Cardiovascular diseases (CVDs) remain the leading cause of global mortality, with myocardial infarction (MI) and subsequent heart failure (HF) posing significant clinical challenges. Despite advancements in pharmacological and surgical interventions, the limited regenerative capacity of the adult human heart necessitates innovative therapeutic strategies. Stem cell-based therapies have emerged as a promising approach to cardiac regeneration, aiming to restore damaged myocardial tissue through cell replacement and paracrine-mediated repair mechanisms. This review provides a comprehensive overview of the current landscape of stem cell therapies for cardiac regeneration, focusing on the molecular mechanisms, cell types, delivery techniques, and recent clinical advancements. We highlight the roles of key signaling pathways, including NOTCH, PI3K/Akt, Wnt/β-catenin, Hippo/YAP, and MAPK, in regulating cardiomyocyte proliferation, angiogenesis, fibrosis, and inflammation. Additionally, we discuss the therapeutic potential of various stem cell types, such as mesenchymal stem cells (MSCs), cardiac progenitor cells (CPCs), induced pluripotent stem cells (iPSCs), and embryonic stem cells (ESCs), in promoting cardiac repair. Despite promising preclinical results, challenges such as low cell retention, immune rejection, and inconsistent clinical outcomes persist. Recent advancements in genetic engineering, and innovative delivery methods, including transendocardial and intracoronary injections, offer new avenues for enhancing therapeutic efficacy. This review underscores the need for further research to optimize stem cell-based therapies, improve clinical trial design, and translate these innovative approaches into effective treatments for heart disease. By addressing these challenges, stem cell therapy holds the potential to revolutionize cardiac regeneration and improve outcomes for patients with ischemic heart disease and heart failure.

Immune system plays a crucial role in the physiological and pathological regulation of the cardiovascular system. The exploration history and milestones of immune system in cardiovascular diseases (CVDs) have evolved from the initial discovery of chronic inflammation in atherosclerosis to large-scale clinical studies confirming the importance of anti-inflammatory therapy in treating CVDs. This progress has been facilitated by advancements in various technological approaches, including multi-omics analysis (single-cell sequencing, spatial transcriptome et al.) and significant improvements in immunotherapy techniques such as chimeric antigen receptor (CAR)-T cell therapy. Both innate and adaptive immunity holds a pivotal role in CVDs, involving Toll-like receptor (TLR) signaling pathway, nucleotide-binding oligomerization domain-containing proteins 1 and 2 (NOD1/2) signaling pathway, inflammasome signaling pathway, RNA and DNA sensing signaling pathway, as well as antibody-mediated and complement-dependent systems. Meanwhile, immune responses are simultaneously regulated by multi-level regulations in CVDs, including epigenetics (DNA, RNA, protein) and other key signaling pathways in CVDs, interactions among immune cells, and interactions between immune and cardiac or vascular cells. Remarkably, based on the progress in basic research on immune responses in the cardiovascular system, significant advancements have also been made in pre-clinical and clinical studies of immunotherapy. This review provides an overview of the role of immune system in the cardiovascular system, providing in-depth insights into the physiological and pathological regulation of immune responses in various CVDs, highlighting the impact of multi-level regulation of immune responses in CVDs. Finally, we also discuss pre-clinical and clinical strategies targeting the immune system and translational implications in CVDs.

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.

Conventional micro-concave systems have been proposed as effective methods for facile cell spheroid formation, culture. However, these systems face challenges in terms of ease of cell transplantation and a low cell survival rate in ischemic disease. We present a novel open/close type hydrogel micro-concave patch (OC) designed for in situ 3D cell spheroid formation, culture, and a transplantable system utilizing a 3D printed mold. Open-type patches were fabricated with a rigid hydrogel, while closed-type patches were prepared with a combination of swellable soft hydrogel and rigid hydrogel. The open-type concave was intended for cell spheroid formation and subsequent transplantation into the ischemic region. Conversely, the close-type concave allowed released cytokines from cell spheroids, which were located inside the concave, to promote survival of transplanted cell spheroid. We hypothesized that transplant of open-type cell spheroids, combined with the release of paracrine factors from close-type cell spheroids, could enhance therapeutic outcomes in ischemic regions. The OC was prepared using different concentration ratios of swellable polyacrylamide (PAAM) hydrogel through 3D printed micropillar mold. Additionally, PAAM was characterized to enhance the compactness of close-type 3D cell spheroids. Transplantation of OC improved the therapeutic effect in a rat cardiac infarction model compared to open-type patches.

Myocardial infarction (MI) is a predominant cause of morbidity and mortality globally. Therapeutic chemokines, such as stromal cell-derived factor 1α (SDF-1α), present a promising opportunity to treat the profibrotic remodeling post-MI if they can be delivered effectively to the injured tissue. However, direct injection of SDF-1α or physical entrapment in a hydrogel has shown limited efficacy. Here, we developed a sustained-release system consisting of SDF-1α loaded poly(lactic-co-glycolic acid) nanoparticles (PLGA NPs) and an injectable porcine cardiac decellularized extracellular matrix (cdECM) hydrogel. This system demonstrated a sustained release of SDF-1α over four weeks while there is one week release for SDF-1α directly encapsulated in the cdECM hydrogel during in vitro testing. The incorporation of PLGA NPs into the cdECM hydrogel significantly enhanced its mechanical properties, increasing the Young's modulus from 561 ± 228 kPa to 1007 ± 2 kPa and the maximum compressive strength from 639 ± 42 kPa to 1014 ± 101 kPa. This nanocomposite hydrogel showed good cell compatibility after 7 days of culture with H9C2 cells, while the released SDF-1α retained its bioactivity, as evidenced by its chemotactic effects in vitro. Furthermore, in vivo studies further highlighted its significant ability to promote angiogenesis in the infarcted area and improve cardiac function after intramyocardial injection. These results demonstrated the therapeutic potential of combining local release of SDF-1α with the cdECM hydrogel for MI treatment.

Mesenchymal stem cell (MSC) therapy for cardiovascular diseases has shown promise; however, sex-specific differences remain understudied. This scientometric analysis provides the first comprehensive overview of sex-specific differences in mesenchymal stem cell (MSC) therapy for cardiovascular diseases, spanning from 1947 to 2024.

We analyzed 61,029 publications using advanced bibliometric tools to identify research hotspots, publication trends, and collaborative networks.

A significant shift in research focus has been observed in the field of mesenchymal stem cell (MSC) therapy for cardiovascular diseases, transitioning from broad cardiovascular concepts in the 20th century to specialized sex-specific considerations in the 21st century. Furthermore, in the 21st-century research landscape, the formation of two distinct clusters for "male" and "female" in VOSviewer-generated network visualizations is highly important, emphasizing the growing recognition of sex-specific differences in MSC therapy responses and outcomes. This shift was accompanied by a marked increase in terminology related to sex-specific differences, with keywords like "genetic association" and "body mass index" forming distinct clusters in recent years.

This analysis underscores the critical need for sex-specific considerations in MSC therapy for cardiovascular disease. The emergence of distinct male and female clusters in research networks emphasizes the importance of tailoring approaches based on sex differences. Key areas identified for future investigation include the role of epigenetics in mediating sex-specific effects and the potential of sex-matched MSC-derived exosomes. These findings pave the way for more effective and personalized approaches in cardiovascular regenerative medicine, potentially leading to improved outcomes through sex-specific therapeutic strategies.

Despite the promising potential of stromal cell therapy in treating myocardial infarction (MI), its effectiveness is limited by poor cell retention and engraftment in ischemic environments. This study introduces a novel strategy that combines the preconditioning of human adipose-derived stromal cells (hADSCs) using OLED-based photobiomodulation (OPBM) and culturing these cells into 3D spheroids. The preconditioned 3D spheroids (APCS group) exhibit significantly enhanced angiogenic, arterialized, and tissue remodeling capabilities compared with those of traditional 2D cultures and non-preconditioned spheroids. In vivo transplantation of these spheroids into the border zone of infarcted area significantly improve cardiac function and reduce adverse remodeling by enhancing anti-fibrosis and angiogenesis including arterialization. The combined strategy with OPBM preconditioning and 3D spheroid culture system can enhance therapeutic potential of hADSCs with multiple paracrine effects for cardiac repair. This novel approach provides next generation of cell therapeutics to overcome the limitation of adult stromal cell therapy in patients with post-MI heart failure.

Stem cell-based therapies are an emerging treatment modality aimed at replenishing lost cardiomyocytes and improving myocardial function after cardiac injury. This review examines the current state of research on injectable stem cell therapies in the setting of cardiovascular disease given their relative simplicity and ability for deep myocardial tissue penetration. Various methods of cell delivery, ranging in level of invasiveness and procedural complexity, have been developed, and numerous cell types have been studied as potential sources of stem cells, each with distinct advantages and disadvantages. We discuss key challenges associated with this approach, including low stem cell retention after transplantation and the innovative biomolecular strategies that have been explored to address this issue. Overall, investigations into the application of stem cells toward cardiac regeneration remain predominantly in the preclinical stage with a number of small, early-phase clinical trials. However, continued scientific advancements in stem cell technology may provide transformative treatment options for patients with heart failure, offering improved survival and quality of life.

Exercise-conditioned mesenchymal stem cells (MSCs) may modulate immune responses and improve white adipose tissue (WAT) function. While MSCs are known to reduce inflammation, it remains unclear if exercise-stimulated MSCs can improve obesity-related dysfunctions. This study is the first to explore how exercise-conditioned MSCs may influence adipose tissue inflammation and remodeling in the context of obesity. MSCs were isolated from exercised- and sedentary donor mice, then cultured in vitro. After culture, MSCs were assessed for differentiation capacity and cytokine gene expression, including Il10, as indicators of immune modulation. Exercise-conditioned MSCs were then transplanted into obese recipient mice. Following transplantation, immune cell profiles, inflammatory markers, and adipocyte morphology in recipient WAT were analyzed. Flow cytometry was used to quantify macrophage subtypes (pro-inflammatory and anti-inflammatory), and histological analysis was performed to measure changes in adipocyte size. Exercise-activated MSCs showed a ± 35% increase in Il10 expression and a ± 20% enhancement in differentiation capacity compared to controls, indicating improved immunomodulatory potential. In recipient mice, transplantation led to a ± 25% reduction in pro-inflammatory macrophages (CD86+ CD206-) and a 15% decrease in adipocyte size within WAT. Additionally, WAT in treated mice showed balanced inflammatory profiles and reduced adipose hypertrophy, suggesting restored immune balance and metabolic health. These findings suggest that exercise-modified MSCs exhibit enhanced immunomodulatory and metabolic regulatory properties. This study provides evidence that exercise enhances MSC characteristics, potentially improving their capacity to modulate adipose tissue immune balance and metabolic function in obesity. Exercise-conditioned MSCs may serve as a foundation for future strategies that integrate exercise-induced stem cell modifications to modulate obesity-related metabolic dysfunction.

Stem cell-based therapy has emerged as a promising approach for heart repair, potentially regenerating damaged heart tissue and improving outcomes for patients with heart disease. However, the efficacy of stem cell-based therapies remains limited by several challenges, including poor cell survival, low retention rates, poor integration, and limited functional outcomes. This article reviews current enhancement strategies to optimize mesenchymal stem cell therapy for cardiac repair. Key approaches include optimizing cell delivery methods, enhancing cell engraftment, promoting cell functions through genetic and molecular modifications, enhancing the paracrine effects of stem cells, and leveraging biomaterials and tissue engineering techniques. By focusing on these enhancement techniques, the paper highlights innovative approaches that can potentially transform stem cell therapy into a more viable and effective treatment option for cardiac repair. The ongoing research and technological advancements continue to push the boundaries, hoping to make stem cell therapy a mainstream treatment for heart disease.

As living biodrugs, mesenchymal stem cells (MSCs) have progressed to phase 3 clinical trials for cardiovascular applications. However, their limited immediate availability hampers their routine clinical use.

To validate our hypothesis that cryopreserved MSCs (CryoMSCs) are as safe and effective as freshly cultured MSC counterparts but carry logistical advantages.

Four databases were systematically reviewed for relevant randomized controlled trials (RCTs) evaluating the safety and efficacy of CryoMSCs from various tissue sources in treating patients with heart disease. A subgroup analysis was performed based on MSC source and post-thaw cell viability to determine treatment effects across different CryoMSCs sources and viability status. Weighted mean differences (WMDs) and odds ratios were calculated to measure changes in the estimated treatment effects. All statistical analyses were performed using RevMan version 5.4.1 software.

Seven RCTs (285 patients) met the eligibility criteria for inclusion in the meta-analysis. During short-term follow-up, CryoMSCs demonstrated a significant 2.11% improvement in left ventricular ejection fraction (LVEF) [WMD (95%CI) = 2.11 (0.66-3.56), P = 0.004, I 2 = 1%], with umbilical cord-derived MSCs being the most effective cell type. However, the significant effect on LVEF was not sustained over the 12 months of follow-up. Subgroup analysis demonstrated a substantial 3.44% improvement in LVEF [WMD (95%CI) = 3.44 (1.46-5.43), P = 0.0007, I 2 = 0%] when using MSCs with post-thaw viability exceeding 80%. There was no statistically significant difference in the frequency of major cardiac adverse events observed in rehospitalization or mortality in patients treated with CryoMSCs vs the control group.

CryoMSCs are a promising option for heart failure patients, particularly considering the current treatment options for cardiovascular diseases. Our data suggest that CryoMSCs could be a viable alternative or complementary treatment to the current options, potentially improving patient outcomes.

Macrophages play a crucial role in cardiac remodeling and prognosis after myocardial infarction (MI). Our previous studies have built a scalable method for preparing scaled stem cell nanovesicles (NVs) and demonstrated their remarkable reparative effects on ischemic heart disease. To further enhance the targeted reparative capabilities of the NVs toward injured myocardium, we employed a dual modification strategy involving platelet membrane coating and miR-181a-5p loading, creating a nanovesicle termed P-181-NV. This study aimed to investigate the efficacy of P-181-NV in targeted reparative interventions for damaged myocardium and to reveal the underlying mechanisms involved. After successful construction and characteristic analysis of P-181-NV, the in vivo tracking techniques demonstrated a significant enhancement in the targeting capacity of P-181-NV toward the injured myocardium. Moreover, P-181-NV showed marked improvements in cardiac function and remodeling as observed through ultrasound echocardiography and Masson's trichrome staining. Furthermore, P-181-NV significantly augmented myocardial cell viability, angiogenic potential, and the polarization ratio of the anti-inflammatory macrophages. The findings of this study underscore the pivotal role of platelet-membrane-coated and miR-181a-5p modified stem cell nanovesicles in facilitating postmyocardial infarction cardiac repair. By modulating macrophage polarization, P-181-NV offers a promising approach for enhancing the efficacy of targeted reparative interventions for damaged myocardium. These results contribute to our understanding of the potential of nanovesicles as therapeutic agents for cardiac repair and regeneration, presenting avenues for future research and clinical applications.

Myocardial infarction (MI) with resulting congestive heart failure is one of the leading causes of death worldwide. Current therapies for treating MI, such as devices, traditional medicine, and surgeries, come with many limitations as patients in their final stages of heart failure have little chances of experiencing any reversible changes. In recent decades, Mesenchymal stem cell (MSC) based therapy has become one of the most popular and rapidly developing fields in treating MI. Their supremacy for clinical applications is partially due to their unique properties and encouraging pre-clinical outcomes in various animal disease models. However, the majority of clinical trials registered for MSC therapy for diverse human diseases, including MI, have fallen short of expectations. This review intends to discuss the recent advances in the clinical application of using MSCs for cardiac repair and discuss challenges facing the clinical translation of MSCs for cardiac regeneration such as restoration of endothelial-cardiomyocyte crosstalk, immunomodulation and immune rejection, poor homing and migration, as well as low retention and survival. Furthermore, we will discuss recent strategies being investigated to help overcome some of these challenges.

Myocardial infarction is a cardiovascular disease that poses a serious threat to human health. The traditional view is that adult mammalian cardiomyocytes have almost no regenerative ability, but recent studies have shown that they have regenerative potential under specific conditions. This article comprehensively describes the research progress of post-infarction cardiomyocyte regeneration, including the characteristics of cardiomyocytes and post-infarction changes, regeneration mechanisms, influencing factors, potential therapeutic strategies, challenges and future development directions, and deeply discusses the specific pathways and targets included in the regeneration mechanism, aiming to provide new ideas and methods for the treatment of myocardial infarction.

Mesenchymal stem cell (MSC)-based therapies show potential to treat ischemic diseases owing to their versatile functions. However, sustaining MSC viability and therapeutic efficacy in ischemic tissues postengraftment remains a significant challenge. This is because, although MSCs are metabolically flexible, they fail to adapt to hypoxic conditions in the absence of glucose, leading to cell death. To overcome these issues, it is aimed to establish an injectable glucose delivery system using starch and amyloglucosidase embedded in alginate microgels. Here, starch/amyloglucosidase (S/A) microgels are engineered to continuously release glucose for seven days via enzymatic hydrolysis, thereby supporting MSC functions under ischemic conditions. In vitro tests under oxygen/glucose-deprived conditions revealed that the S/A microgels not only maintained the viability and intracellular energy but also enhanced the pro-angiogenic and immunomodulatory functions of MSCs. In vivo data further confirmed the pro-survival and pro-angiogenic effects of S/A microgels on MSCs following subcutaneous engraftment in mice. Overall, the developed S/A microgel significantly enhanced the survival and therapeutic potential of MSCs via sustained glucose delivery, highlighting its potential use in advancing MSC-based therapies for ischemic conditions.

Myocardial infarction (MI) is the most common cardiovascular disease (CVD) and the leading cause of mortality worldwide. Recent advancements have identified human endometrial mesenchymal stem cells (hEnMSCs) as a promising candidate for heart regeneration, however, challenges associated with cell-based therapies have shifted focus toward cell-free treatments (CFTs), such as exosome therapy, which show considerable promise for myocardial tissue regeneration. MI was induced in male Wistar rats by occluding the left anterior descending (LAD) coronary artery. The hEnMSCs-derived exosomes (hEnMSCs-EXOs) were encapsulated in injectable fibrin gel inside the cardiac tissue. The encapsulated hEnMSC-EXOs were administered, and their effects on myocardial regeneration, angiogenesis, and heart function were monitored for 30 days post-MI. The treatments were evaluated through histological analysis, echocardiographic parameters of left ventricular internal dimension at end-diastole (LVIDD) and end-systole (LVID), left ventricular end-diastole volume (LVEDV), left ventricular end-systole volume (LVESV), and left ventricular ejection fraction (LVEF) and molecular studies. Histological findings demonstrated significant fibrosis and left ventricular remodeling following MI. Treatment with fibrin gel-encapsulated hEnMSCs-EXOs substantially reduced fibrosis, enhanced angiogenesis, and prevented heart remodeling, leading to improved cardiac function. Notably, 30 days after encapsulated hEnMSCs-EXOs were delivered corresponded with a less inflammatory microenvironment, supporting cardiomyocyte retention in ischemic tissue. This study highlights the potential of encapsulated hEnMSCs-EXOs in fibrin gel as a novel therapeutic strategy for ischemic myocardium repair post-MI. The findings underscore the importance of biomaterials in advancing stem cell-based therapies and lay a foundation for clinical applications to mitigate heart injury following MI.

The objective of this study is to examine the therapeutic efficacy of miR-133a-transfected bone marrow mesenchymal stem cells (BM-MSCs) in restoring damaged myocardium, reducing myocardial fibrosis, and improving cardiac function following myocardial infarction (MI).

Bone marrow mesenchymal stem cells (BM-MSCs) were transfected with miR-133a using lentivirus vectors, and the in vitro transfection efficiency was assessed. A rat MI animal model was established to examine the survival rate of miR-133a-transfected BM-MSCs in ischemic myocardium. The effects of miR-133a transfection on rat primary cardiac fibroblasts were evaluated both in vitro and in vivo.

The experimental group had a significantly higher concentration of double-stranded DNA (dsDNA) compared to the control group. Fluorescent staining revealed an enhanced survival rate of MSCs in the miR-133a transfection group compared to controls. Additionally, the protein and gene expression of apoptosis-related indicators in the infarcted myocardium were lower in the experimental group compared to the control group. Following co-culture with rat primary cardiac fibroblasts, the miR-133a-transfected MSCs exhibited a significantly lower expression of myofibroblast-specific proteins and mRNA compared to controls. The levels of collagen I, connective tissue growth factor (CTGF) protein, and messenger RNA (mRNA) in the infarcted myocardium of rats transplanted with BM-MSCs transfected with miR-133a were significantly lower than those in the control group, and their left ventricular ejection fraction (LVEF) was significantly increased compared with the group that received unmodified BM-MSCs.

Our results demonstrate that miR-133a transfection following MI improves the survival rate of transplanted MSCs in ischemia-hypoxic myocardium, inhibits the transformation of cardiac fibroblasts into myofibroblasts, reduces myocardial fibrosis, and improves cardiac function following MI. This approach holds promise as a novel therapeutic strategy for myocardial repair.

Mesenchymal stem cells (MSCs) have emerged as a promising therapeutic strategy in regenerative medicine, demonstrating significant potential for clinical applications. Evidence suggests that MSCs not only exhibit multipotent differentiation potential but also exert critical therapeutic effects in retinal degenerative diseases via robust paracrine mechanisms. MSCs protect retinal cells from degenerative damage by modulating inflammation, inhibiting apoptosis, alleviating oxidative stress, and suppressing cell death pathways. Furthermore, MSCs contribute to retinal structural and functional stability by facilitating vascular remodeling and donating mitochondria to retinal cells. Of particular interest, MSC-derived exosomes have gained widespread attention as a compelling cell-free therapy. Owing to their potent anti-inflammatory, anti-apoptotic, and vascular-stabilizing properties, exosomes show significant promise for the treatment of retinal degenerative diseases.

Exosomes, cell-derived vesicles produced by cells, are fascinating and drawing growing interest in biomedical exploration due to their exceptional properties. There is intriguing evidence that exosomes are involved in major biological processes, including diseases and regeneration. Exosomes from mesenchymal stem cells (MSCs) have shown promising outcomes in regenerative medicine. Numerous studies suggest that exosomes have several advantages over conventional synthetic nanocarriers, opening novel frontiers for innovative drug delivery. Regenerative medicine has demonstrated the profound therapeutic outcomes of engineered or loaded exosomes from MSCs. Different methods are being used to modify or/load exosomes. These exosomes can improve cell signaling pathways for bone and cartilage diseases, liver diseases, nerve tissues, kidney diseases, skin tissue, and cardiovascular diseases. Despite extensive research, clinical translation of these exosomes remains a challenge. The optimization of cargo loading methods, efficiency, physiological stability, and the isolation and characterization of exosomes present some challenges. The upcoming examination should include the development of large-scale, quality-controllable production approaches, the modification of drug loading approaches, and numerous in vivo investigations and clinical trials. Here, we provided an informative overview of the extracellular vesicles and modification/loading methods of exosomes. We discuss the last exosome research on regeneration disorders, highlighting the therapeutic applications of MSCs-derived exosomes. We also highlight future directions and challenges, underscoring the significance of addressing the main questions in the field.

The World Health Organization has identified Alzheimer's disease (AD), the leading cause of dementia globally, as a public health priority. However, the complex multifactorial pathology of AD means that its etiology remains incompletely understood. Despite being recognized a century ago, incomplete knowledge has hindered the development of effective treatments for AD. Recent scientific advancements, particularly in induced pluripotent stem cell (iPSC) technology, show great promise in elucidating the fundamental mechanisms of AD. iPSCs play a dual role in regenerating damaged cells for therapeutic purposes and creating disease models to understand AD pathology and aid in drug screening. Nevertheless, as an emerging field, iPSC technology requires further technological advancement to develop effective AD treatments in the future. Thus, this review summarizes recent advances in stem cell therapies, specifically iPSCs, aimed at understanding AD pathology and developing treatments.

In patients with acute myocardial infarction (AMI), thrombolytic therapy and revascularization strategies allow complete recanalization of occluded epicardial coronary arteries. However, approximately 35% of patients still experience myocardial ischemia/reperfusion (I/R) injury, which contributing to increased AMI mortality. Therefore, an accurate understanding of myocardial I/R injury is important for preventing and treating AMI. The death of each cell (cardiomyocytes, endothelial cells, vascular smooth muscle cells, cardiac fibroblasts, and mesenchymal stem cells) after myocardial ischemia/reperfusion is associated with apoptosis due to mitochondrial dysfunction. Abnormal opening of the mitochondrial permeability transition pore, aberrant mitochondrial membrane potential, Ca2+ overload, mitochondrial fission, and mitophagy can lead to mitochondrial dysfunction, thereby inducing mitochondrial apoptosis. The manifestation of mitochondrial apoptosis varies according to cell type. Here, we reviewed the characteristics of mitochondrial apoptosis in cardiomyocytes, endothelial cells, vascular smooth muscle cells, cardiac fibroblasts, and mesenchymal stem cells following myocardial ischemia/reperfusion.

Regenerative medicine refers to medical research focusing on repairing, replacing, or regenerating damaged or diseased tissues or organs. Cardiovascular disease (CVDs) is a significant health issue globally and is the leading cause of death in many countries. According to the Centers for Disease Control and Prevention (CDC), one person dies every 34 seconds in the United States from cardiovascular diseases, and according to a World Health Organization (WHO) report, cardiovascular diseases are the leading cause of death globally, taking an estimated 17.9 million lives each year. Many conventional treatments are available using different drugs for cardiovascular diseases, but these treatments are inadequate. Stem cells and nanotechnology are promising research areas for regenerative medicine treating CVDs. Regenerative medicines are a revolutionary strategy for advancing and successfully treating various diseases, intending to control cardiovascular disorders. This review is a comprehensive study of different treatment methods for cardiovascular diseases using different types of biomaterials as regenerative medicines, the importance of different stem cells in therapeutics, the expanded role of nanotechnology in treatment, the administration of several types of stem cells, their tracking, imaging, and the final observation of clinical trials on many different levels as well as it aims to keep readers up to pace on emerging therapeutic applications of some specific organs and disorders that may improve from regenerative medicine shortly.

Globally, people widely recognize cancer as one of the most lethal diseases due to its high mortality rates and lack of effective treatment options. Ongoing research into cancer therapies remains a critical area of inquiry, holding significant social relevance. Currently used treatment, such as chemotherapy, radiation, or surgery, often suffers from other problems like damaging side effects, inaccuracy, and the lack of ability to clear tumors. Conventional cancer therapies are usually imprecise and ineffective and usually develop resistance to treatments and cancer recurs. Cancer patients need fresh and innovative treatment that can reduce side effects while maximizing effectiveness. In recent decades several breakthroughs in these, and other areas of medical research, have paved the way for new avenues of fighting cancer including more focused and more effective alternatives. This study reviews exciting possibilities for mesenchymal stem cells (MSCs), nanomaterials, and microbial agents in the modern realm of cancer treatment. Nanoparticles (NPs) have demonstrated surprisingly high potential. They improve drug delivery systems (DDS) significantly, enhance imaging techniques remarkably, and target cancer cells selectively while protecting healthy tissues. MSCs play a double role in tissue repair and are a vehicle for novel cancer treatments such as gene treatments or NPs loaded with therapeutic agents. Additionally, therapies utilizing microbial agents, particularly those involving bacteria, offer an inventive approach to cancer treatment. This review investigates the potential of nanomaterials, MSCs, and microbial agents in addressing the shortcomings of conventional cancer therapies. We will also discuss the challenges and limitations of using these therapeutic approaches.

Mortality and morbidity from cardiovascular diseases are common worldwide. In order to improve survival and quality of life for this patient population, extensive efforts are being made to establish effective therapeutic modalities. New treatment options are needed, it seems. In addition to treating cardiovascular diseases, cell therapy is one of the most promising medical platforms. One of the most effective therapeutic approaches in this area is stem cell therapy. In stem cell biology, multipotent stem cells and pluripotent stem cells are divided into two types. There is evidence that stem cell therapy could be used as a therapeutic approach for cardiovascular diseases based on multiple lines of evidence. The effectiveness of stem cell therapies in humans has been studied in several clinical trials. In spite of the challenges associated with stem cell therapy, it appears that resolving them may lead to stem cells being used in cardiovascular disease patients. This may be an effective therapeutic approach. By mounting these stem cells on biological scaffolds, their effect can be enhanced.

Cardiovascular disease (CVD) has been the leading cause of death worldwide for many years. In recent years, exosomes have gained extensive attention in the cardiovascular system due to their excellent biocompatibility. Studies have extensively researched miRNAs in exosomes and found that they play critical roles in various physiological and pathological processes in the cardiovascular system. These processes include promoting or inhibiting inflammatory responses, promoting angiogenesis, participating in cell proliferation and migration, and promoting pathological progression such as fibrosis.

This systematic review examines the role of exosomes in various cardiovascular diseases such as atherosclerosis, myocardial infarction, ischemia-reperfusion injury, heart failure and cardiomyopathy. It also presents the latest treatment and prevention methods utilizing exosomes. The study aims to provide new insights and approaches for preventing and treating cardiovascular diseases by exploring the relationship between exosomes and these conditions. Furthermore, the review emphasizes the potential clinical use of exosomes as biomarkers for diagnosing cardiovascular diseases.

Exosomes are nanoscale vesicles surrounded by lipid bilayers that are secreted by most cells in the body. They are heterogeneous, varying in size and composition, with a diameter typically ranging from 40 to 160 nm. Exosomes serve as a means of information communication between cells, carrying various biologically active substances, including lipids, proteins, and small RNAs such as miRNAs and lncRNAs. As a result, they participate in both physiological and pathological processes within the body.

Macrophages are crucial in the heart's development, function, and injury. As part of the innate immune system, they act as the first line of defense during cardiac injury and repair. After events such as myocardial infarction or myocarditis, numerous macrophages are recruited to the affected areas of the heart to clear dead cells and facilitate tissue repair. This review summarizes the roles of resident and recruited macrophages in developing cardiovascular diseases. We also describe how macrophage phenotypes dynamically change within the cardiovascular disease microenvironment, exhibiting distinct pro-inflammatory and anti-inflammatory functions. Recent studies reveal the values of targeting macrophages in cardiovascular diseases treatment and the novel bioengineering technologies facilitate engineered macrophages as a promising therapeutic strategy. Engineered macrophages have strong natural tropism and infiltration for cardiovascular diseases aiming to reduce inflammatory response, inhibit excessive fibrosis, restore heart function and promote heart regeneration. We also discuss recent studies highlighting therapeutic strategies and new approaches targeting engineered macrophages, which can aid in heart injury recovery.

Mesenchymal stromal cells (MSC) are promising stem cell therapy for treating cardiovascular and other degenerative diseases. Diabetes affects the functional capability of MSC and impedes cell-based therapy. Despite numerous studies, the impact of diabetes on MSC myocardial reparative activity, metabolic fingerprint, and the mechanism of dysfunction remains inadequately perceived. We demonstrated that the transplantation of diabetic-MSC (db/db-MSC) into the ischemic myocardium of mice does not confer cardiac benefit post-MI. Metabolomic studies identified defective energy metabolism in db/db-MSC. Furthermore, we found that glypican-3 (GPC3), a heparan sulfate proteoglycan, is highly upregulated in db/db-MSC and is involved in metabolic alterations in db/db-MSC via pyruvate kinase M2 (PKM2) activation. GPC3-knockdown reprogrammed-db/db-MSC restored their energy metabolic rates, immunomodulation, angiogenesis, and cardiac reparative activities. Together, these data indicate that GPC3-metabolic reprogramming in diabetic MSC may represent a strategy to enhance MSC-based therapeutics for myocardial repair in diabetic patients.

The therapeutic potential of bone marrow mesenchymal stromal cells (bmMSCs) to address heart failure needs improvement for better engraftment and survival. This study explores the role of metabolic sorting for human bmMSCs in coculture in vitro and on doxorubicin-induced heart failure mice models. Using functional, epigenetic, and gene expression approaches on cells sorted for mitochondrial membrane potential in terms of their metabolic status, we demonstrated that bmMSCs selected for their glycolytic metabolism presented proliferative advantage and resistance to oxidative stress thereby favoring cell engraftment. Therapeutic use of glycolytic bmMSCs rescued left ventricular ejection fraction and decreased fibrosis in mice models of acute heart failure. Metabolic changes were also related to epigenetic histone modifications such as lysine methylation. By targeting LSD1 (lysine-specific demethylase 1) as a conditioning agent to enhance the metabolic profile of bmMSCs, we deciphered the interplay between glycolysis and bmMSC functionality. Our study elucidates novel strategies for optimizing bmMSC-based treatments for heart failure, highlighting the metabolic properties of bmMSCs as a promising target for more effective cardiovascular regenerative therapies.

This study explored the potential efficacy and safety of therapy with mesenchymal stem cells (MSC) derived from gonadal tissue to address the early stage of myxomatous mitral valve disease (MMVD), the predominant cardiac condition in dogs.

Sixteen dogs diagnosed with MMVD B1 were enrolled in this trial and assigned to either a control group (control group, n = 10) or a group that received MSC derived from gonadal tissue (treatment group, n = 6). In the treatment group, allogeneic MSC derived from gonadal tissue (1 × 106 cells/kg) were intravenously administered at monthly intervals for five or more sessions. Data were compared at baseline and at the endpoint 1-year intervals. The efficacy was assessed using echocardiography, thoracic radiography, NT-proBNP, and the duration from B1 diagnosis to B2 transition to evaluate its effect on MMVD stage progression. Safety was evaluated through physical examinations, blood tests, imaging studies, and monitoring of adverse events.

After 1 year of observation, the control group exhibited deteriorating echocardiographic parameters, whereas the treatment group displayed no substantial differences between baseline and endpoint measurements. Notably, a statistically significant disparity was noted in the left atrial diameter (p < 0.05) and E-wave velocity (p < 0.05) between the two groups, indicating a favorable impact of MSC derived from the gonadal tissue on left atrial pressure. Additionally, in contrast to the control group, the treatment group demonstrated delayed progression to MMVD stage B2, enabling them to prolong their disease duration without requiring cardiac medication (p = 0.038). In quality of life (QoL) metrics following MSC treatment, appetite showed a statistically significant improvement, increasing from 4 to 4.83 (p < 0.05).

Treatment with gonadal tissue-derived MSCs significantly delayed MMVD stage progression, highlighting the broad potential of MSC derived from gonadal tissue for treating complex veterinary conditions.

Stem cell-related therapeutic technologies have garnered significant attention of the research community for their multi-faceted applications. To promote the therapeutic effects of stem cells, the strategies for cell microencapsulation in hydrogel microparticles have been widely explored, as the hydrogel microparticles have the potential to facilitate oxygen diffusion and nutrient transport alongside their ability to promote crucial cell-cell and cell-matrix interactions. Despite their significant promise, there is an acute shortage of automated, standardized, and reproducible platforms to further stem cell-related research. Microfluidics offers an intriguing platform to produce stem cell-laden hydrogel microparticles (SCHMs) owing to its ability to manipulate the fluids at the micrometer scale as well as precisely control the structure and composition of microparticles. In this review, the typical biomaterials and crosslinking methods for microfluidic encapsulation of stem cells as well as the progress in droplet-based microfluidics for the fabrication of SCHMs are outlined. Moreover, the important biomedical applications of SCHMs are highlighted, including regenerative medicine, tissue engineering, scale-up production of stem cells, and microenvironmental simulation for fundamental cell studies. Overall, microfluidics holds tremendous potential for enabling the production of diverse hydrogel microparticles and is worthy for various stem cell-related biomedical applications.

Cardiovascular diseases, particularly ischemic heart disease, area leading cause of morbidity and mortality worldwide. Myocardial infarction (MI) results in extensive cardiomyocyte loss, inflammation, extracellular matrix (ECM) degradation, fibrosis, and ultimately, adverse ventricular remodeling associated with impaired heart function. While heart transplantation is the only definitive treatment for end-stage heart failure, donor organ scarcity necessitates the development of alternative therapies. In such cases, methods to promote endogenous tissue regeneration by stimulating growth factor secretion and vascular formation alone are insufficient. Techniques for the creation and transplantation of viable tissues are therefore highly sought after. Approaches to cardiac regeneration range from stem cell injections to epicardial patches and interposition grafts. While numerous preclinical trials have demonstrated the positive effects of tissue transplantation on vasculogenesis and functional recovery, long-term graft survival in large animal models is rare. Adequate vascularization is essential for the survival of transplanted tissues, yet pre-formed microvasculature often fails to achieve sufficient engraftment. Recent studies report success in enhancing cell survival rates in vitro via tissue perfusion. However, the transition of these techniques to in vivo models remains challenging, especially in large animals. This review aims to highlight the evolution of cardiac patch and stem cell therapies for the treatment of cardiovascular disease, identify discrepancies between in vitro and in vivo studies, and discuss critical factors for establishing effective myocardial tissue regeneration in vivo.

Mesenchymal stem/stromal cells (MSCs) are an attractive platform for cell therapy due to their safety profile and unique ability to secrete broad arrays of immunomodulatory and regenerative molecules. Yet, MSCs are well known to require preconditioning or priming to boost their therapeutic efficacy. Current priming methods offer limited control over MSC activation, yield transient effects, and often induce the expression of pro-inflammatory effectors that can potentiate immunogenicity. Here, we describe a genetic priming method that can both selectively and sustainably boost MSC potency via the controlled expression of the inflammatory-stimulus-responsive transcription factor interferon response factor 1 (IRF1). MSCs engineered to hyper-express IRF1 recapitulate many core responses that are accessed by biochemical priming using the proinflammatory cytokine interferon-γ (IFN-γ). This includes the upregulation of anti-inflammatory effector molecules and the potentiation of MSC capacities to suppress T cell activation. However, we show that IRF1-mediated genetic priming is much more persistent than biochemical priming and can circumvent IFN-γ-dependent expression of immunogenic MHC class II molecules. Together, the ability to sustainably activate and selectively tailor MSC priming responses creates the possibility of programming MSC activation more comprehensively for therapeutic applications.

Advances in stem cell technology offer new possibilities for patients with untreated diseases and disorders. Stem cell-based therapy, which includes multipotent mesenchymal stem cells (MSCs), has recently become important in regenerative therapies. MSCs are multipotent progenitor cells that possess the ability to undergo in vitro self-renewal and differentiate into various mesenchymal lineages. MSCs have demonstrated promise in several areas, such as tissue regeneration, immunological modulation, anti-inflammatory qualities, and wound healing. Additionally, the development of specific guidelines and quality control methods that ultimately result in the therapeutic application of MSCs has been made easier by recent advancements in the study of MSC biology. This review discusses the latest clinical uses of MSCs obtained from the umbilical cord (UC), bone marrow (BM), or adipose tissue (AT) in treating various human diseases such as pulmonary dysfunctions, neurological disorders, endocrine/metabolic diseases, skin burns, cardiovascular conditions, and reproductive disorders. Additionally, this review offers comprehensive information regarding the clinical application of targeted therapies utilizing MSCs. It also presents and examines the concept of MSC tissue origin and its potential impact on the function of MSCs in downstream applications. The ultimate aim of this research is to facilitate translational research into clinical applications in regenerative therapies.

Cardiovascular diseases (CVDs), particularly stroke and myocardial infarction (MI) contributed to the leading cause of death annually among the chronic diseases globally. Despite the advancement of technology, the current available treatments mainly served as palliative care but not treating the diseases. However, the discovery of mesenchymal stem cells (MSCs) had gained a consideration to serve as promising strategy in treating CVDs. Recent evidence also showed that MSCs are the strong candidate to be used as stem cell therapy involving cardiovascular regeneration due to its cardiomyogenesis, anti-inflammatory and immunomodulatory properties, antifibrotic effects and neovascularization capacity. Besides, MSCs could be used for cellular cardiomyoplasty with its transdifferentiation of MSCs into cardiomyocytes, paracrine effects, microvesicles and exosomes as well as mitochondrial transfer. The safety and efficacy of utilizing MSCs have been described in well-established preclinical and clinical studies in which the accomplishment of MSCs transplantation resulted in further improvement of the cardiac function. Tissue engineering could enhance the desired properties and therapeutic effects of MSCs in cardiovascular regeneration by genome-editing, facilitating the cell delivery and retention, biomaterials-based scaffold, and three-dimensional (3D)-bioprinting. However, there are still obstacles in the use of MSCs due to the complexity and versatility of MSCs, low retention rate, route of administration and the ethical and safety issues of the use of MSCs. The aim of this review is to highlight the details of therapeutic properties of MSCs in treating CVDs, strategies to facilitate the therapeutic effects of MSCs through tissue engineering and the challenges faced using MSCs. A comprehensive review has been done through PubMed and National Center for Biotechnology Information (NCBI) from the year of 2010 to 2021 based on some specific key terms such as 'mesenchymal stem cells in cardiovascular disease', 'mesenchymal stem cells in cardiac regeneration', 'mesenchymal stem cells facilitate cardiac repairs', 'tissue engineering of MSCs' to include relevant literature in this review.

While surgical resection is the predominant clinical strategy in the treatment of melanoma, postoperative recurrence and undetectable metastasis are both pernicious drawbacks to this otherwise highly successful approach. Furthermore, the deep cavities result from tumor excision can leave long lasting wounds which are slow to heal and often leave visible scars. These unmet needs are addressed in the present work through the use of a multidimensional strategy, and also promotes wound healing and scar reduction. In the first phase, cell membrane-derived nanovesicles (NVs) are engineered to show PD-1 and dibenzocyclooctyne (DBCO). These are capable of reactivating T cells by blocking the PD-1/PD-L1 pathway. In the second phase, azido (N3) labeled mesenchymal stem cells (MSCs) are cultured into cell sheets using tissue engineering, then apply directly to surgical wounds to enhance tissue repair. Owing to the complementary association between DBCO and N3 groups, PD-1 NVs were accumulated at the site of excision. This strategy can inhibit postoperative tumor recurrence and metastasis, whilst also promoting wound healing and reducing scar formation. The results of this study set a precedent for a new and innovative multidimensional therapeutic strategy in the postoperative treatment of melanoma.

Background: We studied the potential of human bone marrow-derived mesenchymal stem cell conditioned media (hBMSC CM) in protecting endothelial cell properties (viability, proliferation, and migrations) from the deleterious effects produced by the inflammatory environment of H2O2. Additionally, we investigated their impact on the endothelial cells' gene expression of some inflammatory-related genes, namely, TGF-β1, FOS, ATF3, RAF-1, and SMAD3. Methods: Human umbilical vein endothelial cells (HUVECs) were cultured individually under three conditions: alone, with varying concentrations of H2O2, or with varying concentrations of H2O2 and hBMSC CM. HUVEC adhesion, proliferation, and migration were evaluated using the xCELLigence system. The HUVECs' gene expressions were evaluated by real-time polymerase chain reaction (RT-PCR). Results: Generally, we observed enhanced HUVEC viability, proliferation, and migration when cultured in media supplemented with H2O2 and hBMSC CM. Furthermore, the CM modulated the expressions of the studied inflammatory-related genes in HUVECs, promoting a more robust cellular response. Conclusion: This study has illuminated the protective role of hBMSC CM in mitigating the damaging effects of H2O2 on endothelial cell function. Our data demonstrate that hBMSC CM enhances the viability, proliferation, and migration of HUVECs even under oxidative stress conditions. Additionally, the conditioned medium was found to modulate the gene expression of pivotal markers related to inflammation, suggesting a favorable influence on cellular response mechanisms.

Cardiac fibrosis is a significant contributor to heart failure, a condition that continues to affect a growing number of patients worldwide. Various cardiovascular comorbidities can exacerbate cardiac fibrosis. While fibroblasts are believed to be the primary cell type underlying fibrosis, recent and emerging data suggest that other cell types can also potentiate or expedite fibrotic processes. Over the past few decades, clinicians have developed therapeutics that can blunt the development and progression of cardiac fibrosis. While these strategies have yielded positive results, overall clinical outcomes for patients suffering from heart failure continue to be dire. Herein, we overview the molecular and cellular mechanisms underlying cardiac tissue fibrosis. To do so, we establish the known mechanisms that drive fibrosis in the heart, outline the diagnostic tools available, and summarize the treatment options used in contemporary clinical practice. Finally, we underscore the critical role the immune microenvironment plays in the pathogenesis of cardiac fibrosis.

Nowadays, it has become clear that extracellular vesicles (EVs) are not a cellular waste disposal vesicle but are an essential part of an intercellular communication system. Besides the use of EVs in biomarker studies and diagnostics, the potential of EV-therapeutics has been seen by many. They provide unique properties for disease therapy, including strong immune-modulatory actions, the possibility of engineering, low immunogenicity, and the capability of crossing biological barriers. Proof-of-concept of EV-therapeutics for various pathologies has been achieved in preclinical studies. However, clinical trials with EVs have only been emerging slowly. Here, we aim to provide a comprehensive overview of the current state-of-the-art concerning clinical studies using EVs in human therapy. By approaching the current knowledge in a systematic manner, we were able to include 21 reports for meta-analysis of safety and evaluation of efficacy outcomes. Overall, we have shown that EV-based therapy is safe with a low incidence of serious adverse events (SAE; 0.7% (95%-CI: 0.1-5.2%), and adverse events (AE; 4.4% (95%-CI: 0.7-22.2%). Subgroup analysis showed no significant difference in SAE when comparing autologous versus allogeneic administration, as well as engineered versus non-engineered EV products. A significantly higher number of AE was seen in autologous versus allogeneic administration. However, the clinical relevance remains questionable. Evaluation of the clinical outcomes of immunostimulatory, immunosuppressive or regenerative EV-therapies indicated improvement in the majority of treated patients. Despite these promising results, data need to be approached with caution due to a high heterogeneity in the EVs manufacturing methods, study design, and reporting of (S)AE. Overall, we conclude that EV-based therapy is safe and presents a promising opportunity in therapy. More efforts are needed in the standardization and harmonization of reporting of EV isolation and characterization data as well as in the reporting of (S)AE to allow inter-study comparison.