Myocardial infarction (MI) is a severe disease that often associated with impaired angiogenesis and increased myocardial apoptosis. Mesenchymal stromal cells (MSCs) have been a promising candidate for treating myocardial infarction. However, functional heterogeneity of MSCs leads to inconsistent therapeutic efficiency and the current MSCs-based therapy lacks the concept and implementation of precision medicine. In this study, we compared the cardioprotective effect of UCMSCs and ADMSCs targeting the angiogenesis in a mouse MI model and screened out optimum MSCs candidate for precise clinical application.

The gene expression profiles of UCMSCs and ADMSCs were investigated through RNA sequencing analysis. To compare their angiogenic potential, we performed tube formation assay, Matrigel plug assays, and aortic ring assay, and analyzed pro-angiogenic genes via qPCR. Subsequently, UCMSCs and ADMSCs were respectively injected into myocardium after MI surgery in mice. On day 28 post-MI, echocardiography was performed to assess cardiac function. Histological analysis was performed to assess MSCs retention, angiogenesis, and myocardial apoptosis. Additionally, the anti-apoptosis effects mediated by MSCs were further evaluated using flow cytometry in hypoxia H9C2 and HL-1 cells.

The RNA sequencing analysis revealed differences in gene expression related to angiogenesis and apoptosis pathways between UCMSCs and ADMSCs. UCMSCs presented greater pro-angiogenesis activity than ADMSCs in vitro and in vivo. Both of UCMSCs and ADMSCs improved cardiac function, decreased infarction area and inhibited cardiomyocyte apoptosis while promoting angiogenesis post-MI in mice. Notably, ADMSCs exerted a better cardioprotective function than UCMSCs and stronger anti-apoptotic effect on residual cardiomyocytes.

The protection of residual cells survival played a more prominent role than angiogenesis in MSCs-based therapy for acute MI. Our study provides new insights into therapeutic strategies and suggests that the optimal type of MSCs can be screened based on their tissue heterogeneity for precise clinical applications in acute MI.

Heart failure (HF) represents the terminal stage of cardiovascular disease and remains a leading cause of mortality. Epidemiological studies indicate a high prevalence and mortality rate of HF globally. Current treatment options primarily include pharmacological and non-pharmacological approaches. With the development of mesenchymal stem cell (MSC) transplantation technology, increasing research has shown that stem cell therapy and exosomes derived from these cells hold promise for repairing damaged myocardium and improving cardiac function, becoming a hot topic in clinical treatment for HF. However, this approach also presents certain limitations. This review summarizes the mechanisms of HF, current treatment strategies, and the latest progress in the application of MSCs and their exosomes in HF therapy.

The study aimed to evaluate the relationship between immunonutritional indicators such as the systemic immune-inflammation index (SII), the Naples prognostic score (NPS), nutritional risk index (NRI), serum albumin (ALB), total cholesterol (TC) and all-cause mortality in adult stroke patients. Data were obtained from the National Health and Nutrition Examination Survey (NHANES) databases for 2005-2018. To determine mortality outcomes, participants were matched with National Death Index records until December 31, 2019. Spearman's correlation analysis and the random survival forest (RSF) were employed to assess the relationships among NPS, NRI, SII, ALB, and TC, and to determine the most predictive indicator for all-cause mortality in stroke patients. For the selected prognostic indicator, Kaplan-Meier survival analysis and Cox proportional hazards regression models were subsequently utilized to evaluate their associations with all-cause mortality in stroke patients. The study included 1076 stroke patients, with a median (IQR) age of 67 (56, 77) years. During a median follow-up of 67 months, a total of 372 (weighted 31%) stroke participants died from all causes. Among the immunonutritional indicators evaluated, NPS had the strongest predictive power for all-cause mortality in stroke patients. The Kaplan-Meier curve and Log-rank test showed that all-cause mortality was higher in the higher NPS group (3-4) compared to the lower NPS group (0-2) (P < 0.001). After adjusting for multiple potential confounders, the Cox regression model indicated that the higher NPS (3-4) group remained an independent predictor for higher all-cause mortality risk (HR = 1.89, 95% CI 1.44-2.47, P < 0.001). As a comprehensive evaluation index of inflammation and nutrition, NPS is a powerful predictor of all-cause mortality in stroke patients.

Exosomes are vesicles secreted by cells, typically ranging from 30 to 150 nm in diameter, and serve as crucial mediators of intercellular communication. Exosomes are capable of loading various therapeutic substances, such as small molecule compounds, proteins, and oligonucleotides, thereby making them an ideal vehicle for drug delivery. The distinctive biocompatibility, high stability, and targeting properties of exosomes render them highly valuable for future treatments of diseases like cancer and cardiovascular diseases. Despite the potential advantage of exosomes in delivering biologically active molecules, the techniques for the preparation, purification, preservation, and other aspects of stem cell exosomes are not yet mature enough. In this paper, we briefly introduce the composition, biogenesis, and benefits of exosomes, and primarily focus on summarizing the isolation and purification methods of exosomes, the preparation of engineered exosomes, and their clinical applications, to better provide new ideas for the development of exosome drug delivery systems.

Regenerative medicine is one of the effective approaches for myocardial infarcted (MI) tissue due to the low capacity of heart for regeneration. However, cell therapy with local administration has shown poor cell retention in the targeted area and limited engraftment capacity at the intended location, resulting in inadequate tissue regeneration. The present study involves mesenchymal stem cell-derived exosomes and encapsulated cells in small and injectable calcium alginate microgels by a specialized microfluidic device to decrease inflammation and increase cell retention in the infarcted tissue. The results have shown that our microfluidic system can produce monodisperse cardiac cell-laden alginate microgels within the size range of <100 μm that are easily injectable. Our in vivo findings on the MI rat model demonstrated that the combination of cardiac cell-laden calcium alginate microgels with mesenchymal stem cells derived exosomes resulted in a higher increase in echocardiography, heart-specific gene expressions, and cardiac markers results compared to the other groups. However, the administration of exosomes or cardiac cells separately has shown a small amount of regeneration. Encapsulating cardiac cells of specific sizes along with exosomes produced from mesenchymal stem cells can be potentially applied as an effective method for regenerating the myocardium following infarction.

After myocardial infarction (MI), the heart undergoes necrosis, inflammation, scar formation, and remodeling. While restoring blood flow is crucial, it can cause ischemia-reperfusion (IR) injury, driven by reactive oxygen species (ROSs), which exacerbate cell death and tissue damage. This study introduces a mathematical model capturing key post-MI dynamics, including inflammatory responses, IR injury, cardiac remodeling, and stem cell therapy. The model uses nonlinear ordinary differential equations to simulate these processes under varying conditions, offering a predictive tool to understand MI pathophysiology better and optimize treatments.

After myocardial infarction (MI), left ventricular remodeling progresses through three distinct yet interconnected phases. The first phase captures the immediate dynamics following MI, prior to any medical intervention. This stage is mathematically modeled using the system of ordinary differential equations: The second and third stages of the remodeling process account for the system dynamics of medical treatments, including oxygen restoration and subsequent stem cell injection at the injury site.

We simulate heart tissue and immune cell dynamics over 30 days for mild and severe MI using the novel mathematical model under medical treatment. The treatment involves no intervention until 2 h post-MI, followed by oxygen restoration and stem cell injection at day 7, which is shown experimentallyand numerically to be optimal. The simulation incorporates a baseline ROS threshold (Rc) where subcritical ROS levels do not cause cell damage.

This study presents a novel mathematical model that extends a previously published framework by incorporating three clinically relevant parameters: oxygen restoration rate (ω), patient risk factors (γ), and neutrophil recruitment profile (δ). The model accounts for post-MI inflammatory dynamics, ROS-mediated ischemia-reperfusion (IR) injury, cardiac remodeling, and stem cell therapy. The model's sensitivity highlights critical clinical insights: while oxygen restoration is vital, excessive rates may exacerbate ROS-driven IR injury. Additionally, heightened patient risk factors (e.g., smoking, obesity) and immunodeficiency significantly impact tissue damage and recovery. This predictive tool offers valuable insights into MI pathology and aids in optimizing treatment strategies to mitigate IR injury and improve post-MI outcomes.

After prolonged space operations, astronauts showed maladaptive atrophy within mostly left-ventricular myocardium, resulting in cardiac dysfunction. However, the mechanism of cardiac dysfunction under microgravity conditions is unclear, and the relevant prevention and treatment measures also need to be explored. Through simulating the microgravity environment with a tail suspension (TS) model, we found that long-term exposure to microgravity promotes aging of mouse hearts, which is closely related to cardiac dysfunction. The intravenous administration of adipose-derived mesenchymal stem cells (ADSCs) emerged preventive and therapeutic effect against myocardial senescence and the decline in cardiac function. Plasma metabolomics analysis suggests the loss of NAD+ in TS mice and motivated myocardial NAD + metabolism and utilization in ADSCs-treated mice, likely accounting for ADSCs' function. Oral administration of nicotinamide mononucleotide (NMN, a NAD + precursor) showed similar therapeutic effect to ADSCs treatment. Collectively, these data implicate the effect of ADSCs in microgravity-induced cardiac dysfunction and provide new therapeutic ideas for aging-related maladaptive cardiac remodeling.

Mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) are a promising treatment for myocardial infarction (MI), but their therapeutic efficacy is limited by inefficient accumulation at the target site. A minimally invasive MSC EV therapy that enhances EV accumulation at the disease site and extends EV retention could significantly improve post-infarct cardiac regeneration. Here, we show that EVs decorated with the next-generation of high-affinity (HiA) heterodimerizing leucine zippers, termed HiA Zippersomes, amplify targetable surface areas through in situ crosslinking and exhibited ~7-fold enhanced accumulation within the infarcted myocardium in mice after 3 days and continued to be retained up to Day 21, surpassing the performance of unmodified EVs. After MI in mice, HiA Zippersomes increase the ejection fraction by 53% and 100% compared with unmodified EVs and phosphate-buffered saline (PBS), respectively. This notable improvement in cardiac function played a crucial role in restoring healthy heart performance. HiA Zippersomes also robustly decrease infarct size by 52% and 60% compared with unmodified EVs and PBS, respectively, thus representing a promising platform for minimally invasive vesicle delivery to the infarcted heart compared to intramyocardial injections.

Cardiac fibrosis is a significant driver of congestive heart failure, a syndrome that continues to affect a growing patient population globally. Cardiac fibrosis results from a constellation of complex processes at the transcription, receptor, and signaling axes levels. Various mediators and signaling cascades, such as the transformation growth factor-beta pathway, have been implicated in the pathophysiology of cardiac tissue fibrosis. Our understanding of these markers and pathways has improved in recent years as more advanced technologies and assays have been developed, allowing for better delineation of the crosstalk between specific factors. There is mounting evidence suggesting that epigenetic modulation plays a pivotal role in the progression of cardiac fibrosis. Transcriptional regulation of key pro- and antifibrotic pathways can accentuate or blunt the rate and extent of fibrosis at the tissue level. Exosomes, micro-RNAs, and long noncoding RNAs all belong to factors that can impact the epigenetic signature in cardiac fibrosis. Herein, we comprehensively review the latest literature about exosomes, their contents, and cardiac fibrosis. In doing so, we highlight the specific transcriptional factors with pro- or antifibrotic properties. We also assimilate the data supporting these mediators' potential utility as diagnostic or prognostic biomarkers. Finally, we offer insight into where further work can be done to fill existing gaps to translate preclinical findings better and improve clinical outcomes.

Myocardial infarction (MI) remains a leading cause of mortality worldwide. Despite patients with MI benefit from timely reperfusion therapies, the rates of mortality and morbidity remain substantial, suggesting an enduring need for the development of new approaches. Molecular mechanisms underlying myocardial ischemic injury are associated with both cardiomyocytes and non-cardiomyocytes. Exosomes are nano-sized extracellular vesicles released by almost all eukaryotic cells. They facilitate the communication between various cells by transferring information via their cargo and altering different biological activities in recipient cells. Studies have created great prospects for therapeutic applications of exosomes in MI, as demonstrated through their beneficial effect on heart function and reducing ventricular remodeling in association with fibrosis, angiogenesis, apoptosis, and inflammation. Of note, myocardial ischemic injury is primarily due to restricted blood flow, reducing oxygen availability, and causing inefficient utilization of energy substrates. However, the impact of exosomes on cardiac energy metabolism has not been adequately investigated. Although exosomes have been engineered for targeted delivery to enhance clinical efficacy, challenges must be overcome to utilize them reliably in the clinic. In this review, we summarize the research progress of exosomes for MI with a focus on the known and unknown regarding the role of exosomes in energy metabolism in cardiomyocytes and non-cardiomyocytes; as well as potential research avenues of exosome-mitochondrial energy regulation as well as therapeutic challenges. We aim to help identify more efficient molecular targets that may promote the clinical application of exosomes.

Cell therapy can protect cardiomyocytes from hypoxia, primarily via paracrine secretions, including extracellular vesicles (EVs). Since EVs fulfil specific biological functions based on their cellular origin, we hypothesised that EVs from human cardiac stromal cells (CMSCLCs) obtained from coronary artery bypass surgery may have cardioprotective properties.

This study characterises CMSCLC EVs (C_EVs), miRNA cargo, cardioprotective efficacy and transcriptomic modulation of hypoxic human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). C_EVs are compared to bone marrow mesenchymal stromal cell EVs (B_EVs) which are a known therapeutic EV type.

Cells were characterised for surface markers, gene expression and differentiation potential. EVs were compared for yield, phenotype, and ability to protect hiPSC-CMs from hypoxia/reoxygenation injury. EV dose was normalised by both protein concentration and particle count, allowing direct comparison. C_EV and B_EV miRNA cargo was profiled and RNA-seq was performed on EV-treated hypoxic hiPSC-CMs, then data were integrated by multi-omics. Confirmatory experiments were carried out using miRNA mimics.

At the same dose, C_EVs were more effective than B_EVs at protecting CM integrity, reducing apoptotic markers, and cell death during hypoxia. While C_EVs and B_EVs shared 70-77% similarity in miRNA content, C_EVs contained unique miRNAs, including miR-202-5p, miR-451a and miR-142-3p. Delivering miRNA mimics confirmed that miR-1260a and miR-202/451a/142 were cardioprotective, and the latter upregulated protective pathways similar to whole C_EVs.

This study demonstrates the potential of cardiac tissues, routinely discarded following surgery, as a valuable source of EVs for myocardial infarction therapy. We also identify miR-1260a as protective of CM hypoxia.

Acid-sensing ion channel 1 (ASIC1) is critical in acidotoxicity and significantly contributes to neuronal death in cerebral stroke. Pharmacological inhibition of ASIC1 has been shown to reduce neuronal death. However, the potential of utilizing exosomes derived from pluripotent stem cells to achieve inhibition of Asic1 remains to be explored. Developing qualified exosome products with precise and potent active ingredients suitable for clinical application is also ongoing. Here, we adopt small RNA-seq to interrogate the miRNA contents in exosomes of pluripotent stem cell induced mesenchymal stem cell (iMSC). RNA-seq was used to compare the oxygen-glucose deprivation-damaged neurons before and after the delivery of exosomes. We used Western blot to quantify the Asic1 protein abundance in neurons before and after exosome treatment. An in vivo test on rats validated the neuroprotective effect of iMSC-derived exosome and its active potent miRNA hsa-mir-125b-5p. We demonstrate that pluripotent stem cell-derived iMSCs produce exosomes with consistent miRNA contents and sustained expression. These exosomes efficiently rescue injured neurons, alleviate the pathological burden, and restore neuron function in rats under oxygen-glucose deprivation stress. Furthermore, we identify hsa-mir-125b-5p as the active component responsible for inhibiting the Asic1a protein and protecting neurons. We validated a novel therapeutic strategy to enhance acidosis resilience in cerebral stroke by utilizing exosomes derived from pluripotent stem cells with specific miRNA content. This holds promise for cerebral stroke treatment with the potential to reduce neuronal damage and improve clinical patient outcomes.

Myocardial infarction (MI) is a major cause of mortality and morbidity worldwide. The intercellular communication in post-infarction angiogenesis remains unclear.

In this study, we explored the role and mechanism of action of M2 macrophage-derived exosomes (M2-exos) in angiogenesis after MI. M2-exos were harvested and injected intramyocardially at the onset of MI. Two distinct endothelial cells (ECs) were cultured with M2-exos to explore the direct effects on angiogenesis.

We showed that M2-exos improved cardiac function, reduced infarct size, and enhanced angiogenesis after MI. Moreover, M2-exos promoted angiogenesis in vitro; the molecules loaded in the vesicles were responsible for its proangiogenic effects. We further validated that higher abundance of miR-132-3p in M2-exos, which recapitulate their functions, was required for the cardioprotective effects exerted by M2-exos. Mechanistically, miR-132-3p carried by M2-exos down-regulate the expression of THBS1 through direct binding to its 3´UTR and the proangiogenic effects of miR-132-3p were largely reversed by THBS1 overexpression.

Our findings demonstrate that M2-exos promote angiogenesis after MI by transporting miR-132-3p to ECs, and by binding to THBS1 mRNA directly and negatively regulating its expression. These findings highlight the role of M2-exos in cardiac repair and provide novel mechanistic understanding of intercellular communication in post-infarction angiogenesis.

Heart failure is a root cause of morbidity and mortality worldwide. Due to the limited regenerative capacity of the heart following myocardial injury, stem cell-based therapies have been considered a hopeful approach for improving cardiac regeneration. In recent years, different kinds of cell products have been investigated regarding their potential to treat patients with heart failure. Despite special attention to cell therapy and its products, therapeutic efficacy has been disappointing, and clinical application is not affordable. In the past few years, a subset of small extracellular vehicles (EVs), commonly known as "exosomes," was reported to grant regenerative and cardioprotective signals at a value similar to their donor cells. The conceptual advantage is that they may be ideally used without evoking a relevant recipient immune response or other adverse effects associated with viable cells. The evidence related to their beneficial effects in animal models of heart failure is rapidly growing. However, there is remarkable heterogeneity regarding source cells, isolation process, effective dosage, and delivery mode. This brief review will focus on the latest research and debates on regenerative potential and cardiac repair of exosomes from different sources, such as cardiac/non-cardiac stem, somatic cells, and progenitor cells. Overall, the current state of research on exosomes as an experimental therapy for heart diseases will be discussed.

Ischemic heart disease (IHD) is a leading cause of disability and death worldwide, with immune regulation playing a crucial role in its pathogenesis. Various immune cells are involved, and as one of the key immune cells residing in the heart, macrophages play an indispensable role in the inflammatory and reparative processes during cardiac ischemia. Exosomes, extracellular vesicles containing lipids, nucleic acids, proteins, and other bioactive molecules, have emerged as important mediators in the regulatory functions of macrophages and hold promise as a novel therapeutic target for IHD. This review summarizes the regulatory mechanisms of different subsets of macrophages and their secreted exosomes during cardiac ischemia over the past five years. It also discusses the current status of clinical research utilizing macrophages and their exosomes, as well as strategies to enhance their therapeutic efficacy through biotechnology. The aim is to provide valuable insights for the treatment of IHD.

Cardiac repair remains a thorny issue for survivors of acute myocardial infarction (AMI), due to the regenerative inertia of myocardial cells. Cell-free therapies, such as exosome transplantation, have become a potential strategy for myocardial injury. The aim of this study was to investigate the role of engineered exosomes in overexpressing Growth Differentiation Factor-15 (GDF-15) (GDF15-EVs) after myocardial injury, and their molecular mechanisms in cardiac repair.

H9C2 cells were transfected with GDF-15 lentivirus or negative control. The exosomes secreted from H9C2 cells were collected and identified. The cellular apoptosis and autophagy of H2O2-injured H9C2 cells were assessed by Western blotting, TUNEL assay, electron microscopy, CCK-8 and caspase 3/7 assay. A rat model of AMI was constructed by ligating the left anterior descending artery. The anti-apoptotic, pro-angiogenic effects of GDF15-EVs treatment, as well as ensuing functional and histological recovery were evaluated. Then, mRNA sequencing was performed to identify the differentially expressed mRNAs after GDF15-EVs treatment.

GDF15-EVs inhibited apoptosis and promoted autophagy in H2O2 injured H9C2 cells. GDF15-EVs effectively decreased the infarct area and enhanced the cardiac function in rats with AMI. Moreover, GDF15-EVs hindered inflammatory cell infiltration, inhibited cell apoptosis, and promoted cardiac angiogenesis in rats with AMI. RNA sequence showed that telomerase reverse transcriptase (TERT) mRNA was upregulated in GDF15-EVs-treated H9C2 cells. AMPK signaling was activated after GDF15-EVs. Silencing TERT impaired the protective effects of GDF15-EVs on H2O2-injured H9C2 cells.

GDF15-EVs could fulfil their protective effects against myocardial injury by upregulating the expression of TERT and activating the AMPK signaling pathway. GDF15-EVs might be exploited to design new therapies for AMI.

Cardiovascular diseases (CVDs) continue to be a significant global health concern. Many studies have reported promising outcomes from using MSCs and their secreted exosomes in managing various cardiovascular-related diseases like myocardial infarction (MI). MSCs and exosomes have demonstrated considerable potential in promoting regeneration and neovascularization, as well as exerting beneficial effects against apoptosis, remodeling, and inflammation in cases of myocardial infarction. Nonetheless, ensuring the durability and effectiveness of MSCs and exosomes following in vivo transplantation remains a significant concern. Recently, novel methods have emerged to improve their effectiveness and robustness, such as employing preconditioning statuses, modifying MSC and their exosomes, targeted drug delivery with exosomes, biomaterials, and combination therapy. Herein, we summarize the novel approaches that intensify the therapeutic application of MSC and their derived exosomes in treating MI.

Acute myocardial infarction (AMI) is the leading cause of cardiovascular death and remains the most common cause of heart failure. Reopening of the occluded artery, i.e., reperfusion, is the only way to save the myocardium. However, the expected benefits of reducing infarct size are disappointing due to the reperfusion paradox, which also induces specific cell death. These ischemia-reperfusion (I/R) lesions can account for up to 50% of final infarct size, a major determinant for both mortality and the risk of heart failure (morbidity). In this review, we provide a detailed description of the cell death and inflammation mechanisms as features of I/R injury and cardioprotective strategies such as ischemic postconditioning as well as their underlying mechanisms. Due to their biological properties, the use of mesenchymal stromal/stem cells (MSCs) has been considered a potential therapeutic approach in AMI. Despite promising results and evidence of safety in preclinical studies using MSCs, the effects reported in clinical trials are not conclusive and even inconsistent. These discrepancies were attributed to many parameters such as donor age, in vitro culture, and storage time as well as injection time window after AMI, which alter MSC therapeutic properties. In the context of AMI, future directions will be to generate MSCs with enhanced properties to limit cell death in myocardial tissue and thereby reduce infarct size and improve the healing phase to increase postinfarct myocardial performance.

Ischemic heart disease, a leading cause of death worldwide, manifests clinically as myocardial infarction. Contemporary therapies using mesenchymal stromal cells (MSCs) and their derivative (exosomes, EXOs) were developed to decrease the progression of cell damage during ischemic injury. Laminin alpha 2 (LAMA2) is an important extracellular matrix protein of the heart. Here, we generated MSC-derived exosomes cultivated under LAMA2 coating to enhance human-induced pluripotent stem cell (hiPSC)-cardiomyocyte recognition of LAMA2-EXOs, thus, increasing cell protection during ischemia reoxygenation. We mapped the mRNA content of LAMA2 and gelatin-EXOs and identified 798 genes that were differentially expressed, including genes associated with cardiac muscle development and extracellular matrix organization. Cells were treated with LAMA2-EXOs 2 h before a 4 h ischemia period (1% O2, 5% CO2, glucose-free media). LAMA2-EXOs had a two-fold protective effect compared to non-treatment on plasma membrane integrity and the apoptosis activation pathway; after a 1.5 h recovery period (20% O2, 5% CO2, cardiomyocyte-enriched media), cardiomyocytes treated with LAMA2-EXOs showed faster recovery than did the control group. Although EXOs had a protective effect on endothelial cells, there was no LAMA2-enhanced protection on these cells. This is the first report of LAMA2-EXOs used to treat cardiomyocytes that underwent ischemia-reoxygenation injury. Overall, we showed that membrane-specific EXOs may help improve cardiomyocyte survival in treating ischemic cardiovascular disease.

Mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) are a promising treatment for myocardial infarction, but their therapeutic efficacy is limited by inefficient accumulation at the target site. A non-invasive MSC EV therapy that enhances EV accumulation at the disease site and extends EV retention could significantly improve post-infarct cardiac regeneration. Here we show that EVs decorated with the next-generation of high-affinity heterodimerizing leucine zippers, termed high-affinity (HiA) Zippersomes, amplify targetable surface areas through in situ crosslinking and exhibited ∼7-fold enhanced accumulation within the infarcted myocardium in mice after three days and continued to be retained up to day 21, surpassing the performance of unmodified EVs. After myocardial infarction in mice, high-affinity Zippersomes increase the ejection fraction by 53% and 100% compared with unmodified EVs and PBS, respectively. This notable improvement in cardiac function played a crucial role in restoring healthy heart performance. High-affinity Zippersomes also robustly decrease infarct size by 52% and 60% compared with unmodified EVs and PBS, respectively, thus representing a promising platform for non-invasive vesicle delivery to the infarcted heart.

Therapeutic delivery to the heart remains inefficient and poses a bottleneck in modern drug delivery. Surgical application and intramyocardial injection of therapeutics carry high risks for most heart attack patients. To address these limitations, we have developed a non-invasive strategy for efficient cardiac accumulation of therapeutics using in situ crosslinking. Our approach achieves high cardiac deposition of therapeutics without invasive intramyocardial injections. Patients admitted with myocardial infarction typically receive intravenous access, which would allow painless administration of Zippersomes alongside standard of care.

Myocardial infarction (MI) is the leading cause of heart failure (HF), accounting for high mortality and morbidity worldwide. As a consequence of ischemia/reperfusion injury during MI, multiple cellular processes such as oxidative stress-induced damage, cardiomyocyte death, and inflammatory responses occur. In the next stage, the proliferation and activation of cardiac fibroblasts results in myocardial fibrosis and HF progression. Therefore, developing a novel therapeutic strategy is urgently warranted to restrict the progression of pathological cardiac remodeling. Recently, targeting long non-coding RNAs (lncRNAs) provided a novel insight into treating several disorders. In this regard, numerous investigations have indicated that several lncRNAs could participate in the pathogenesis of MI-induced cardiac remodeling, suggesting their potential therapeutic applications. In this review, we summarized lncRNAs displayed in the pathophysiology of cardiac remodeling after MI, emphasizing molecular mechanisms. Also, we highlighted the possible translational role of lncRNAs as therapeutic targets for this condition and discussed the potential role of exosomes in delivering the lncRNAs involved in post-MI cardiac remodeling.

This study delves into the role of FBLN5 in pelvic organ prolapse (POP) and its molecular mechanisms, focusing on the FOSL1/miR-222/MEIS1/COL3A1 axis. Gene relationships linked to POP were confirmed using bioinformatics databases like GEO and StarBase. Primary human uterosacral ligament fibroblasts (hUSLF) were extracted and subjected to mechanical stretching. Cellular cytoskeletal changes were examined via phalloidin staining, intracellular ROS levels with a ROS kit, cell apoptosis through flow cytometry, and cell senescence using β-galactosidase staining. FBLN5's downstream targets were identified, and the interaction between FOSL1 and miR-222 and miR-222 and MEIS1 were validated using assays. In rat models, the role of FBLN5 in POP was assessed using bladder pressure tests. Results indicated diminished FBLN5 expression in uterine prolapse. Enhanced FBLN5 countered mechanical damage in hUSLF cells by downregulating FOSL1. FOSL1 augmented miR-222, inhibiting MEIS1, which subsequently fostered COL3A1 transcription. In rat models, the absence of FBLN5 exacerbated POP by influencing the FOSL1/miR-222/MEIS1/COL3A1 pathway. FBLN5's protective role likely involves regulating the above axis and boosting COL3A1 expression. Further research is needed to validate the effectiveness and safety of this mechanism in human patients and to propose potential new treatment options.

Exosomes are nanoscale extracellular vesicles secreted by cells and enclosed by a lipid bilayer membrane containing various biologically active cargoes such as proteins, lipids, and nucleic acids. Engineered exosomes generated through genetic modification of parent cells show promise as drug delivery vehicles, and they have been demonstrated to have great therapeutic potential for treating cancer, cardiovascular, neurological, and immune diseases, but systematic knowledge is lacking regarding optimization of drug loading and assessment of delivery efficacy. This review summarizes current approaches for engineering exosomes and evaluating their drug delivery effects, and current techniques for assessing exosome drug loading and release kinetics, cell targeting, biodistribution, pharmacokinetics, and therapeutic outcomes are critically examined. Additionally, this review synthesizes the latest applications of exosome engineering and drug delivery in clinical translation. The knowledge compiled in this review provides a framework for the rational design and rigorous assessment of exosomes as therapeutics. Continued advancement of robust characterization methods and reporting standards will accelerate the development of exosome engineering technologies and pave the way for clinical studies.

Heart diseases are the primary cause of mortality and morbidity worldwide which inflict a heavy social and economic burden. Among heart diseases, most deaths are due to myocardial infarction (MI) or heart attack, which occurs when a decrement in blood flow to the heart causes injury to cardiac tissue. Despite several available diagnostic, therapeutic, and prognostic approaches, heart disease remains a significant concern. Exosomes are a kind of small extracellular vesicles released by different types of cells that play a part in intercellular communication by transferring bioactive molecules important in regenerative medicine. Many studies have reported the diagnostic, therapeutic, and prognostic role of exosomes in various heart diseases. Herein, we reviewed the roles of exosomes as new emerging agents in various types of heart diseases, including ischemic heart disease, cardiomyopathy, arrhythmia, and valvular disease, focusing on pathogenesis, therapeutic, diagnostic, and prognostic roles in different areas. We have also mentioned different routes of exosome delivery to target tissues, the effects of preconditioning and modification on exosome's capability, exosome production in compliance with good manufacturing practice (GMP), and their ongoing clinical applications in various medical contexts to shed light on possible clinical translation.

The integration of abiotic materials with live cells has emerged as an exciting strategy for the control of cellular functions. Exoskeletons consisting ofmetal-organic frameworks are generated to produce partial-coated bone marrow stem cells (BMSCs) to overcome low cell survival leading to disappointing effects for cell-based cardiac therapy. Partially coated exoskeletons can promote the survival of suspended BMSCs by integrating the support of exoskeletons and unimpaired cellular properties. In addition, partial exoskeletons exhibit protective effects against detrimental environmental conditions, including reactive oxygen species, pH changes, and osmotic pressure. The partial-coated cells exhibit increased intercellular adhesion forces to aggregate and adhere, promoting cell survival and preventing cell escape during cell therapy. The exoskeletons interact with cell surface receptors integrin α5β1, leading to augmented biological functions with profitable gene expression alteration, such as Vegfa, Cxcl12, and Adm. The partial-coated BMSCs display enhanced cell retention in infarcted myocardium through non-invasive intravenous injections. The repair of myocardial infarction has been achieved with improved cardiac function, myocardial angiogenesis, proliferation, and inhibition of cell apoptosis. This discovery advances the elucidation of potential molecular and cellular mechanisms for cell-exoskeleton interactions and benefits the rational design and manufacture of next-generation nanobiohybrids.

Recently, ex-vivo gene therapy has emerged as a promising approach to enhance the therapeutic potential of mesenchymal stem cells (MSCs) by introducing functional genes in vitro. Here, we explored the need of using selection markers to increase the gene delivery efficiency and evaluated the potential risks associated with their use in the manufacturing process. We used MSCs/CD that carry the cytosine deaminase gene (CD) as a therapeutic gene and a puromycin resistance gene (PuroR) as a selection marker. We evaluated the correlation between the therapeutic efficacy and the purity of therapeutic MSCs/CD by examining their anti-cancer effect on co-cultured U87/GFP cells. To simulate in vivo horizontal transfer of the PuroR gene in vivo, we generated a puromycin-resistant E. coli (E. coli/PuroR) by introducing the PuroR gene and assessed its responsiveness to various antibiotics. We found that the anti-cancer effect of MSCs/CD was directly proportional to their purity, suggesting the crucial role of the PuroR gene in eliminating impure unmodified MSCs and enhancing the purity of MSCs/CD during the manufacturing process. Additionally, we found that clinically available antibiotics were effective in inhibiting the growth of hypothetical microorganism, E. coli/PuroR. In summary, our study highlights the potential benefits of using the PuroR gene as a selection marker to enhance the purity and efficacy of therapeutic cells in MSC-based gene therapy. Furthermore, our study suggests that the potential risk of horizontal transfer of antibiotics resistance genes in vivo can be effectively managed by clinically available antibiotics.

The morbidity and mortality of myocardial infarction (MI) are increasing worldwide. Mesenchymal stem cells (MSCs) are multipotent stem cells with self-renewal and differentiation capabilities that are essential in tissue healing and regenerative medicine. However, the low implantation and survival rates of transplanted cells hinder the widespread clinical use of stem cells. Exosomes are naturally occurring nanovesicles that are secreted by cells and promote the repair of cardiac function by transporting noncoding RNA and protein. In recent years, MSC-derived exosomes have been promising cell-free treatment tools for improving cardiac function and reversing cardiac remodeling. This review describes the biological properties and therapeutic potential of exosomes and summarizes some engineering approaches for exosomes optimization to enhance the targeting and therapeutic efficacy of exosomes in MI.

The World Health Organization reports that cardiovascular diseases (CVDs) represent 32% of all global deaths. The ineffectiveness of conventional therapies in CVDs encourages the development of novel, minimally invasive therapeutic strategies for the healing and regeneration of damaged tissue. The self-renewal capacity, multilineage differentiation, lack of immunogenicity, and immunosuppressive properties of mesenchymal stem cells (MSCs) make them a promising option for CVDs. However, growing evidence suggests that myocardial regeneration occurs through paracrine factors and extracellular vesicle (EV) secretion, rather than through differentiation into cardiomyocytes. Research shows that stem cells secrete or surface-shed into their culture media various cytokines, chemokines, growth factors, anti-inflammatory factors, and EVs, which constitute an MSC-conditioned medium (MSC-CM) or the secretome. The use of MSC-CM enhances cardiac repair through resident heart cell differentiation, proliferation, scar mass reduction, a decrease in infarct wall thickness, and cardiac function improvement comparable to MSCs without their side effects. This review highlights the limitations and benefits of therapies based on stem cells and their secretome as an innovative treatment of CVDs.

Atrial fibrillation (AF) is the most frequent arrhythmia, and myocardial fibrosis (MF) has a close association with atrial remodeling and leads to AF. This study aimed to explore the function of the long non-coding RNA (lncRNA) differentiation antagonizing non-protein coding RNA (Dancr)/microRNA (miR)-146b-5p/Smad5 axis on MF in AF mice.

AF mouse models were established. Overexpression Dancr lentivirus was injected into AF mice to increase Dancr expression in myocardial tissues. LncRNA Dancr, miR-146b-5p, and Smad5 expression levels and inflammatory factors (IL-18 and TNF-α) in the myocardial tissues were measured. MF was measured and the expression levels of MF-related genes (COL1A1, α-SMA, and FN1) were detected. In addition, in vitro HL-1 cell rapid pacing models were constructed, and after lncRNA Dancr and miR-146b-5p-related construct transfection, cell viability and cell apoptosis were determined.

LncRNA Dancr up-regulation ameliorated MF in the AF mice, reduced IL-18 and TNF-α expression levels in myocardial tissues, and decreased COL1A1, α-SMA, and FN1 expression levels. The in vitro HL-1 cell rapid pacing models suggested that miR-146b-5p overexpression reversed the inhibitory effects of lncRNA Dancr overexpression on MF in HL-1 cells, and Smad5 interference reversed the ameliorative effects of miR-146b-5p interference on MF in HL-1 cells.

LncRNA Dancr can sponge miR-146b-5p to promote Smad5 expression, thereby delaying MF in AF mice.

Exosomes, mainly derived from mesenchymal stem cells, provide a good reference for cardiac function repair and clinical application in cardiac and vascular diseases by regulating cardiomyocyte viability, inflammatory levels, angiogenesis, and ventricular remodeling after a heart injury. This review presents the cardioprotective efficacy of mesenchymal stem cell-originated exosomes and explores the underlying molecular mechanisms. Furthermore, we expound on several efficient approaches to transporting exosomes into the heart in clinical application and comment on the advantages and disadvantages of each method.

Oxidative stress-induced myocardial apoptosis and necrosis are critically involved in ischemic infarction, and several sources of extracellular vesicles appear to be enriched in therapeutic activities. The central objective was to identify and validate the differential exosome miRNA repertoire in human cardiac progenitor cells (CPC). CPC exosomes were first analyzed by LC-MS/MS and compared by RNAseq with exomes of human mesenchymal stromal cells and human fibroblasts to define their differential exosome miRNA repertoire (exo-miRSEL). Proteomics demonstrated a highly significant representation of cardiovascular development functions and angiogenesis in CPC exosomes, and RNAseq analysis yielded about 350 different miRNAs; among the exo-miRSEL population, miR-935 was confirmed as the miRNA most significantly up-regulated; interestingly, miR-935 was also found to be preferentially expressed in mouse primary cardiac Bmi1+high CPC, a population highly enriched in progenitors. Furthermore, it was found that transfection of an miR-935 antagomiR combined with oxidative stress treatment provoked a significant increment both in apoptotic and necrotic populations, whereas transfection of a miR-935 mimic did not modify the response. Conclusion. miR-935 is a highly differentially expressed miRNA in exo-miRSEL, and its expression reduction promotes oxidative stress-associated apoptosis. MiR-935, together with other exosomal miRNA members, could counteract oxidative stress-related apoptosis, at least in CPC surroundings.

Acute myocardial infarction has long been the leading cause of death in coronary heart disease, which is characterized by irreversible cardiomyocyte death and restricted blood supply. Conventional reperfusion therapy can further aggravate myocardial injury. Stem cell therapy, especially with mesenchymal stem cells (MSCs), has emerged as a promising approach to promote cardiac repair and improve cardiac function. MSCs may induce these effects by secreting exosomes containing therapeutically active RNA, proteins and lipids. Notably, normal cardiac function depends on intracardiac paracrine signaling via exosomes, and exosomes secreted by cardiac cells can partially reflect changes in the heart during disease, so analyzing these vesicles may provide valuable insights into the pathology of myocardial infarction as well as guide the development of new treatments. The present review examines how exosomes produced by MSCs and cardiac cells may influence injury after myocardial infarction and serve as therapies against such injury. Video Abstract.

Bone marrow mesenchymal stem cell (BMSC)-derived exosomes have been verified to perform an effective role in treating acute myocardial infarction (MI). Herein, we aimed to investigate the role of BMSC-derived exosomes carrying itchy E3 ubiquitin ligase (ITCH) in MI and the underlying mechanism involved.

BMSCs were isolated from rat bone marrow and exosomes were extracted using ultra-high speed centrifugation. Exosomes uptake by cardiomyoblasts was determined by PKH-67 staining. Rat cardiomyoblast cell line H9C2 was stimulated by hypoxia, as in vitro model. H9C2 cell apoptosis was determined by flow cytometry. Cell viability was examined by cell counting kit-8 assay. Western blotting was performed to determine the expression of ITCH, apoptosis signal-regulated kinase-1 (ASK1), and apoptotic-related protein cleaved-caspase 3 and Bcl-2. Ubiquitination assay was employed to measure the levels of ASK1 ubiquitination.

Exosomes derived from BMSCs were endocytosed by H9C2 cardiomyoblasts. BMSC-Exo downregulated cleaved-caspase 3 expression, upregulated Bcl-2 expression, further suppressed H9C2 cell apoptosis under hypoxia treatment, meanwhile the expression of ASK1 was downregulated, and similar effects were observed in BMSC-cultured supernatant (BMSC-S). However, these effects were reversed by exosome inhibitor GW4869. BMSC-derived exosomes enhanced ASK1 ubiquitination and degradation. Mechanically, exosomes of ITCH-knockdown BMSCs promoted H9C2 cell apoptosis and upregulated ASK1 expression. Overexpression of ITCH enhanced ASK1 ubiquitination and degradation. Further, the protein expression of ASK1 and cleaved-caspase 3 was upregulated and Bcl-2 protein expression was downregulated. ITCH-knockdown BMSC exosomes increased cardiomyoblast apoptosis.

BMSC-derived exosomes carrying ITCH suppressed cardiomyoblast apoptosis, promoted cardiomyoblast viability, and improved myocardial injury in AMI by mediating ASK1 ubiquitination.

Extracellular vesicles (EVs) derived from bone marrow mesenchymal stem cells (MSCs) pretreated with atorvastatin (ATV) (MSCATV-EV) have a superior cardiac repair effect on acute myocardial infarction (AMI). The mechanisms, however, have not been fully elucidated. This study aims to explore whether inflammation alleviation of infarct region via macrophage polarization plays a key role in the efficacy of MSCATV-EV.

MSCATV-EV or MSC-EV were intramyocardially injected 30 min after coronary ligation in AMI rats. Macrophage infiltration and polarization (day 3), cardiac function (days 0, 3, 7, 28), and infarct size (day 28) were measured. EV small RNA sequencing and bioinformatics analysis were conducted for differentially expressed miRNAs between MSCATV-EV and MSC-EV. Macrophages were isolated from rat bone marrow for molecular mechanism analysis. miRNA mimics or inhibitors were transfected into EVs or macrophages to analyze its effects on macrophage polarization and cardiac repair in vitro and in vivo.

MSCATV-EV significantly reduced the amount of CD68+ total macrophages and increased CD206+ M2 macrophages of infarct zone on day 3 after AMI compared with MSC-EV group (P < 0.01-0.0001). On day 28, MSCATV-EV much more significantly improved the cardiac function than MSC-EV with the infarct size markedly reduced (P < 0.05-0.0001). In vitro, MSCATV-EV also significantly reduced the protein and mRNA expressions of M1 markers but increased those of M2 markers in lipopolysaccharide-treated macrophages (P < 0.05-0.0001). EV miR-139-3p was identified as a potential cardiac repair factor mediating macrophage polarization. Knockdown of miR-139-3p in MSCATV-EV significantly attenuated while overexpression of it in MSC-EV enhanced the effect on promoting M2 polarization by suppressing downstream signal transducer and activator of transcription 1 (Stat1). Furthermore, MSCATV-EV loaded with miR-139-3p inhibitors decreased while MSC-EV loaded with miR-139-3p mimics increased the expressions of M2 markers and cardioprotective efficacy.

We uncovered a novel mechanism that MSCATV-EV remarkably facilitate cardiac repair in AMI by promoting macrophage polarization via miR-139-3p/Stat1 pathway, which has the great potential for clinical translation.

The widespread use of therapeutic glucocorticoids has increased the incidences of glucocorticoid-induced osteoporosis (GIOP). Oxidative stress and mitochondrial dysfunction are major causes of GIOP; therefore, alleviation of excess oxidative stress in osteoblasts is a potential therapeutic strategy for osteoporosis. Exosomes derived from ADSCs (ADSCs-Exos), as novel cell-free therapeutics, can modulate various biological processes, such as immunomodulation, reduce oxidative damage, and promote tissue repair as well as regeneration. In this study, ADSCs-Exos restored the viability and osteogenic potential of MC3T3-E1 cells by attenuating apoptosis, oxidative damage, intracellular ROS generation, and mitochondrial dysfunction. Moreover, after pretreatment with ADSCs-Exos, Nrf2 expressions were upregulated in Dex-stimulated osteoblasts. Inhibitory assays showed that silencing Nrf2 partially eliminated the protective effects of ADSCs-Exos. The rat model assays confirmed that ADSCs-Exos alleviated the Dex-induced increase in oxidation levels, restored bone mass of the distal femur, and increased the expressions of Nrf2 and osteogenic markers in bone tissues. Thus, ADSCs-Exos alleviated apoptosis and oxidative stress by regulating Nrf2/HO-1 expressions after Dex and prevented the development of GIOP in vivo.

Mesenchymal stem cells (MSCs), as a kind of pluripotent stem cells, have attracted much attention in orthopedic diseases, geriatric diseases, metabolic diseases, and sports functions due to their osteogenic potential, chondrogenic differentiation ability, and adipocyte differentiation. Anti-inflammation, anti-fibrosis, angiogenesis promotion, neurogenesis, immune regulation, and secreted growth factors, proteases, hormones, cytokines, and chemokines of MSCs have been widely studied in liver and kidney diseases, cardiovascular and cerebrovascular diseases. In recent years, many studies have shown that the extracellular vesicles of MSCs have similar functions to MSCs transplantation in all the above aspects. Here we review the research progress of MSCs and their exocrine vesicles in recent years.

Exosomes, which contain miRNA, have been receiving growing attention in cardiovascular therapy because of their role in mediating cell-cell communication, autophagy, apoptosis, inflammation, and angiogenesis. Several studies have suggested that miRNA derived from exosomes can be used to detect myocardial infarctions (MI) in patients. Basic research also suggests that exosomes could serve as a potential therapeutic target for treating acute myocardial infarction. Ischemia/reperfusion (IR) injury is associated with adverse cardiac events after acute MI. We aim to review the potential benefits and mechanisms of exosomes in treating MI and IR injury.

Extracellular vesicles (EVs), acting as an important ingredient of intercellular communication through paracrine actions, have gained tremendous attention in the field of tissue engineering (TE). Moreover, these nanosized extracellular particles (30-140 nm) can be incorporated into biomaterials according to different principles to facilitate signal delivery in various regenerative processes directly or indirectly. Bioactive biomaterials as the carrier will extend the retention time and realize the controlled release of EVs, which further enhance their therapeutic efficiency in tissue regeneration. Herein, the basic biological characteristics of EVs are first introduced, and then their outstanding performance in exerting direct impacts on target cells in tissue regeneration as well as indirect effects on promoting angiogenesis and regulating the immune environment, due to specific functional components of EVs (nucleic acid, protein, lipid, etc.), is emphasized. Furthermore, different design ideas for suitable EV-loaded biomaterials are also demonstrated. In the end, this review also highlights the engineered strategies, which aim at solving the problems related to natural EVs such as highly heterogeneous functions, inadequate tissue targeting capabilities, insufficient yield and scalability, etc., thus promoting the therapeutic pertinence and clinical potential of EV-based approaches in TE.

While stem cell transplantation has emerged as a promising approach to improving wound healing outcomes, the application of stem cells to date has been limited by the poor survival and retention of these cells once transplanted. The survival, development, and migratory activity of transplanted cells can be improved through the use of three-dimensional (3D) culture systems. Here, a novel alginate microsphere-collage hydrogel (AMS-Col gel) 3D culture system was developed and found to improve human umbilical cord mesenchymal stem cell (hUCMSC) survival, permitting their sustained release so as to promote wound healing. Through hematoxylin and eosin staining and Masson's trichrome staining, the prepared hUCMSCs-AMS-Col gel was found to exhibit wound healing activity. On day 7 following the hUCMSCs-AMS-Col gel treatment of model wounds, improved collagen fiber deposition and re-epithelialization were evident, with complete epithelial regeneration as of day 14 and near-total wound healing was evident as of day 21. This hUCMSCs-AMS-Col gel was also associated with increased VEGF and FGF2 expression. Together, these data indicate that AMS-Col gels are a promising and novel form of 3D cell culture system capable of improving hUCMSC-mediated wound healing, highlighting the potential clinical utility of this regenerative strategy.