglein-1c is enriched in MSC exosomes and taken up by ischemic myocardium. Collectively, our results indicate that this newly developed bioorthogonal system can provide crucial insights into exosome homing, as well as the uptake and biodistribution of exosomal proteins.

• bioorthogonal labeling
• cardiac ischemia
• click reaction
• exosomes
• extracellular vesicles
• mesenchymal stem cells

Methods for suppressing the host immune system over the long term and improving transplantation tolerance remain a primary issue in organ transplantation. Cell therapy is an emerging therapeutic strategy for immunomodulation after transplantation. Mesenchymal stem cells (MSCs) are adult multipotent stem cells with wide differentiation potential and immunosuppressive properties, which are mostly used in regenerative medicine and immunomodulation. In addition, emerging research suggests that MSC-derived exosomes have the same therapeutic effects as MSCs in many diseases, while avoiding many of the risks associated with cell transplantation. Their unique immunomodulatory properties are particularly important in the immune system-overactive graft environment. In this paper, we review the effects of MSC-derived exosomes in the immune regulation mechanism after organ transplantation and graft-versus-host disease (GvHD) from various perspectives, including immunosuppression, influencing factors, anti-inflammatory properties, mediation of tissue repair and regeneration, and the induction of immune tolerance. At present, the great potential of MSC-derived exosomes in immunotherapy has attracted a great deal of attention. Furthermore, we discuss the latest insights on MSC-derived exosomes in organ transplantation and GvHD, especially its commercial production concepts, which aim to provide new strategies for improving the prognosis of organ transplantation patients.

• GvHD
• MSC-derived exosomes
• immune tolerance
• immunomodulation
• transplantation

Cardiovascular diseases have been regarded as the leading cause of death around the world, with myocardial infarction (MI) being the most severe form. MI leads to myocardial apoptosis, cardiomyocyte fibrosis, and cardiomyocyte hypertrophy, ultimately leading to heart failure, and death. Micro RNAs (miRNAs) participate in the genesis and progression of myocardial pathology after MI by playing an important regulatory role. This review aims to summarize all available knowledge on the role of miRNAs in the myocardial pathological process after MI to uncover potential major target pathways. In addition, the main therapeutic methods and their latest progress are also reviewed. miRNAs can regulate the main signaling pathways as well as pathological processes. Thus, they have the potential to induce therapeutic effects. Hence, the combination of miRNAs with recently developed exosome nanocomplexes may represent the future direction of therapeutics.

• MI
• apoptosis
• fibrosis
• hypertrophy
• miRNA

With cardiovascular diseases affecting millions of patients, new treatment strategies are urgently needed. The use of stem cell based approaches has been investigated during the last decades and promising effects have been achieved. However, the beneficial effect of stem cells has been found to being partly due to paracrine functions by alterations of their microenvironment and so an interesting field of research, the “stem- less” approaches has emerged over the last years using or altering the microenvironment, for example, via deletion of senescent cells, application of micro RNAs or by modifying the cellular energy metabolism via targeting mitochondria. Using autologous muscle-derived mitochondria for transplantations into the affected tissues has resulted in promising reports of improvements of cardiac functions in vitro and in vivo. However, since the targeted treatment group represents mainly elderly or otherwise sick patients, it is unclear whether and to what extent autologous mitochondria would exert their beneficial effects in these cases. Stem cells might represent better sources for mitochondria and could enhance the effect of mitochondrial transplantations. Therefore in this review we aim to provide an overview on aging effects of stem cells and mitochondria which might be important for mitochondrial transplantation and to give an overview on the current state in this field together with considerations worthwhile for further investigations.

• aging
• cardiovascular
• heart
• mitochondria
• senescence
• stem cell
• transplantation