Intramyocardial injection of platelet gel promotes endogenous repair and augments cardiac function in rats with myocardial infarction.
ABSTRACT: This study sought to explore the therapeutic potential of platelet gel for the treatment of myocardial infarction.Cardiac dysfunction after acute myocardial infarction is a major cause of heart failure. Current therapy relies on prompt reperfusion and blockage of secondary maladaptive pathways by small molecules. Platelet gels are biomaterials rich in cytokines and growth factors, which can be manufactured in an autologous manner and are effective in various models of wound healing. However, the potential utility of platelet gel in cardiac regeneration has yet to be tested.Platelet gel was derived from syngeneic rats and its morphology, biocompatibility, secretion of beneficial factors, and in vivo degradation profile were characterized.After delivery into infarcted rat hearts, the gel was efficiently infiltrated by cardiomyocytes and endothelial cells. Gel-treated hearts exhibited enhanced tissue protection, greater recruitment of endogenous regeneration, higher capillary density, and less compensatory myocyte hypertrophy. The cardiac function of control-injected animals deteriorated over the 6-week time course, while that of platelet gel-injected animals did not. In addition, the gel did not exacerbate inflammation in the heart.Intramyocardial injection of autologous platelet gel ameliorated cardiac dysfunction after myocardial infarction. The striking functional benefits, the simplicity of manufacturing, and the potentially autologous nature of this biomaterial provide impetus for further translation.
Project description:Vascular regeneration in ischemic hearts has been considered a target for new therapeutic strategies. It has been reported that ETV2 is essential for vascular development, injury-induced neovascularization and direct cell reprogramming of non-endothelial cells into endothelial cells. Thus, the objective of this study was to explore the therapeutic potential of ETV2 in murine models of myocardial infarction in vivo. Direct myocardial delivery of lentiviral ETV2 into rodents undergoing myocardial infarction dramatically upregulated the expression of markers for angiogenesis as well as anti-fibrosis and anti-inflammatory factors in vivo. Consistent with these findings, echocardiography showed significantly improved cardiac function in hearts with induced myocardial infarction upon ETV2 injection compared to that in the control virus-injected group as determined by enhanced ejection fraction and fractional shortening. In addition, ETV2-injected hearts were protected against massive fibrosis with a remarkable increase in capillary density. Interestingly, major fractions of capillaries were stained positive for ETV2. In addition, ECs infected with ETV2 showed enhanced proliferation, suggesting a direct role of ETV2 in vascular regeneration in diseased hearts. Furthermore, culture media from ETV2-overexpressing cardiac fibroblasts promoted endothelial cell migration based on scratch assay. Importantly, intramyocardial injection of the adeno-associated virus form of ETV2 into rat hearts with induced myocardial infarction designed for clinical applicability consistently resulted in significant augmentation of cardiac function. We provide compelling evidence that ETV2 has a robust effect on vascular regeneration and enhanced cardiac repair after myocardial infarction, highlighting a potential therapeutic function of ETV2 as an efficient means to treat failing hearts.
Project description:The emerging field of stem cell therapy and biomaterials has begun to provide promising strategies for the treatment of ischemic cardiomyopathy. Platelet gel and cardiosphere-derived cells (CDCs) are known to be beneficial when transplanted separately post-myocardial infarction (MI). We hypothesize that pre-seeding platelet gel with CDCs can enhance therapeutic efficacy. Platelet gel and CDCs were derived from venous blood and heart biopsies of syngeneic rats, respectively. In vitro, the viability, growth, and morphology of CDCs cultured in platelet gel were characterized. When delivered into infarcted rat hearts, platelet gel pre-seeded with CDCs was more efficiently populated with endogenous cardiomyocytes and endothelial cells than platelet gel alone. Recruitment of endogenous c-kit positive cells was enhanced in the hearts treated with gel with CDC. At 3 weeks, the hearts treated with CDC-seeded platelet gel exhibited the greatest attenuation of adverse left ventricular (LV) remodeling and the highest cardiac function (i.e., LV ejection fraction) as compared to hearts transplanted with Gel only or vehicle controls. Histological analysis revealed that, though some transplanted CDCs differentiated into cardiomyocytes and endothelial cells in the recipients' hearts, most of the incremental benefit arose from CDC-mediated endogenous repair. Pre-seeding platelet gel with CDCs enhanced the functional benefit of biomaterial therapy for treating myocardial infarction.
Project description:Injectable biomaterials have been evaluated as potential new therapies for myocardial infarction (MI) and heart failure. These materials have improved left ventricular (LV) geometry and ejection fraction, yet there remain concerns that biomaterial injection may create a substrate for arrhythmia. Since studies of this risk are lacking, we utilized optical mapping to assess the effects of biomaterial injection and interstitial spread on cardiac electrophysiology. Healthy and infarcted rat hearts were injected with a model poly(ethylene glycol) hydrogel with varying degrees of interstitial spread. Activation maps demonstrated delayed propagation of action potentials across the LV epicardium in the hydrogel-injected group when compared to saline and no-injection groups. However, the degree of the electrophysiological changes depended on the spread characteristics of the hydrogel, such that hearts injected with highly spread hydrogels showed no conduction abnormalities. Conversely, the results of this study indicate that injection of a hydrogel exhibiting minimal interstitial spread may create a substrate for arrhythmia shortly after injection by causing LV activation delays and reducing gap junction density at the site of injection. Thus, this work establishes site of delivery and interstitial spread characteristics as important factors in the future design and use of biomaterial therapies for MI treatment.Biomaterials for treating myocardial infarction have become an increasingly popular area of research. Within the past few years, this work has transitioned to some large animals models, and Phase I & II clinical trials. While these materials have preserved/improved cardiac function the effect of these materials on arrhythmogenesis, which is of considerable concern when injecting anything into the heart, has yet to be understood. Our manuscript is therefore a first of its kind in that it directly examines the potential of an injectable material to create a substrate for arrhythmias. This work suggests that site of delivery and distribution in the tissue are important criteria in the design and development of future biomaterial therapies for myocardial infarction treatment.
Project description:Congestive heart failure developing after acute myocardial infarction (AMI) is a major cause of morbidity and mortality. Clinical trials of cell-based therapy after AMI evidenced only a moderate benefit. We could show previously that suspensions of apoptotic peripheral blood mononuclear cells (PBMC) are able to reduce myocardial damage in a rat model of AMI. Here we experimentally examined the biochemical mechanisms involved in preventing ventricular remodelling and preserving cardiac function after AMI. Cell suspensions of apoptotic cells were injected intravenously or intramyocardially after experimental AMI induced by coronary artery ligation in rats. Administration of cell culture medium or viable PBMC served as controls. Immunohistological analysis was performed to analyse the cellular infiltrate in the ischaemic myocardium. Cardiac function was quantified by echocardiography. Planimetry of the infarcted hearts showed a significant reduction of infarction size and an improvement of post AMI remodelling in rats treated with suspensions of apoptotic PBMC (injected either intravenously or intramoycardially). Moreover, these hearts evidenced enhanced homing of macrophages and cells staining positive for c-kit, FLK-1, IGF-I and FGF-2 as compared to controls. A major finding in this study further was that the ratio of elastic and collagenous fibres within the scar tissue was altered in a favourable fashion in rats injected with apoptotic cells. Intravenous or intramyocardial injection of apoptotic cell suspensions results in attenuation of myocardial remodelling after experimental AMI, preserves left ventricular function, increases homing of regenerative cells and alters the composition of cardiac scar tissue. The higher expression of elastic fibres provides passive energy to the cardiac scar tissue and results in prevention of ventricular remodelling.
Project description:Although clinical trials of autologous whole bone marrow for cardiac repair demonstrate promising results, many practical and mechanistic issues regarding this therapy remain highly controversial. Here, we report the results of a randomized study of bone-marrow-derived mesenchymal stem cells, administered to pigs, which offer several new insights regarding cellular cardiomyoplasty. First, cells were safely injected by using a percutaneous-injection catheter 3 d after myocardial infarction. Second, cellular transplantation resulted in long-term engraftment, profound reduction in scar formation, and near-normalization of cardiac function. Third, transplanted cells were pre-prepared from an allogeneic donor and were not rejected, a major practical advance for widespread application of this therapy. Together, these findings demonstrate that the direct injection of cellular grafts into damaged myocardium is safe and effective in the perii-nfarct period. The direct delivery of cells to necrotic myocardium offers a valuable alternative to intracoronary cell injections, and the use of allogeneic mesenchymal stem cells provides a valuable strategy for cardiac regenerative therapy that avoids the need for preparing autologous cells from the recipient.
Project description:Tissue engineering offers an exciting possibility for cardiac repair post myocardial infarction. We assessed the effects of combined polyethylene glycol hydrogel (PEG), human induced pluripotent stem cell-derived cardiomyocyte (iPSC-CM), and erythropoietin (EPO) therapy in a rat model of myocardial infarction. PEG with/out iPSC-CMs and EPO; iPSC-CMs in saline; or saline alone was injected into infarcted hearts shortly after infarction. Injection of almost any combination of the therapeutics limited acute elevations in chamber volumes. After 10 weeks, attenuation of ventricular remodeling was identified in all groups that received PEG injections, while ejection fractions were significantly increased in the gel-EPO, cell, and gel-cell-EPO groups. In all treatment groups, infarct thickness was increased and regions of muscle were identified within the scar. However, no grafted cells were detected. Hence, iPSC-CM-encapsulating bioactive hydrogel therapy can improve cardiac function post myocardial infarction and increase infarct thickness and muscle content despite a lack of sustained donor-cell engraftment.
Project description:The adult heart has been considered as an organ with limited regenerating capability due to mature cardiomyocytes exit the cell cycle and stop proliferating. It has been reported that miR-17-92 cluster plays a key role in cardiomyocyte proliferation. According to the seed sequence, miR-17-92 cluster includes miR-18, miR-19, miR-20 and miR-92 families. Here, we show that intra-cardiac injection of miR-19 mimic into adult mouse hearts protects heart from myocardial infarction injury with reduced apoptosis, enhanced cardiomyocyte proliferation and cardiac regeneration. We performed the RNA-seq profiling in both injection of control mimic and miR-19 mimic post myocardial infarction. The transcriptome analysis indicates that genes related to immune response and cardiac remodeling were repressed by miR-19 in infarcted hearts. Overall design: Examine expression of mRNAs in control mimic and miR-19 mimic injected hearts after myocardium infarction
Project description:Since both myocardium and vasculature in the heart are excessively damaged following myocardial infarction (MI), therapeutic strategies for treating MI hearts should concurrently target both so as to achieve true cardiac repair. Here we demonstrate a concomitant method that exploits the advantages of cardiomyocytes derived from human induced pluripotent stem cells (hiPSC-CMs) and human mesenchymal stem cell-loaded patch (hMSC-PA) to amplify cardiac repair in a rat MI model. Epicardially implanted hMSC-PA provide a complimentary microenvironment which enhances vascular regeneration through prolonged secretion of paracrine factors, but more importantly it significantly improves the retention and engraftment of intramyocardially injected hiPSC-CMs which ultimately restore the cardiac function. Notably, the majority of injected hiPSC-CMs display adult CMs like morphology suggesting that the secretomic milieu of hMSC-PA constitutes pleiotropic effects in vivo. We provide compelling evidence that this dual approach can be a promising means to enhance cardiac repair on MI hearts.
Project description:Reduced regenerative capacity of aged stem cells hampers the benefits of autologous cell therapy for cardiac regeneration. This study investigated whether neuron-derived neurotrophic factor (NDNF) could rejuvenate aged human bone marrow (hBM)- multipotent mesenchymal stromal cells (MSCs) and whether the rejuvenated hBM-MSCs could improve cardiac repair after ischemic injury. Over-expression of NDNF in old hBM-MSCs decreased cell senescence and apoptosis. Engraftment of NDNF over-expressing old hBM-MSCs into the ischemic area of mouse hearts resulted in improved cardiac function after myocardial infarction, while promoting implanted stem cell survival. Our findings suggest NDNF could be a new factor to rejuvenate aged stem cells and improve their capability to repair the aged heart after injury.
Project description:Ischemic heart disease represents the leading cause of death worldwide. Heart failure following myocardial infarction (MI) is associated with severe fibrosis formation and cardiac remodeling. Recently, injectable hydrogels have emerged as a promising approach to repair the infarcted heart and improve heart function through minimally invasive administration. Here, a novel injectable human amniotic membrane (hAM) matrix is developed to enhance cardiac regeneration following MI. Human amniotic membrane is isolated from human placenta and engineered to be a thermoresponsive, injectable gel around body temperature. Ultrasound-guided injection of hAM matrix into rat MI hearts significantly improves cardiac contractility, as measured by ejection fraction (EF), and decrease fibrosis. The results of this study demonstrate the feasibility of engineering as an injectable hAM matrix and its efficacy in attenuating degenerative changes in cardiac function following MI, which may have broad applications in tissue regeneration.