Background: Exosomes are membranous vesicles generated by almost all cells. Recent studies demonstrated that mesenchymal stem cell–derived exosomes possessed many effects, including antiapoptosis, anti‐inflammatory effects, stimulation of angiogenesis, anticardiac remodeling, and recovery of cardiac function on cardiovascular diseases. However, targeting of exosomes to recipient cells precisely in vivo still remains a problem. Ligand fragments or homing peptides discovered by phage display and in vivo biopanning methods fused to the enriched molecules on the external part of exosomes have been exploited to improve the ability of exosomes to target specific tissues or organs carrying cognate receptors. Herein, we briefly elucidated how to improve targeting ability of exosomes to ischemic myocardium. Methods and Results: We used technology of molecular cloning and lentivirus packaging to engineer exosomal enriched membrane protein (Lamp2b) fused with ischemic myocardium‐targeting peptide CSTSMLKAC (IMTP). In vitro results showed that IMTP‐exosomes could be internalized by hypoxia‐injured H9C2 cells more efficiently than blank‐exosomes. Compared with blank‐exosomes, IMTP‐exosomes were observed to be increasingly accumulated in ischemic heart area ( P <0.05). Meanwhile, attenuated inflammation and apoptosis, reduced fibrosis, enhanced vasculogenesis, and cardiac function were detected by mesenchymal stem cell–derived IMTP‐exosome treatment in ischemic heart area. Conclusions: Our research concludes that exosomes engineered by IMTP can specially target ischemic myocardium, and mesenchymal stem cell–derived IMTP‐exosomes exert enhanced therapeutic effects on acute myocardial infarction.

Mesenchymal stem cells (MSCs) are derived from a wide range of sources and easily isolated and cultured. MSCs have the capacity for in vitro amplification and self-renewal, low immunogenicity and immunomodulatory properties, and under certain conditions, MSCs can be differentiated into a variety of cells. In the cardiovascular system, MSCs can protect the myocardium by reducing the level of inflammation, promoting the differentiation of myocardial cells around infarct areas and angiogenesis, increasing apoptosis resistance, and inhibiting fibrosis, which are ideal qualities for cardiovascular repair. Preclinical studies have shown that MSCs can be transplanted and improve cardiac repair, but challenges, such as their low rate of migration to the ischemic myocardium, low tissue retention, and low survival rate after transplantation, remain. This article reviews the potential and methods of MSC transplantation in the treatment of cardiovascular diseases (CVDs) and the challenges of the clinical use of MSCs.

Background: Myocardial infarction (MI) is a severe disease that often associated with dysfunction of angiogenesis. Cell-based therapies for MI using mesenchymal stem cell (MSC)-derived exosomes have been well studied due to their strong proangiogenic effect. Genetic modification is one of the most common methods to enhance exosome therapy. This study investigated the proangiogenic and cardioprotective effect of exosomes derived from hypoxia-inducible factor 1-alpha (HIF-1α)-modified MSCs. Methods: Lentivirus containing HIF-1α overexpressing vector was packaged and used to infect MSCs. Exosomes were isolated from MSC-conditioned medium by ultracentrifugation. Human umbilical vein endothelial cells (HUVECs) were treated under hypoxia condition for 48 h co-cultured with PBS, control exosomes, or HIF-1α-overexpressed exosomes, respectively. Then the preconditioned HUVECs were subjected to tube formation assay, Transwell assay, and EdU assay to evaluate the protective effect of exosomes. Meanwhile, mRNA and secretion levels of proangiogenic factors were measured by RT-qPCR and ELISA assays. In vivo assays were conducted using the rat myocardial infarction model. PBS, control exosomes, or HIF-1α-overexpressed exosomes were injected through tail vein after MI surgery. Heart function was assessed by echocardiography at days 3, 14, and 28. At day 7, mRNA and protein expression levels of proangiogenic factors in the peri-infarction area and circulation were evaluated, respectively. At day 28, hearts were collected and subjected to H&E staining, Masson’s trichrome staining, and immunofluorescent staining. Results: HIF-1α-overexpressed exosomes rescued the impaired angiogenic ability, migratory function, and proliferation of hypoxia-injured HUVECs. Simultaneously, HIF-1α-overexpressed exosomes preserved heart function by promoting neovessel formation and inhibiting fibrosis in the rat MI model. In addition, both in vitro and in vivo proangiogenic factors mRNA and protein expression levels were elevated after HIF-1α-overexpressed exosome application. Conclusion: HIF-1α-overexpressed exosomes could rescue the impaired angiogenic ability, migration, and proliferation of hypoxia-pretreated HUVECs in vitro and mediate cardioprotection by upregulating proangiogenic factors and enhancing neovessel formation.

Inflammasomes are protein complexes of the innate immune system that initiate inflammation in response to either exogenous pathogens or endogenous danger signals. Inflammasome multiprotein complexes are composed of three parts: a sensor protein, an adaptor, and pro-caspase-1. Activation of the inflammasome leads to the activation of caspase-1, which cleaves pro-inflammatory cytokines such as IL-1β and IL-18, leading to pyroptosis. Effectors of the inflammasome not only provide protection against infectious pathogens, but also mediate control over sterile insults. Aberrant inflammasome signaling has been implicated in the development of cardiovascular and metabolic diseases, cancer, and neurodegenerative disorders. Here, we review the role of the inflammasome as a double-edged sword in various diseases, and the outcomes can be either good or bad depending on the disease, as well as the genetic background. We highlight inflammasome memory and the two-shot activation process. We also propose the M- and N-type inflammation model, and discuss how the inflammasome pathway may be targeted for the development of novel therapy.

Our study aim was to evaluate the therapeutic efficacy and mechanisms of miR-133-overexpressing mesenchymal stem cells (MSCs) on acute myocardial infarction. Rat MSCs were isolated and purified by whole bone marrow adherent culturing. After transfection with the agomir or antagomir of miR-133, MSCs were collected for assay of cell vitality, apoptosis, and cell cycle progression. At the same time, exosomes were isolated from the supernatant to analyze the paracrine miR-133. For in-vivo studies, constitutive activation of miR-133 in MSCs was achieved by lentivirus-mediated miR-133 overexpression. A rat myocardial infarction model was created by ligating the left anterior descending coronary artery, while control MSCs (vector-MSCs) or miR-133-overexpressed MSCs (miR-133-MSCs) were injected into the zone around the myocardial infarction. Subsequently, myocardial function was evaluated by echocardiography on days 7 and 28 post infarction. Finally the infarcted hearts were collected on days 7 and 28 for myocardial infarct size measurement and detection of snail 1 expression. Hypoxia-induced apoptosis of MSCs obviously reduced, along with enhanced expression of total poly ADP-ribose polymerase protein, after miR-133 agomir transfection, while the apoptosis rate increased in MSCs transfected with miR-133 antagomir. However, no change in cell viability and cell-cycle distribution was observed in control, miR-133-overexpressed, and miR-133-interfered MSCs. Importantly, rats transplanted with miR-133-MSCs displayed more improved cardiac function after acute myocardial infarction, compared with those that received vector-MSC injection. Further studies indicated that cardiac expression of snail 1 was significantly repressed by adjacent miR-133-overexpressing MSCs, and both the inflammatory level and the infarct size decreased in miR-133-MSC-injected rat hearts. miR-133-MSCs obviously improved cardiac function in a rat model of myocardial infarction. Transplantation of miR-133-overexpressing MSCs provides an effective strategy for cardiac repair and modulation of cardiac-related diseases.

Adipose-derived stem cells (ADSCs) are easily obtained and expanded, and have emerged as a novel source of adult stem cells for the treatment of cardiovascular diseases. These cells have been shown to have the capability of differentiating into cardiomyocytes, vascular smooth muscle cells, and endothelial cells. Furthermore, ADSCs secrete a series of paracrine factors to promote neovascularization, reduce apoptosis, and inhibit fibrosis, which contributes to cardiac regeneration. As a novel therapy in the regenerative field, ADSCs still face various limitations, such as low survival and engraftment. Thus, engineering and pharmacological studies have been conducted to solve these problems. Investigations have moved into phase I and II clinical trials examining the safety and efficacy of ADSCs in the setting of myocardial infarction. In this review, we discuss the differentiation and paracrine functions of ADSCs, the strategies promoting their therapeutic efficacy, and their clinical usage.