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AimsCardiomyopathy patients are prone to ventricular arrhythmias (VA) and sudden cardiac death. Current therapies to prevent VA include radiofrequency ablation to destroy slowly conducting pathways of viable myocardium which support re-entry. Here, we tested the reverse concept, namely that boosting local tissue viability in zones of slow conduction might eliminate slow conduction and suppress VA in ischaemic cardiomyopathy.Methods and resultsExosomes are extracellular vesicles laden with bioactive cargo. Exosomes secreted by cardiosphere-derived cells (CDCEXO) reduce scar and improve heart function after intramyocardial delivery. In a VA-prone porcine model of ischaemic cardiomyopathy, we injected CDCEXO or vehicle into zones of delayed conduction defined by electroanatomic mapping. Up to 1-month post-injection, CDCEXO, but not the vehicle, decreased myocardial scar, suppressed slowly conducting electrical pathways, and inhibited VA induction by programmed electrical stimulation. In silico reconstruction of electrical activity based on magnetic resonance images accurately reproduced the suppression of VA inducibility by CDCEXO. Strong anti-fibrotic effects of CDCEXO, evident histologically and by proteomic analysis from pig hearts, were confirmed in a co-culture assay of cardiomyocytes and fibroblasts.ConclusionBiological substrate modification by exosome injection may be worth developing as a non-destructive alternative to conventional ablation for the prevention of recurrent ventricular tachyarrhythmias.

The aim of this study was to explore the In Vitro effects of stromal-derived factor-1a (SDF-1a) on the migration and proliferation of c-kit+ cardiac stem cells. The lentivirus containing SDF-1a (LV-SDF-1a) was constructed. Primary myocardial fibroblasts were transfected by LV-SDF-1a, followed by primary culture of cardiac tissue cells and separation of c-kit+ cardiac stem cells with a flow cytometer, in order to investigate the effects of SDF-1a on the migration and proliferation of c-kit+ cardiac stem cells using cell co-culture, immunofluorescence and EdU tracing technologies. The results showed that myocardial fibroblasts could secrete SDF-1a after the transfection with LV-SDF-1a. High-purity c-kit+ cardiac stem cells were obtained through flow cytometry sorting and the positive rate was about 40%. The c-kit+ cardiac stem cells cultured In Vitro could be differentiated into cTnT positive cardiomyocyte-like cells. After co-culture of myocardial fibroblasts and c-kit+ cardiac stem cells transfected with lentivirus, SDF-1a might increase the migration of c-kit+ cardiac stem cells, but SDF-1a did not promote the proliferation of c-kit+ cardiac stem cells. In conclusion, the myocardial fibroblasts transfected with lentivirus can highly express SDF-1a, c-kit+ cardiac stem cells can be differentiated into cTnT positive cardiomyocyte-like cells and SDF-1a can effectively enhance the migration of c-kit+ cardiac stem cells but fails to stimulate the proliferation. [ABSTRACT FROM AUTHOR]

Mortality in infants with hypoplastic left heart syndrome (HLHS) is strongly correlated with right ventricle (RV) dysfunction. Cell therapy has demonstrated potential improvements of RV dysfunction in animal models related to HLHS, and neonatal human derived c-kit+ cardiac-derived progenitor cells (CPCs) show superior efficacy when compared to adult human cardiac-derived CPCs (aCPCs). Neonatal CPCs (nCPCs) have yet to be investigated in humans. The CHILD trial (Autologous Cardiac Stem Cell Injection in Patients with Hypoplastic Left Heart Syndrome) is a Phase I/II trial aimed at investigating intramyocardial administration of autologous nCPCs in HLHS infants by assessing the feasibility, safety, and potential efficacy of CPC therapy. Using an open-label, multicenter design, CHILD investigates nCPC safety and feasibility in the first enrollment group (Group A/Phase I). In the second enrollment group, CHILD uses a randomized, double-blinded, multicenter design (Group B/Phase II), to assess nCPC efficacy based on RV functional and structural characteristics. The study plans to enroll 32 patients across 4 institutions: Group A will enroll 10 patients, and Group B will enroll 22 patients. CHILD will provide important insights into the therapeutic potential of nCPCs in patients with HLHS. Clinical Trial Registrationhttps://clinicaltrials.gov/ct2/home NCT03406884, First posted January 23, 2018. [ABSTRACT FROM AUTHOR]

The heart's limited regenerative capacity raises the need for novel stem cell-based therapeutic approaches for cardiac regeneration. However, the use of stem cells is restrictive due to poor determination of their properties and the factors that regulate them. Here, we investigated the role of desmin, the major muscle-specific intermediate filament protein, in the characteristics and differentiation capacity of cardiac side population (CSP) and Sca1+ stem cells of adult mice. We found that desmin deficiency affects the microenvironment of the cells and leads to increased numbers of CSP but not Sca1+ cells; CSP subpopulation composition is altered, the expression of the senescence marker p16INK4a in Sca1+ cells is increased, and early cardiomyogenic commitment is impaired. Specifically, we found that mRNA levels of the cardiac transcription factors Mef2c and Nkx2.5 were significantly reduced in des−/− CSP and Sca1+ cells, while differentiation of CSP and Sca1+ cells demonstrated that in the absence of desmin, the levels of Nkx2.5, Mef2c, Tnnt2, Hey2, and Myh6 mRNA are differentially affected. Thus, desmin deficiency restricts the regenerative potential of CSP and Sca1+ cells, both directly and indirectly through their microenvironment. [ABSTRACT FROM AUTHOR]

Summary: Heart failure secondary to cardiomyocyte loss and/or dysfunction is the number one killer worldwide. The field of myocardial regeneration with its far-reaching primary goal of cardiac remuscularization and its hard-to-accomplish translation from bench to bedside, has been filled with ups and downs, steps forward and steps backward, controversies galore and, unfortunately, scientific scandals. Despite the present morass in which cardiac remuscularization is stuck in, the search for clinically effective regenerative approaches remains keenly active. Starting with a concise overview of the still highly debated regenerative capacity of the adult mammalian heart, we focus on the main interventions, that have reached or are close to clinical use, critically discussing key findings, successes, and failures. Finally, some promising and innovative approaches for myocardial repair/regeneration still at the pre-clinical stage are discussed to offer a holistic view on the future of myocardial repair/regeneration for the prevention/management of heart failure in the clinical scenario. Funding: This research was funded by Grants from the Ministry of University and Research PRIN2015 2015ZTT5KB_004; PRIN2017NKB2N4_005; PON-AIM – 1829805-2.

Myocardial cell loss is hypothesized to be irreversible but latest research indicates that human cardiac stem cells (hCSCs) may have a therapeutic use for cardiac repair; however, their properties and the regulatory mechanisms for their development have not been thoroughly explored. Stem cells are a population of cells with the potential for self-regeneration and differentiation into cell types that can play an important role in embryogenesis and embryonic development. So far, seven types of cardiac stem cells with different molecular phenotypes and differentiation potentials have been discovered and studied. Increased proliferation and differentiation of these cells in areas of cardiac ischemia is a significant factor in the repair and enhancement of heart injury. This role of endogenic cardiac stem cells can be regulated by factors. Numerous causes, such as paracrine and autocrine factors, extracellular matrixes and genetic factors. In general, it is well known that these variables could have an appropriate role to improve the effectiveness of the treatment of heart lesions. The work of cytokines and growth factors has been found to play an important role in increasing endogenous cardiac stem cell proliferation and migration capacity. One of the successful approaches is to use these factors along with cardiac stem cells to boost the repair efficiency of heart injury. Therefore, in the present review study, the types of cardiac stem cells and their molecular phenotype, cardiac stem cell genetics and their ability to treat heart injury have been studied. Understanding the molecular processes and messaging pathways involved in success Cardiac stem cells offer an effective approach to the production and presentation of cardiac lesion therapy using cardiac stem cells. [ABSTRACT FROM AUTHOR]

Abstract Background Cardiac stem cells (CSCs) exhibit age-dependent characteristics. Cited2 has been implicated in the regulation of heart development; however, there is little known about how Cited2 affects CSC aging. Results Cited2 mRNA and protein level was downregulated in aging heart tissue and CSCs. Old (O)-CSCs showed decreased differentiation and proliferation capacities as compared to Young (Y)-CSCs, the decrease in cell proliferation, increase in apoptosis, and cell cycle arrest in G0/G1 phase in CSCs are mediated by knocdown CITED2expression in (Y)-CSCs. Conclusions Cited2 plays an important role in cell cycle progression and in maintaining the balance between CSC proliferation and apoptosis in the process of aging without influencing cell fate decisions. These findings have important implications for cell-based therapies for heart repair.

Purpose: Adult cardiac stem cells have ability to regenerate and repair cardiac cells through proper stimulation. Cardiac regeneration capacity decreases with ageing, while physical activities play a positive role in this case. The aim of this study was the effect of high intensity interval and continues training on cardiac stem cells function and myocardial regeneration capacity in male rats.Methods: Twenty-four Vistar male rats (365.6±13.3 g, 6-8 month) were divided into three groups HIIT (high intensity) continuous and control. The training protocol was performed 5 sessions per week for 6 weeks. The heart rats were extracted and c-Kit and Ki67 values were analyzed by Immunohistochemistry and Nkx2.5 gene expression for cardiac stem cells was measured by Real Time-PCR. The data were analyzed by one-way ANOVA (P≤0.05).Results: According to the results of this study, there was a significant increase in c-Kit cells in the HIIT (P=0.001) and in the continuous group (P=0.018) and Significant increase in positive Ki67 cells in the HIIT group (P=0.001) and continuous group (P=0.05). This increase was greater in the HIIT group. As well as a significant increase was observed in the Nkx2.5 gene expression in the HIIT training group (P=0.015) and in the continuous group (P=0.03) which increased in the continuous group was grater.Conclusion: The results showed that the intensity of training is more effective for cardiac regeneration adaptation and HIIT have more positive effects on differentiation of cardiac stem cells.

The heart has been regarded as a terminally differentiated organ for decades. There are numerous indicators for the potency of myocardial regeneration, which opens up new avenues for the treatment of heart disease. Cardiac stem cells (CSCs) have been discovered in the human heart and they play a vital role in myocardial regeneration. This review discusses the distribution, properties and proliferation of CSCs in the myocardium of patients with heart disease. Additionally, the potency of myocardial regeneration in patients with heart disease is discussed.

Cardiovascular diseases are the most common cause of death in the world. The development of heart failure is mainly due to the loss of cardiomyocytes following myocardial infarction and the absence of endogenous myocardial repair. Numerous studies have focused on cardiac stem cells (CSCs) due to their therapeutic benefit, particularly in the treatment of heart failure. It has previously been demonstrated that CSCs are able to promote the regeneration of cardiomyocytes in animals following myocardial infarction. However, the underlying mechanism(s) remain unclear. This review mainly discusses the cardioprotective effect of CSCs and the effect of CSCs on the function of cardiomyocytes, and compares the efficacies of CSCs from rats, mice and humans, thereby contributing to an improved understanding of CSCs as a promising treatment option for heart failure.

Aims To establish pre-clinical proof of concept that sustained subcutaneous delivery of the secretome of human cardiac stem cells (CSCs) can be achieved in vivo to produce significant cardioreparative outcomes in the setting of myocardial infarction. Methods and results Rats were subjected to permanent ligation of left anterior descending coronary artery and randomized to receive subcutaneous implantation of TheraCyte devices containing either culture media as control or 1 × 106 human W8B2+ CSCs, immediately following myocardial ischaemia. At 4 weeks following myocardial infarction, rats treated with W8B2+ CSCs encapsulated within the TheraCyte device showed preserved left ventricular ejection fraction. The preservation of cardiac function was accompanied by reduced fibrotic scar tissue, interstitial fibrosis, cardiomyocyte hypertrophy, as well as increased myocardial vascular density. Histological analysis of the TheraCyte devices harvested at 4 weeks post-implantation demonstrated survival of human W8B2+ CSCs within the devices, and the outer membrane was highly vascularized by host blood vessels. Using CSCs expressing plasma membrane reporters, extracellular vesicles of W8B2+ CSCs were found to be transferred to the heart and other organs at 4 weeks post-implantation. Furthermore, mass spectrometry-based proteomic profiling of extracellular vesicles of W8B2+ CSCs identified proteins implicated in inflammation, immunoregulation, cell survival, angiogenesis, as well as tissue remodelling and fibrosis that could mediate the cardioreparative effects of secretome of human W8B2+ CSCs. Conclusions Subcutaneous implantation of TheraCyte devices encapsulating human W8B2+ CSCs attenuated adverse cardiac remodelling and preserved cardiac function following myocardial infarction. The TheraCyte device can be employed to deliver stem cells in a minimally invasive manner for effective secretome-based cardiac therapy. [ABSTRACT FROM AUTHOR]

Background: The heavy burden of cardiovascular diseases demands innovative therapeutic strategies dealing with cardiomyocyte loss. Cardiac Stem Cells (CSCs) are renewable cells in the myocardium with differentiation and endocrine functions. However, their functions are significantly inhibited in conditions of severe hypoxia or inflammation. The mechanism of hypoxia affecting CSCs is not clear. Interleukin-6 (IL-6) appears active in both hypoxic and inflammatory microenvironments. The aim of this study was to explore whether IL-6 is related to CSC apoptosis and autophagy under severe hypoxia., Methods: In this study, rat CSCs were extracted by alternate digestion. The interaction of miR-98 and IL-6 mRNA was detected by the dual luciferase method, and qPCR was applied to confirm the effect of miR-98 on IL-6 expression. The effect of IL-6 on CSC apoptosis was measured by flow cytometry and the effect of IL-6 on CSC autophagy by transmission electron microscopy. The western blot method was applied to detect the effect of IL-6 on the expressions of proteins related to apoptosis and autophagy. ANOVA and Dunnett T3's test were employed in the statistical analysis. When p < 0.05, the difference was significant., Results: Under severe hypoxia conditions, IL-6 increased CSC apoptosis and decreased p-STAT3 expression significantly. CSC apoptosis increased significantly after inhibition of the STAT3 signaling pathway under severe hypoxia. IL-6 could also significantly inhibit CSCs' autophagy and block their autophagy flow under severe hypoxic conditions. Meanwhile, it was confirmed that miR-98 had a binding site on IL-6 mRNA and miR-98 significantly inhibited IL-6 mRNA expression in CSCs under severe hypoxic conditions., Conclusion: miR-98/IL-6/STAT3 has been found to be involved in the regulation of CSCs' apoptosis and autophagy under severe hypoxic conditions and there might be a mutual linkage between CSCs' apoptosis and their autophagy., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

In exploring therapeutic options for ischemic heart disease (IHD) and heart failure, cell-based cardiac repair has gained prominence. This systematic review delves into the current state of knowledge surrounding cell-based therapies for cardiac repair. Employing a comprehensive search across relevant databases, the study identifies 35 included studies with diverse cell types and methodologies. Encouragingly, these findings reveal the promise of cell-based therapies in cardiac repair, demonstrating significant enhancements in left ventricular ejection fraction (LVEF) across the studies. Mechanisms of action involve growth factors that stimulate angiogenesis, differentiation, and the survival of transplanted cells. Despite these positive outcomes, challenges persist, including low engraftment rates, limitations in cell differentiation, and variations in clinical reproducibility. The optimal dosage and frequency of cell administration remain subjects of debate, with potential benefits from repeated dosing. Additionally, the choice between autologous and allogeneic stem cell transplantation poses a critical decision. This systematic review underscores the potential of cell-based therapies for cardiac repair, bearing implications for innovative treatments in heart diseases. However, further research is imperative to optimize cell type selection, delivery techniques, and long-term efficacy, fostering a more comprehensive understanding of cell-based cardiac repair., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Abouzid et al.)

Experimental data demonstrated that the regenerative potential and immunomodulatory capacity of cardiosphere-derived cells (CDCs) is mediated by paracrine mechanisms. In this process, extracellular vesicles derived from CDCs (EV-CDCs) are key mediators of their therapeutic effect. Considering the future applicability of these vesicles in human diseases, an accurate preclinical-to-clinical translation is needed, as well as an exhaustive molecular characterization of animal-derived therapeutic products. Based on that, the main goal of this study was to perform a comprehensive characterization of proteins and miRNAs in extracellular vesicles from porcine CDCs as a clinically relevant animal model. The analysis was performed by identification and quantification of proteins and miRNA expression profiles. Our results revealed the presence of clusters of immune-related and cardiac-related molecular biomarkers in EV-CDCs. Additionally, considering that priming stem cells with inflammatory stimuli may increase the therapeutic potential of released vesicles, here we studied the dynamic changes that occur in the extracellular vesicles from IFNγ-primed CDCs. These analyses detected statistically significant changes in several miRNAs and proteins. Notably, the increase in interleukin 6 (IL6) protein, as well as the increase in mir-125b (that targets IL6 receptor) was especially relevant. These results suggest a potential involvement of EV-CDCs in the regulation of the IL6/IL6R axis, with implications in inflammatory-mediated diseases.

Cardiomyopathy is a common complication in diabetic patients. Ventricular dysfunction without coronary atherosclerosis and hypertension is driven by hyperglycemia, hyperinsulinemia and impaired insulin signaling. Cardiomyocyte death, hypertrophy, fibrosis, and cell signaling defects underlie cardiomyopathy. Notably, detrimental effects of the diabetic milieu are not limited to cardiomyocytes and vascular cells. The diabetic heart acquires a senescent phenotype and also suffers from altered cellular homeostasis and the insufficient replacement of dying cells. Chronic inflammation, oxidative stress, and metabolic dysregulation damage the population of endogenous cardiac stem cells, which contribute to myocardial cell turnover and repair after injury. Therefore, deficient myocardial repair and the progressive senescence and dysfunction of stem cells in the diabetic heart can represent potential therapeutic targets. While our knowledge of the effects of diabetes on stem cells is growing, several strategies to preserve, activate or restore cardiac stem cell compartments await to be tested in diabetic cardiomyopathy.

Background/Aims: C-kit-positive cardiac stem cells (CSCs) may have potential as a treatment for cardiovascular disease. However, the low survival rates of c-kit-positive CSCs present a major challenge during the transplantation process. Methods: The hierarchical structure of the 3D cell scaffold was characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray diffraction (XRD), and N2 adsorption-desorption isotherms. Analyses of the proliferation and migration performances of the IGF-1 scaffold on c-kit-positive CSCs were conducted by experiments including QuantiT PicoGreen dsDNA and transwell assays. Results: In this study, we synthesized for the first time a novel hierarchical macro-mesoporous silica material (denoted MS15-c) in a one-pot procedure for the release of insulin-like growth factor-1 (IGF-1) and a three-dimensional (3D) cell scaffold. Both macropores and mesopores were visible in MS15-c and enabled the sustained release of IGF-1, extending its half-life and enhancing CSC proliferation and migration. Proliferation and migration were detected by QuantiT PicoGreen dsDNA and transwell assays, respectively. Moreover, an in vivo experiment was conducted to detect heart function with the addition of MS15-c. The new strategy proposed in this paper may extend the bio-applications of 3D cell scaffolds, thus permitting the sustained release of growth factors and efficient promotion of cell proliferation. Conclusion: This work successfully demonstrated an effective strategy for the construction of MS15-c cell scaffolds with hierarchical macro-mesoporous structures. The macro-mesoporous structures gave cell scaffolds the ability to release a growth factor to facilitate cell growth, while the scaffold structure promoted cell proliferation.

Introduction: Aging is accompanied by anatomical and physiological changes in most tissues and organs, especially the reduction of cells, tissues, and vascular levels. Endothelial progenitor cells are involved in maintaining endothelial health, preventing endothelial dysfunction, and increasing neovascularization process. Cardiac stem cells are effective in the regeneration and repair of heart tissue. Regular exercise training increases both of these cells. We aimed to investigate the effect of eight weeks of moderate and intense interval training on gene expression of endothelial progenitor cells and cardiac stem cells in aged rats. Materials and Methods: Twenty-one Wistar female rats with the mean age of 24±1 months and the mean weight of 265±44 g were randomly divided into three groups of control (n=7), moderate exercise (n=7), and intense exercise (n=7) groups. Both exercise groups were trained for 8 weeks, 3 sessions a week, each session for 40 minutes with 28 meters per minute in the moderate intensity exercise group and 34 meters per minute in the high intensity group. Forty-eight hours after the last training session, the rats were anesthetized and their cardiac tissue was isolated. CD34 and KDR gene expression for endothelial progenitor cells and c-Kit expression for cardiac stem cells were measured. Findings: The results showed that the level of c-Kit gene expression in both groups of moderate (P=0.0001) and intense (P=0.0001) training significantly increased compared to the control group. This increase was significantly higher in the intense training group (P=0.0001). Eight weeks of moderate interval training significantly increased the expression level of CD34 (P=0.0001) and KDR (P=0.0001) genes. Also, eight weeks of high intensity interval training resulted in a significant increase in the level of gene expression of CD34 (P=0.0001) and KDR (P=0.0001). This accumulative effect in the intense training group was significantly higher compared to the moderate group (CD34: P=0.0001 and KDR: P=0.0001). Conclusion: The results of this study showed that regular interval training with two different intensity levels raises the level of gene expression of endothelial progenitor cells and cardiac stem cells. This increase is dependent on the intensity of training. High intensity interval training seems to stimulate the regeneration of heart tissue and development of coronary artery. These findings can be used to improve cell therapy and cardiac rehabilitation after injury and myocardial dysfunction, especially in the elderly.

Background/Aims: Hyperglycemia is an important risk factor for the most severe cardiovascular diseases in patients with diabetes. It has been demonstrated that cardiac stem cells (CSCs) play a pivotal role in the maintenance of cardiac homeostasis and regeneration. However, the mechanism underlying the influence of diabetes on CSCs remains unclear. This study demonstrated that hyperglycemia might promote adipogenesis in CSCs, which induces a decline in myocardial regeneration capability in diabetes. Methods: CSCs were isolated and cultured in high-glucose medium. The levels of β-catenin and TCF-4 in CSCs were determined by immunofluorescence staining and western blot analysis. Adipogenic transcriptional factors and CSCs markers were also examined by flow cytometry and western blot analysis after adipogenesis induction. In addition, Oil Red O staining was performed to investigate lipid droplet formation during adipogenesis induction with or without LiCl, a potent activator of TCF/β-catenin-dependent transcription. Results: High-glucose conditions inhibited nuclear translocation of β-catenin/TCF-4 and promoted adipogenesis in CSCs. After adipogenesis induction, expression of adipogenic transcriptional factors (PPARγ, ADD1, and C/EBPα) were increased (P < 0.01) and that of CSCs markers (c-Kit, Sca-1, MDR-1, and isl-1) were decreased (P< 0.01) in CSCs in the high-glucose group. Furthermore, lipid droplet formation was increased in CSCs cultured with high glucose, while LiCl attenuated lipid droplet formation in these CSCs (P < 0.01). Conclusion: These results demonstrated that hyperglycemia inhibited the β-catenin/TCF-4 pathway and promoted CSCs adipogenesis. Our findings suggest a new opportunity for future interventional strategie for abnormal myocardial regeneration and epicardial fat in patients with diabetes.

Wei Chen,1 Jing Ju,1 Yehong Yang,2 Hao Wang,3 Wenjie Chen,1 Xuelan Zhao,1 Hongying Ye,2 Yu Zhang1 1Department of Geriatrics, Huashan Hospital, Fudan University, Shanghai, China; 2Department of Endocrinology, Huashan Hospital, Fudan University, Shanghai, China; 3Core Center of Animal Facility, School of Medicine, Fudan University, Shanghai, China Introduction: Diabetic cardiomyopathy is characterized by an imbalance between myocyte death and regeneration mediated by the progressive loss of cardiac stem and progenitor cells (CSPCs) by apoptosis and necrosis due to the activation of oxidative stress with diabetes. In this study, we evaluated the beneficial effect of astragalus polysaccharides (APS) therapy on the protection of CSPCs through its antioxidative capacity in diabetic hearts.Materials and methods: Streptozotocin (STZ)-induced diabetic mice and heterozygous (SOD2+/-) knockout mice were employed and administered with APS. Ventricular CSPCs were isolated for oxidative evaluation. The abundance, apoptosis and proliferation, reactive oxygen species (ROS) formation, oxidative damage, and SOD2 protein levels and activities were evaluated in ventricular CSPCs.Results: We confirmed that APS increased the CSPC abundance, reduced the apoptosis of CSPCs, and enhanced the proliferation of CSPCs in both STZ-induced diabetic mice and nondiabetic SOD2+/- mice. In addition, therapy of APS enhanced SOD2 protein levels and enzyme activities, and inhibited ROS formation and oxidative damage of CSPCs from both STZ-induced diabetic mice and nondiabetic SOD2+/- mice.Conclusion: Our findings demonstrated the positive effect of APS on the rescue of CSPC preservation in diabetes, dependent on the inhibition of oxidative stress-mediated apoptosis. Keywords: diabetes, cardiac stem cells, cardiac progenitor cells, oxidative stress, cardio­myopathy, oxidation

We studied the effects of apoptotic bodies of cardiomyocytes (ApBc) and fibroblasts (ApBf) on myocardial regeneration and contractility in rats and the dynamics of RNA concentrations in cardiomyocytes and fibroblasts at different stages of apoptosis. ApBc increase the contractility of rat myocardium, while ApBf reduce it. ApBc stimulate the development of clones of cardiomyocyte precursors in the myocardium, while ApBf stimulate the formation of endothelial precursor clones. In doxorubicin cardiomyopathy, ApBc, similar to the reference drug (ACE inhibitor) improve animal survival, while ApBf produce no such effect. RNA concentrations in cardiomyocytes and fibroblasts before apoptosis and at the beginning of cell death significantly differed, while in apoptotic bodies of these cells, it was practically the same. It has been hypothesized that RNA complex present in ApBc and ApBf represents an "epigenetic code" of directed differentiation of cardiac stem cells. [ABSTRACT FROM AUTHOR]

Stem cells represent an old niche with various new potential therapeutics. Besides drug treatment, reperfusion procedures and surgical revascularization, stem cell therapy could be a good option in ischemic cardiac diseases. A study was performed on a small group of cases who died of cardiac arrhythmia secondary to scarring myocardial infarctions. Tissue cardiac samples were taken from these cases (from the anterior and lateral wall of the left ventricle), for microscopy examination, in order to investigate the presence of cardiac stem cells (CSC). Multiple series of histological sections were also performed and examined, along with immunohistochemical analysis (IHC). The cells were identified in close contact with the residual ischemic cardiomyocytes, in the proximity of the myocardial collagenous scar, in old myocardial infarctions. They were activated by hypoxic ischemia and were influenced by the capillary microvascular density and the interstitial micro-environment conditions. In chronic intermittent ischemia they seem to turn themselves from dormant quiescent cells into activated progenitor committed cells. [ABSTRACT FROM AUTHOR]

Aims Cardiosphere-derived cells (CDCs) are cardiac progenitor cells that exhibit disease-modifying bioactivity in various models of cardiomyopathy and in previous clinical studies of acute myocardial infarction (MI), dilated cardiomyopathy, and Duchenne muscular dystrophy. The aim of the study was to assess the safety and efficacy of intracoronary administration of allogeneic CDCs in the multicentre, randomized, double-blinded, placebo-controlled, intracoronary ALLogeneic heart STem cells to Achieve myocardial Regeneration (ALLSTAR) trial. Methods and results We enrolled patients 4 weeks to 12 months after MI, with left ventricular ejection fraction (LVEF) ≤45% and LV scar size ≥15% of LV mass by magnetic resonance imaging (MRI). A pre-specified interim analysis was performed when 6-month MRI data were available. The trial was subsequently stopped due to the low probability of detecting a significant treatment effect of CDCs based on the primary endpoint. Patients were randomly allocated in a 2:1 ratio to receive CDCs or placebo in the infarct-related artery by stop-flow technique. The primary safety endpoint was the occurrence, during 1-month post-intracoronary infusion, of acute myocarditis attributable to allogeneic CDCs, ventricular tachycardia- or ventricular fibrillation-related death, sudden unexpected death, or a major adverse cardiac event (death or hospitalization for heart failure or non-fatal MI or need for left ventricular assist device or heart transplant). The primary efficacy endpoint was the relative percentage change in infarct size at 12 months post-infusion as assessed by contrast-enhanced cardiac MRI. We randomly allocated 142 eligible patients of whom 134 were treated (90 to the CDC group and 44 to the placebo group). The mean baseline LVEF was 40% and the mean scar size was 22% of LV mass. No primary safety endpoint events occurred. There was no difference in the percentage change from baseline in scar size (P  = 0.51) between CDCs and placebo groups at 6 months. Compared with placebo, there were significant reductions in LV end-diastolic volume (P  = 0.02), LV end-systolic volume (P  = 0.02), and N-terminal pro b-type natriuretic peptide (NT-proBNP) (P  = 0.02) at 6 months in CDC-treated patients. Conclusion Intracoronary infusion of allogeneic CDCs in patients with post-MI LV dysfunction was safe but did not reduce scar size relative to placebo at 6 months. Nevertheless, the reductions in LV volumes and NT-proBNP reveal disease-modifying bioactivity of CDCs. Trial registration Clinicaltrials.gov identifier: NCT01458405. Open in new tab Download slide Open in new tab Download slide [ABSTRACT FROM AUTHOR]

Critical limb ischemia (CLI) is the most advanced stage of peripheral artery disease, associated with significant risk of limb loss, morbidity and mortality; however, there remains unmet therapeutic needs for arterial revascularization and ischemic tissue repair. Stem cell therapies have emerged as compelling candidates due to beneficial proangiogenic and immunosuppressive function. Nevertheless, in vivo efficacy was insufficient in proliferation, differentiation and survival/engraftment rate. Cardiac stem cells (CSCs) was firstly attempted for CLI as a novel therapeutic modality to provide superior angiogenic potency to bone marrow-derived stem cells (BMSCs). It was noted that CSCs demonstrated 3.2-fold in HGF, 2.9-fold in VEGF and 8.7-fold in PDGF-B higher gene expressions compared to BMSCs. To enhance the hypoxia-induced proangiogenic effect, CSCs were transfected with hypoxia-inducible factor-1 alpha (HIF-1α) by using electroporation method, specifically optimized for CSCs yielding 45.77% of transfection efficiency and 89.75% of viability. HIF-1α overexpression significantly increased CSC survival in hypoxia, proangiogenic factors production and endothelial differentiation. In mouse hind limb ischemia model, local intramuscular delivery of CSC overexpressing HIF-1α (HIF-CSC) significantly improved the blood flow recovery. Histological analysis revealed that muscle degeneration and fibrosis in the ischemic limb were attenuated. Local delivery of HIF-CSC might be a promising option for ischemic tissue restoration. Unlabelled Image • Cardiac stem cells (CSC) show better proangiogenic potential than BMSCs. • HIF-1α gene is transfected into CSC by electroporation. • Overexpression of HIF-1α augments migration and endothelial differentiation of CSC. • The injection of HIF-CSC with fibrin gel improves blood perfusion in limb ischemia. [ABSTRACT FROM AUTHOR]

Cardiovascular regeneration aims to renew damaged or necrotic tissue and to enhance cardiac functional performance. Despite the hope arisen from the introduction and use of stem cells (SCs) as a novel cardiac regenerative approach, to-this-date, clinical trial findings are still ambivalent despite preclinical successes. Concurrently, noninvasive magnetic resonance imaging (MRI) advances have been based on nanotechnological breakthroughs that have (a) allowed fluorinated nanoparticles and ultrasmall iron oxide single-cell labeling, (b) explored imaging detection sensitivity limits (for preclinical/low-field clinical settings), and (c) accomplished cellular tracking in vivo. Nevertheless, outcomes have been far from ideal. Herein, the recently developed preclinical and clinical 1H and 19F MRI approaches for direct cardiac SC labeling techniques intended for cellular implantation and their potential for tracking these cells in health and infarcted states are summarized. To this extent, the potential preclinical and clinical values of 19F MRI and tracking of SCs for cardiac regeneration in myocardial infarction are questioned and challenged. [ABSTRACT FROM AUTHOR]

Abstract Background Cardiac stem cells (CSCs) transplantation has been regarded as an optimal therapeutic approach for cardiovascular disease. However, inferior survival and low differentiation efficiency of these cells in the local infarct site reduce their therapeutic efficacy. In this study, we investigated the influence of hypoxia preconditioning (HP) on CSCs survival and cardiogenic differentiation in vitro and explored the relevant mechanism. Methods CSCs were obtained from Sprague–Dawley rats and cells of the third passage were cultured in vitro and exposed to hypoxia (1% O2). Cells survival and apoptosis were evaluated by MTS assay and flow cytometry respectively. Cardiogenic differentiation was induced by using 5-azacytidine for another 24 h after the cells experienced HP. Normoxia (20% O2) was used as a negative control during the whole process. Cardiogenic differentiation was assessed 2 weeks after the induction. Relevant molecules were examined after HP and during the differentiation process. Anti-hypoxia-inducible factor-1α (HIF-1α) small interfering RNA (siRNA), anti-apelin siRNA, and anti-putative receptor protein related to the angiotensin receptor AT1 (APJ) siRNA were transfected in order to block their expression, and relevant downstream molecules were detected. Results Compared with the normoxia group, the hypoxia group presented more rapid growth at time points of 12 and 24 h (p

Background & Objectives: C-kit+ cells are the most important cardiac stem cells and have Myogenic and Vasculogenic properties. Exercise training tends to stimulate these cells. This study aims to investigate the effect of intense and moderate interval aerobic training and curcumin consumption on the gene expression of c-Kit stem cells of heart in old rats. Materials &Methods: 35 Wistar old female rats of about two years were randomly divided into 5 groups: control, saline, curcumin, moderate training + curcumin and intense training + curcumin. 30 mg Curcumin for each kg of their body weight was given by gavage to the rats in experimental groups 3 days a week. The saline group was given the same amount of saline. Both groups underwent interval aerobic training on treadmill 3 sessions per week for 8 weeks, with high and medium intensity. 48 hours after the last training and gavage, c-Kit gene expression for cardiac stem cells was measured. Results: The results indicated that in each Curcumin group, c-Kit level increased significantly compared to that of the control group (P=0.003). The mean of moderate exercise + curcumin group was significantly higher than the mean of curcumin, saline and control groups (P

c-Kit, a type III receptor tyrosine kinase (RTK), is involved in multiple intracellular signaling whereby it is mainly considered a stem cell factor receptor, which participates in vital functions of the mammalian body, including the human. Furthermore, c-kit is a necessary yet not sufficient marker to detect and isolate several types of tissue-specific adult stem cells. Accordingly, c-kit was initially used as a marker to identify and enrich for adult cardiac stem/progenitor cells (CSCs) that were proven to be clonogenic, self-renewing and multipotent, being able to differentiate into cardiomyocytes, endothelial cells and smooth muscle cells in vitro as well as in vivo after myocardial injury. Afterwards it was demonstrated that c-kit expression labels a heterogenous cardiac cell population, which is mainly composed by endothelial cells while only a very small fraction represents CSCs. Furthermore, c-kit as a signaling molecule is expressed at different levels in this heterogenous c-kit labeled cardiac cell pool, whereby c-kit low expressers are enriched for CSCs while c-kit high expressers are endothelial and mast cells. This heterogeneity in cell composition and expression levels has been neglected in recent genetic fate map studies focusing on c-kit, which have claimed that c-kit identifies cells with robust endothelial differentiation potential but with minimal if not negligible myogenic commitment potential. However, modification of c-kit gene for Cre Recombinase expression in these Cre/Lox genetic fate map mouse models produced a detrimental c-kit haploinsufficiency that prevents efficient labeling of true CSCs on one hand while affecting the regenerative potential of these cells on the other. Interestingly, c-kit haploinsufficiency in c-kit-deficient mice causes a worsening myocardial repair after injury and accelerates cardiac aging. Therefore, these studies have further demonstrated that adult c-kit-labeled CSCs are robustly myogenic and that the adult myocardium relies on c-kit expression to regenerate after injury and to counteract aging effects on cardiac structure and function.

Over the years strong evidence has been accumulated showing that aerobic physical exercise exerts beneficial effects on the prevention and reduction of cardiovascular risk. Exercise in healthy subjects fosters physiological remodeling of the adult heart. Concurrently, physical training can significantly slow-down or even reverse the maladaptive pathologic cardiac remodeling in cardiac diseases, improving heart function. The underlying cellular and molecular mechanisms of the beneficial effects of physical exercise on the heart are still a subject of intensive study. Aerobic activity increases cardiovascular nitric oxide (NO) released mainly through nitric oxidase synthase 3 activity, promoting endothelium-dependent vasodilation, reducing vascular resistance, and lowering blood pressure. On the reverse, an imbalance between increasing free radical production and decreased NO generation characterizes pathologic remodeling, which has been termed the “nitroso-redox imbalance”. Besides these classical evidence on the role of NO in cardiac physiology and pathology, accumulating data show that NO regulate different aspects of stem cell biology, including survival, proliferation, migration, differentiation, and secretion of pro-regenerative factors. Concurrently, it has been shown that physical exercise generates physiological remodeling while antagonizes pathologic remodeling also by fostering cardiac regeneration, including new cardiomyocyte formation. This review is therefore focused on the possible link between physical exercise, NO, and stem cell biology in the cardiac regenerative/reparative response to physiological or pathological load. Cellular and molecular mechanisms that generate an exercise-induced cardioprotective phenotype are discussed in regards with myocardial repair and regeneration. Aerobic training can benefit cells implicated in cardiovascular homeostasis and response to damage by NO-mediated pathways that protect stem cells in the hostile environment, enhance their activation and differentiation and, in turn, translate to more efficient myocardial tissue regeneration. Moreover, stem cell preconditioning by and/or local potentiation of NO signaling can be envisioned as promising approaches to improve the post-transplantation stem cell survival and the efficacy of cardiac stem cell therapy.

Myocardial infarction (MI) is a major cause of morbidity and mortality worldwide. Until recently, it was thought that myocardium was not able to repair itself, but studies have now shown that resident cardiac stem cells have regenerative capacity, and stem cell therapy may be a novel approach for cardiac muscle repair and regeneration. Stem cell‐derived paracrine factors have been shown to regulate ventricular remodeling, inflammation, apoptosis, cardiomyocytes regeneration, and neovascularization in regions of infarcted cardiac tissue. In this review, we summarize the evidence from cellular, animal, and clinical studies supporting the potential clinical significance of stem cell therapy as a novel therapeutic approach for the treatment of MI. [ABSTRACT FROM AUTHOR]

c-Kit, a type III receptor tyrosine kinase (RTK), is involved in multiple intracellular signaling whereby it is mainly considered a stem cell factor receptor, which participates in vital functions of the mammalian body, including the human. Furthermore, c-kit is a necessary yet not sufficient marker to detect and isolate several types of tissue-specific adult stem cells. Accordingly, c-kit was initially used as a marker to identify and enrich for adult cardiac stem/progenitor cells (CSCs) that were proven to be clonogenic, self-renewing and multipotent, being able to differentiate into cardiomyocytes, endothelial cells and smooth muscle cells in vitro as well as in vivo after myocardial injury. Afterwards it was demonstrated that c-kit expression labels a heterogenous cardiac cell population, which is mainly composed by endothelial cells while only a very small fraction represents CSCs. Furthermore, c-kit as a signaling molecule is expressed at different levels in this heterogenous c-kit labeled cardiac cell pool, whereby c-kit low expressers are enriched for CSCs while c-kit high expressers are endothelial and mast cells. This heterogeneity in cell composition and expression levels has been neglected in recent genetic fate map studies focusing on c-kit, which have claimed that c-kit identifies cells with robust endothelial differentiation potential but with minimal if not negligible myogenic commitment potential. However, modification of c-kit gene for Cre Recombinase expression in these Cre/Lox genetic fate map mouse models produced a detrimental c-kit haploinsufficiency that prevents efficient labeling of true CSCs on one hand while affecting the regenerative potential of these cells on the other. Interestingly, c-kit haploinsufficiency in c-kit-deficient mice causes a worsening myocardial repair after injury and accelerates cardiac aging. Therefore, these studies have further demonstrated that adult c-kit-labeled CSCs are robustly myogenic and that the adult myocardium relies on c-kit expression to regenerate after injury and to counteract aging effects on cardiac structure and function. [ABSTRACT FROM AUTHOR]

Herein, we maximize the labeling efficiency of cardiac progenitor cells (CPCs) using perfluorocarbon nanoparticles (PFCE-NP) and 19F MRI detectability, determine the temporal dynamics of single-cell label uptake, quantify the temporal viability/fluorescence persistence of labeled CPCs in vitro, and implement in vivo, murine cardiac CPC MRI/tracking that could be translatable to humans. FuGENEHD-mediated CPC PFCE-NP uptake is confirmed with flow cytometry/confocal microscopy. Epifluorescence imaging assessed temporal viability/fluorescence (up to 7 days [D]). Nonlocalized murine 19F MRS and cardiac MRI studied label localization in terminal/longitudinal tracking studies at 9.4 T (D1-D8). A 4-8 fold 19F concentration increase is evidenced in CPCs for FuGENE vs. directly labeled cells. Cardiac 19F signals post-CPC injections diminished in vivo to ~31% of their values on D1 by D7/D8. Histology confirmed CPC retention, dispersion, and macrophage-induced infiltration. Intra-cardiac injections of PFCE-NP-labeled CPCs with FuGENE can be visualized/tracked in vivo for the first time with 19F MRI. Proposed models of temporally dependent 19F decreases in tracking studies. Murine cardiac 19F MRI following an intramyocardial injection of labeled cardiac progenitor cells (CPCs) and associated signal changes within a period spanning day 1 (D1) to D8 (middle and middle-top) post-injection. Schematics on the four corners represent typical image voxels containing injected, labeled CPCs, apoptotic CPCs, and perfluorocarbon nanoparticles (PFCE-NPs), and the prominent mechanisms postulated to affect the voxel-volume averaged 19F MRI signal intensity, as these modulate intracellular/extracellular volume and fluorine content. Possible relaxation changes (T 1 , T 2) are ignored. Unlabelled Image [ABSTRACT FROM AUTHOR]

Cardiac stem/progenitors are being used in the clinic to treat patients with a range of cardiac pathologies. However, improvements in heart function following treatment have been reported to be variable, with some showing no response. This discrepancy in response remains unresolved. Mesenchymal stem cells (MSCs) have been highlighted as a regenerative tool as these cells display both immunomodulatory and proregenerative activities. The purpose of this study was to derive a cardiac MSC population to provide an alternative/support to current therapies. We derived human cardiac-mesenchymal stem cell-like cells (CMSCLC), so named as they share some MSC characteristics. However, CMSCLC lack the MSC trilineage differentiation capacity, being capable of only rare adipogenic differentiation and demonstrating low/no osteogenic or chondrogenic potential, a phenotype that may have advantages following transplantation. Furthermore, CMSCLC expressed low levels of p16, high levels of MHCI, and low levels of MHCII. A lack of senescent cells would also be advantageous for cells to be used therapeutically, as would the ability to modulate the immune response. Crucially, CMSCLC display a transcriptional profile that includes genes associated with cardioprotective/cardiobeneficial effects. CMSCLC are also secretory and multipotent, giving rise to cardiomyocytes and endothelial cells. Our findings support CMSCLC as a novel cell population suitable for use for transplantation. [ABSTRACT FROM AUTHOR]

Aim: The aim of this study was to evaluate the formulation of a synthetic IGF-1 (pIGF-1) in PLGA microparticles (MP). Methods: Poly (lactic-co-glycolic acid) (PLGA) MPs loaded with pIGF-1 were prepared, characterised and evaluated using double emulsion solvent evaporation method. Results: Spherical MPs showed an average particle size of 2 µm, encapsulation efficiency (EE) of 67% and 50% degradation over 15 days. With a view to enhancing retention in the myocardium, the MP formulation was encapsulated in a cross-linked hyaluronic acid hydrogel. pIGF-1 released from MPs and from MPs suspended in hyaluronic acid hydrogel remained bioactive, determined by a significant increase in cellular proliferation of c-kit+ cells. Conclusion: This formulation has potential for loco-regional delivery to damaged myocardium to promote the survival of cardiomyocytes. [ABSTRACT FROM AUTHOR]