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It has been nearly 15 years since the discovery of human-induced pluripotent stem cells (iPSCs). During this time, differentiation methods to targeted cells have dramatically improved, and many types of cells in the human body can be currently generated at high efficiency. In the cardiovascular field, the ability to generate human cardiomyocytes in vitro with the same genetic background as patients has provided a great opportunity to investigate human cardiovascular diseases at the cellular level to clarify the molecular mechanisms underlying the diseases and discover potential therapeutics. Additionally, iPSC-derived cardiomyocytes have provided a powerful platform to study drug-induced cardiotoxicity and identify patients at high risk for the cardiotoxicity; thus, accelerating personalized precision medicine. Moreover, iPSC-derived cardiomyocytes can be sources for cardiac cell therapy. Here, we review these achievements and discuss potential improvements for the future application of iPSC technology in cardiovascular diseases.

Cardiovascular diseases (CVDs) are a group of disorders of the blood vessels and heart, which are considered as the leading causes of death worldwide. The pathology of CVDs could be related to the functional abnormalities of multiple cell types in the heart. Single-cell RNA sequencing (scRNA-seq) technology is a powerful method for characterizing individual cells and elucidating the molecular mechanisms by providing a high resolution of transcriptomic changes at the single-cell level. Specifically, scRNA-seq has provided novel insights into CVDs by identifying rare cardiac cell types, inferring the trajectory tree, estimating RNA velocity, elucidating the cell–cell communication, and comparing healthy and pathological heart samples. In this review, we summarize the different scRNA-seq platforms and published single-cell datasets in the cardiovascular field, and describe the utilities and limitations of this technology. Lastly, we discuss the future perspective of the application of scRNA-seq technology into cardiovascular research.

Diabetic cardiomyopathy (DC) is associated with impaired endoplasmic reticulum (ER) function, development of ER stress, and induction of cardiac cell apoptosis. Preventive effects of BiP inducer X (BIX) were investigated against DC characteristic changes in a type 2 diabetes rat model. To establish diabetes, a high-fat diet and a single dose of streptozotocin were administered. Then, animals were assigned into the following groups: control, BIX, diabetic animals monitored for one, two, and three weeks. Diabetic rats were treated with BIX for one, two, and three weeks. Expressions of various ER stress and apoptotic markers were assessed by immunoblotting method. CHOP gene expression was assessed by Real-time PCR. Tissue expression of BiP was evaluated by immunohistochemistry method. Hematoxylin and eosin and Masson's trichrome staining were performed to assess histological changes in the left ventricle. Cardiac cell apoptosis was examined using TUNEL assay. BIX administration suppressed the activation of the ER stress markers and cleavage of procaspase-3 in the diabetic rats. Likewise, tissue expression of BiP protein was increased, while CHOP mRNA levels were decreased. These results were accompanied by reducing cardiac fibrosis and myocardial cell apoptosis suggesting protective effects of BIX against the development of DC by decreasing cardiomyocyte apoptosis and fibrosis.

Purpose We review the history of cardiac cell therapy, highlighting lessons learned from initial adult stem cell (ASC) clinical trials. We present pluripotent stem cell–derived cardiomyocytes (PSC-CMs) as a leading candidate for robust regeneration of infarcted myocardium but identify several issues that must be addressed before successful clinical translation. Methods We conducted an unstructured literature review of PubMed-listed articles, selecting the most comprehensive and relevant research articles, review articles, clinical trials, and basic or translation articles in the field of cardiac cell therapy. Articles were identified using the search terms adult stem cells, pluripotent stem cells, cardiac stem cell, and cardiac regeneration or from references of relevant articles, Articles were prioritized and selected based on their impact, originality, or potential clinical applicability. Findings Since its inception, the ASC therapy field has been troubled by conflicting preclinical data, academic controversies, and inconsistent trial designs. These issues have damaged perceptions of cardiac cell therapy among investors, the academic community, health care professionals, and, importantly, patients. In hindsight, the key issue underpinning these problems was the inability of these cell types to differentiate directly into genuine cardiomyocytes, rendering them unable to replace damaged myocardium. Despite this, beneficial effects through indirect paracrine or immunomodulatory effects remain possible and continue to be investigated. However, in preclinical models, PSC-CMs have robustly remuscularized infarcted myocardium with functional, force-generating cardiomyocytes. Hence, PSC-CMs have now emerged as a leading candidate for cardiac regeneration, and unpublished reports of first-in-human delivery of these cells have recently surfaced. However, the cardiac cell therapy field's history should serve as a cautionary tale, and we identify several translational hurdles that still remain. Preclinical solutions to issues such as arrhythmogenicity, immunogenicity, and poor engraftment rates are needed, and next-generation clinical trials must draw on robust knowledge of mechanistic principles of the therapy. Implications The clinical transplantation of functional stem cell–derived heart tissue with seamless integration into native myocardium is a lofty goal. However, considerable advances have been made during the past 2 decades. Currently, PSC-CMs appear to be the best prospect to reach this goal, but several hurdles remain. The history of adult stem cell trials has taught us that shortcuts cannot be taken without dire consequences, and it is essential that progress not be hurried and that a worldwide, cross-disciplinary approach be used to ensure safe and effective clinical translation.

iPSCs are promising and have potential benefits for medical use, understanding human organogenesis, and cell therapy for advanced diseases. iPSCs are derived pluripotent cells which can further differentiate into functional human cell-lineages, such as neuronal, epithelial cells, cardiac cell, immune cell, and blood cells, etc. Thirteen years on, the discovery of iPSC has revolutionized the field of regenerative medicine, and also the number of clinical studies using iPSC has been growing rapidly worldwide. However, Japan is leading the race of iPSC-based studies and clinical trials due to government support. The Japanese government implemented the world’s fastest approval system and set to host first pretrial clinical studies using iPSC derived therapeutic products. Also, multinational companies of Japan are investing enormously in iPSC-based research for mobilization of iPSC-derived regenerative products to the research institution globally. This review presents an overview of iPSCs, potential benefits, commercialization of iPSC, iPSC-based pretrial clinical studies, and iPSC biobanking in Japan.

Various cell-based therapies are currently investigated in an attempt to tackle the high morbidity and mortality associated with heart failure. The need for these therapies to move towards the clinic is pressing. Therefore, preclinical large animal studies that use non-autologous cells are needed to evaluate their potential. However, non-autologous cells are highly immunogenic and trigger immune rejection responses resulting in potential loss of efficacy. To overcome this issue, adequate immunosuppressive regimens are of imminent importance but clear guidelines are currently lacking. In this review, we assess the immunological barriers regarding non-autologous cell transplantation and immune modulation with immunosuppressive drugs. In addition, we provide recommendations with respect to immunosuppressive regimens in preclinical cardiac cell-replacement studies.

Cardiovascular disease is the leading cause of human mortality and disability worldwide, primarily due to myocardial infarction (MI) and the resultant heart failure. To address this, animal models of MI have been developed to better understand the pathophysiological process and to enable the discovery and development of new therapies. The most commonly used small and large mammal models of MI accurately reproduce histopathologically the four characteristic post-MI phases: cardiac cell death, inflammation, myocardial repair and remodelling. However, differences between the time of onset of each characteristic phase and the kinetics of various cellular reactions between human MI and animal models, and between animal models, require careful consideration when defining the variables to be analysed and the timepoints of assessment in experimental studies. Typically, the progression of the different phases post-MI occur more rapidly in rodent models compared with large-animal models and man, suggesting the use of large-animal models is more translational for studying human MI. This review provides an overview of the main anatomopathological features of small and large animal models of MI and discusses the key species-specific histopathological similarities and differences.

This study evaluated the effects of tomato sauce and lycopene on hepatic and cardiac cell biomarkers in rats fed a high-fat diet. Animals were split into five groups: control group, high-fat group (HG), high-fat tomato sauce group, high-fat lycopene 2 mg, and high-fat lycopene 4 mg. Food and water were offered

The field of cardiac cell therapy is under siege. Legacies of excessive hype, scientific misconduct and dead ends have fuelled the prevailing scepticism. However, promising clinical data, along with more trenchant mechanistic understanding, together provide glimmers of hope for the future of cell therapy for the heart.

The adult human heart can only adapt to heart diseases by starting a myocardial remodeling process to compensate for the loss of functional cardiomyocytes, which ultimately develop into heart failure. In recent decades, the evolution of new strategies to regenerate the injured myocardium based on cellular reprogramming represents a revolutionary new paradigm for cardiac repair by targeting some key signaling molecules governing cardiac cell fate plasticity. While the indirect reprogramming routes require an in vitro engineered 3D tissue to be transplanted in vivo, the direct cardiac reprogramming would allow the administration of reprogramming factors directly in situ, thus holding great potential as in vivo treatment for clinical applications. In this framework, cellular reprogramming in partnership with nanotechnologies and bioengineering will offer new perspectives in the field of cardiovascular research for disease modeling, drug screening, and tissue engineering applications. In this review, we will summarize the recent progress in developing innovative therapeutic strategies based on manipulating cardiac cell fate plasticity in combination with bioengineering and nanotechnology-based approaches for targeting the failing heart.

Cardiovascular diseases (CVD) are the leading cause of morbidity and mortality worldwide. Conventional therapies involving surgery or pharmacological strategies have shown limited therapeutic effects due to a lack of cardiac tissue repair. Gene therapy has opened an avenue for the treatment of cardiac diseases through manipulating the underlying gene mechanics. Several gene therapies for cardiac diseases have been assessed in clinical trials, while the clinical translation greatly depends on the delivery technologies. Non-viral vectors are attracting much attention due to their safety and facile production compared to viral vectors. In this review, we discuss the recent progress of non-viral gene therapies for the treatment of cardiovascular diseases, with a particular focus on myocardial infarction (MI). Through a summary of delivery strategies with which to target cardiac tissue and different cardiac cells for MI treatment, this review aims to inspire new insights into the design/exploitation of non-viral delivery systems for gene cargos to promote cardiac repair/regeneration.

Due to multiple mutations of SARS-CoV-2, the mystery of defeating the virus is still unknown. Cardiovascular complications are one of the most concerning effects of COVID-19 recently, originating from direct and indirect mechanisms. These complications are associated with long-term Cardio-vascular diseases and can induce sudden cardiac death in both infected and recovered COVID-19 patients. The purpose of this research is to do a competitive analysis between conventional techniques with the upgraded alternative 3D bioprinting to replace the damaged portion of the myocardium. Additionally, this study focuses on the potential of 3D bioprinting to be a novel alternative. Finally, current challenges and future perspective of 3D bioprinting technique is briefly discussed.

Purpose of Review Cardiac cell-based therapy represents a promising approach for cardiac repair. However, one of the main challenges is cardiac arrhythmias associated with stem cell transplantation. The current review summarizes the recent progress in model systems for addressing mechanisms of arrhythmogenesis in cardiac repair. Recent Findings Animal models have been extensively developed for mechanistic studies of cardiac arrhythmogenesis. Advances in human induced pluripotent stem cells (hiPSCs), patient-specific disease models, tissue engineering, and gene editing have greatly enhanced our ability to probe the mechanistic bases of cardiac arrhythmias. Additionally, recent development in multiscale computational studies and machine learning provides yet another powerful tool to quantitatively decipher the mechanisms of cardiac arrhythmias. Summary Advancing efforts towards the integrations of experimental and computational studies are critical to gain insights into novel mitigation strategies for cardiac arrhythmias in cell-based therapy.

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.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.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.

Much has been written about arrhythmias in structurally normal hearts. In this review, we focus on rapid ventricular arrhythmias that occur in hearts having a pathogenic genetic variant that has been found in families in which arrhythmias occur. We discuss these mutations in terms of their effect on cardiac cell electrical function and initiation of arrhythmias. We also focus on Purkinje cells, their anatomic networks, and their molecular signatures as the sites of origin of arrhythmias. We discuss therapeutic options for treatment of these potentially life-threatening arrhythmias. Although all Purkinje-based arrhythmias are not included (eg, conduction block rhythms), syndromes discussed include idiopathic ventricular fibrillation, catecholaminergic polymorphic ventricular tachycardia, long QT syndrome, Andersen-Tawil syndrome, and Brugada syndrome.

Involuntary cardiac pumping supplies oxygen and nutrients into coronary and peripheral arteries, which has been recognized as main dynamics of body. Among the molecules regarding cardiac dynamics, we aimed to investigate whether oxidative stress would induce the production of the exercise hormone and its levels could be regulated by herbal medicine, which represents “Heart Governs Vessels.” We searched MEDLINE for exercise hormone and screened titles and abstracts. The primary human myocardial, coronary arterial and peripheral cell lines were treated with hydrogen peroxide to mimic oxidative stress condition. Activity of irisin, an exercise hormone, was measured by ELISA assay. Expression of NADPH oxidase 2, an irisin’s putative target, was determined by immunoblot assay. Among the cardiovascular effects, we found that left ventricular systolic functions could be affected by several molecules, including irisin. In primary myocardial, coronary arterial and peripheral cell lines, irisin secretion and NADPH oxidase 2 expression was increased by 75 µM hydrogen peroxide. Interestingly, ChungliJagam-tang inhibited NOX2 activities by 31.45%, 42.62%, and 47.22% in an oxidative stress-induced primary myocardial, coronary arterial and peripheral cell lines, respectively. In conclusion, the changes in NOX2 level under an oxidative stress condition which mimicked left ventricular functions are associated with cardiac irisin activities and they were controlled by the herbal prescription on “Heart Governs Vessels”.

The novel self-healing hydrogel is a typical intelligent and multi-functional biomedical material. It is of great significance to resolve the challenge of repairing damages in flexible biomaterials, which could facilitate intelligent activity and efficiency in biomaterials. The present paper reviews the design strategies and performance of recently developed self-healing hydrogels and their applications in tissue engineering, including transplantation of neural stem cells, repair of the central nervous system, bone regeneration, regeneration of cartilage-bone tissue complex, cardiac cell therapy, as well as hemostasis. Such advances and applications promote the innovative design and fabrication of intelligent multifunctional hydrogels and offer new opportunities to increase the diversity of flexible self-healing materials. Such a synthesis of research and applications lays a foundation for further development of intelligent hydrogels for tissue engineering and their application in the biomedical field.

The retraction of >30 falsified studies by Anversa et al. has had a disheartening impact on the cardiac cell therapeutics field. The premise of heart muscle regeneration by the transdifferentiation of bone marrow cells or putative adult resident cardiac progenitors has been largely disproven. Over the past 18 years, a generation of physicians and scientists has lost years chasing these studies, and patients have been placed at risk with little scientific grounding. Funding agencies invested hundreds of millions of dollars in irreproducible work, and both academic institutions and the scientific community ignored troubling signals over a decade of questionable work. Our collective retrospective analysis identifies preventable problems at the level of the editorial and peer-review process, funding agencies and academic institutions. This Perspective provides a chronology of the forces that led to this scientific debacle, integrating direct knowledge of the process. We suggest a science-driven path forward that includes multiple novel approaches to the problem of heart muscle regeneration. Chien et al. reflect on lessons learned following the recent announcement that 31 papers from the Anversa laboratory on cardiac cell therapy are being retracted.

Cardiac diseases are the leading cause of deaths worldwide; however, to date, there has been limited progress in the development of therapeutic options for these conditions. Animal models have been the most extensively studied methods to recapitulate a wide variety of cardiac diseases, but these models exhibit species-specific differences in physiology, metabolism and genetics, which lead to inaccurate and unpredictable drug safety and efficacy results, resulting in drug attrition. The development of human pluripotent stem cell (hPSC) technology in theory guarantees an unlimited source of human cardiac cells. These hPSC-derived cells are not only well suited for traditional two-dimensional (2-D) monoculture, but also applicable to more complex systems, such as three-dimensional (3-D) organoids, tissue engineering and heart on-a-chip. In this review, we discuss the application of hPSCs in heart disease modeling, cell therapy, and next-generation drug discovery. While the hPSC-related technologies still require optimization, their advances hold promise for revolutionizing cell-based therapies and drug discovery.

Immune checkpoint inhibitors (ICIs) have transformed the treatment of various cancers, including malignancies once considered untreatable. These agents, however, are associated with inflammation and tissue damage in multiple organs. Myocarditis has emerged as a serious ICI-associated toxicity, because, while seemingly infrequent, it is often fulminant and lethal. The underlying basis of ICI-associated myocarditis is not completely understood. While the importance of T cells is clear, the inciting antigens, why they are recognized, and the mechanisms leading to cardiac cell injury remain poorly characterized. These issues underscore the need for basic and clinical studies to define pathogenesis, identify predictive biomarkers, improve diagnostic strategies, and develop effective treatments. An improved understanding of ICI-associated myocarditis will provide insights into the equilibrium between the immune and cardiovascular systems.

Myocardial infarction (MI) causes cardiac cell death, induces persistent inflammatory responses, and generates harmful pathological remodeling, which leads to heart failure. Biomedical approaches to restore blood supply to ischemic myocardium, via controlled delivery of angiogenic and immunoregulatory proteins, may present an efficient treatment option for coronary artery disease (CAD). Vascular endothelial growth factor (VEGF) is necessary to initiate neovessel formation, while platelet-derived growth factor (PDGF) is needed later to recruit pericytes, which stabilizes new vessels. Anti-inflammatory cytokines like interleukin-10 (IL-10) can help optimize cardiac repair and limit the damaging effects of inflammation following MI. To meet these angiogenic and anti-inflammatory needs, an injectable polymeric delivery system composed of encapsulating micelle nanoparticles embedded in a sulfonated reverse thermal gel was developed. The sulfonate groups on the thermal gel electrostatically bind to VEGF and IL-10, and their specific binding affinities control their release rates, while PDGF-loaded micelles are embedded in the gel to provide the sequential release of the growth factors. An in vitro release study was performed, which demonstrated the sequential release capabilities of the delivery system. The ability of the delivery system to induce new blood vessel formation was analyzed in vivo using a subcutaneous injection mouse model. Histological assessment was used to quantify blood vessel formation and an inflammatory response, which showed that the polymeric delivery system significantly increased functional and mature vessel formation while reducing inflammation. Overall, the results demonstrate the effective delivery of therapeutic proteins to promote angiogenesis and limit inflammatory responses.

The concept that cell‐based repair of myocardial injury might be possible was introduced almost two decades ago; however, the field of cardiovascular reparative medicine has been criticized as translation to clinically effective approaches has been slow. The recent retraction of a series of papers has further impacted perception of this area of research. As researchers, clinicians, and teachers in this field, we felt it incumbent to critically appraise the current state of cardiac cell repair, determine what can be learned from past mistakes, and formulate best practices for future work. This special communication summarizes an introspective assessment of what has fallen short, how to prevent similar issues, and how the field might best move forward in the service of science and patients.

The chaotic spatio-temporal electrical activity during life-threatening cardiac arrhythmias like ventricular fibrillation is governed by the dynamics of vortex-like spiral or scroll waves. The organizing centers of these waves are called wave tips (2D) or filaments (3D) and they play a key role in understanding and controlling the complex and chaotic electrical dynamics. Therefore, in many experimental and numerical setups it is required to detect the tips of the observed spiral waves. Most of the currently used methods significantly suffer from the influence of noise and are often adjusted to a specific situation (e.g. a specific numerical cardiac cell model). In this study, we use a specific type of deep neural networks (UNet), for detecting spiral wave tips and show that this approach is robust against the influence of intermediate noise levels. Furthermore, we demonstrate that if the UNet is trained with a pool of numerical cell models, spiral wave tips in unknown cell models can also be detected reliably, suggesting that the UNet can in some sense learn the concept of spiral wave tips in a general way, and thus could also be used in experimental situations in the future (ex-vivo, cell-culture or optogenetic experiments).

Fabry disease (FD) is a lysosomal storage disorder, depending on defects in alpha-galactosidase A (GAL) activity. At the clinical level, FD shows a high phenotype variability. Among them, cardiovascular dysfunction is often recurrent or, in some cases, is the sole symptom (cardiac variant) representing the leading cause of death in Fabry patients. The existing therapies, besides specific symptomatic treatments, are mainly based on the restoration of GAL activity. Indeed, mutations of the galactosidase alpha gene (GLA) cause a reduction or lack of GAL activity leading to globotriaosylceramide (Gb3) accumulation in several organs. However, several other mechanisms are involved in FD’s development and progression that could become useful targets for therapeutics. This review discusses FD’s cardiovascular phenotype and the last findings on molecular mechanisms that accelerate cardiac cell damage.

Adult cardiomyocytes are terminally differentiated cells that result in minimal intrinsic potential for the heart to self-regenerate. The introduction of novel approaches in cardiac tissue engineering aims to repair damages from cardiovascular diseases. Recently, conductive biomaterials such as carbon- and gold-based nanomaterials, conductive polymers, and ceramics that have outstanding electrical conductivity, acceptable mechanical properties, and promoted cell-cell signaling transduction have attracted attention for use in cardiac tissue engineering. Nevertheless, comprehensive classification of conductive biomaterials from the perspective of cardiac cell function is a subject for discussion. In the present review, we classify and summarize the unique properties of conductive biomaterials considered beneficial for cardiac tissue engineering. We attempt to cover recent advances in conductive biomaterials with a particular focus on their effects on cardiac cell functions and proposed mechanisms of action. Finally, current problems, limitations, challenges, and suggested solutions for applications of these biomaterials are presented.

The cardiovascular system is the first system in the body to reach a functional state, at around the 21st and 22nd day of gestation. As a result, any aortic arch anatomical variant results from the aberrant embryologic migration and/or differentiation of undifferentiated cardiac cell precursors. Initially, six paired aortic channels encircle the embryonic pharynx. They supply the developing pharyngeal arches and arise from the aortic sac. These channels run dorsally, embedded in the mesenchyme of the pharyngeal arches, and terminate in the right and left dorsal aortae.

Introduction: Sepsis remains a significant cause of mortality in the intensive care unit till today. Recent research suggests nearly one in four deaths in people with heart failure is caused by sepsis. Overexpression of mammalian Pellino-1 (Peli1), a E3 ubiquitin ligase, causes inhibition of apoptosis, oxidative stress, and preservation of cardiac function in a myocardial infarction model. Therefore, in the present study, we explored the possibility to overcome sepsis mediated heart failure by overexpressing Peli1 (AMPEL1Tg/+) in a mouse model of severe sepsis. Methods: C57BL/6J (WT) and AMPEL1 Tg/+ mice were divided into Wild-type sham (WTS), Wild-type Cecal Ligation and Puncture (WTCLP), AMPEL1 Tg/+ sham (AMPEL1 Tg/+ S) and AMPEL1 Tg/+ CLP. Cardiac function (LVEF, FS) by two-dimensional echocardiography was assessed pre-procedure, at 6, and 24 hours post-surgery. Serum IL-6 and TNF-alpha (ELISA) at 6 hours and cardiac apoptosis (TUNEL assay) at 24 hours were measured. Results are expressed as mean ± SEM. Results: Analysis of echocardiographic parameters (EF, FS) preoperatively and among the sham groups were similar however there was significant preservation of post-procedure LVEF (%) in the AMPEL1 Tg/+ CLP at the 6 hour (AMPEL1 Tg/+ :52.7 ± 3.71 vs WT:40.7 ±2.46, p=0.013, n=10-11) and 24-hour time point (AMPEL1 Tg/+ :63.1 ± 1.63 vs WT:49.3 ± 4.41, p=0.002, n=9-11) compared to WT. Similar trend was observed in estimation of FS (%) at 6 hours (AMPEL1 Tg/+ :26.3 ± 2.22 vs WT:19.3 ±1.37, p=0.014, n=10-11) and 24 hours (AMPEL1 Tg/+ :32.4 ± 1.89 vs WT:24.4 ± 2.67, p=0.031, n=9-11). A marked decrease in serum IL-6 (AMPEL1 Tg/+ :259.7 ± 18.70 vs WT:483.2 ± 24.01, pTg/+ :86.89 ± 14.36 vs WT:161.8 ± 20, p=0.012, n=6, pg/mL) was observed in the AMPEL1 Tg/+ CLP at 6 hours. The preserved cardiac function in CLP was further supported by a noticeable decrease in cardiac apoptosis (% TUNEL positive cells) at 24 hours in the AMPEL1 Tg/+ CLP group (4.7 ± 0.94 vs 11.7 ± 2.82, p=0.040, n=6,) compared to WTCLP. Conclusions: Thus, Peli1 overexpression is a novel approach that preserved cardiac function, reduced inflammatory markers, and apoptosis following severe sepsis in a murine genetic model.

Introduction: iPS cell-derived cardiac cell sheet (iPS sheet) transplantation is expected to have both cytokine paracrine effect and mechanical effect on the failed heart. In order to clarify the latter effect, we utilized the cardiac simulator “UT-Heart” to quantitatively evaluate the improvement of pumping function of the left ventricle with myocardial infarction covered by the thickened iPS sheet in silico. The direct mechanical impact of iPS sheet with various thicknesses was calculated first, and then the remodeling effect of fiber orientation was investigated. Patient and Method: An infarcted heart model based on the actual patient’s data was created on the computer and an iPS sheet was virtually implanted under the following assumptions: (1) electrophysiologically synchronized with the underlying cardiac muscle, (2) covered the infarct area entirely, (3) the fiber orientation of sheet was parallel to that of the epicardial tissue when attached, (4) if remodeling occurs, the fiber orientations of myocardial tissue and the attached sheet change such that the contraction force and the fiber strains are homogenized in the heart. The UT-Heart simulation was performed while changing iPS sheet thickness from 1mm to 5mm. Results: The LVEF of 18.0 % at pre-implantation was improved to 18.5 % with 1 mm thickness, and 19.6 % with 5 mm thickness without remodeling assumption as shown in the left of the figure. If LV remodeling occurs, the LVEF was improved to 20.9 % with 1mm thickness and 22.8 % with 5mm thickness. The LVESP was 10 mmHg higher than that of pre-implantation even when 1mm thickness was implanted. Conclusion: The direct mechanical effect of the thickened iPS sheet on the distressed LV was quantitatively evaluated in silico. Because changes in fiber orientation have a significant impact on pumping function, the remodeling assumption used herein should be experimentally verified in the future.

Exosomes are small particles secreted from cells through an endosomal sorting complexes required for transport (ESCRT)-mediated pathway that releases vesicles into the extracellular matrix following fusion of the endosomal multivesicular body to the plasma membrane. Initially thought to be a waste disposal system for the cell, exosomes are now recognized as important mediators in cellular communication, transporting nucleic acid, protein and lipid. We hypothesize that microRNA (miRNA) transcriptomic profiles isolated from exosomes are distinct for each cardiovascular lineage in healthy control patients. Using induced pluripotent stem cells (iPSC), established differentiation protocols and a high-yield mechanical-sorting device (ExoTIC), we characterized the transcriptomic profiles of exosomal secretions derived from cardiomyocytes (CM), cardiac fibroblasts (CF) and endothelial cells (EC). We identified 120 miRNAs from 94 miRNA genes to be secreted at appreciable levels. We discovered 1) let-7 miRNA precursors are depleted in iPSC secretomes; 2) only a subset of total cellular miRNAs are present; 3) a common core of miRNAs are secreted by all three cardiac cell types; and 4) distinct enrichment or depletion of different mature miRNAs in each exosome type. The exosomal transcriptomic profiles of each lineage was compared to a published atlas of miRNA from seventeen tissue types from the human body. miR-302c known to be specific to pluripotent cells and is enriched in iPSC exosomes and found in bone, reflecting hematopoietic stem cells. miR-1, critical for cardiac development and pathology, is secreted by iPSC-CM and enriched in striated muscle and myocardium. miR-151 is secreted by iPSC-CF and is expressed ubiquitously. The relative enrichment of miRNAs in different cardiac tissues could be used to quantifying the cellular content of heterogenous mixtures of iPSC-derived cardiac lineages. We developed a ratiometric cell purity assay that can sensitively detect iPSC contamination in iPSC-CM differentiations.

The mechanism underlying dilated cardiomyopathy (DCM) in children without a known genetic disorder are unclear. In contrast to adult DCM patients, there is an unmet need for therapeutic options that improve survival in pediatric DCM. Therefore, we performed single nuclei RNA sequencing (snRNA-seq) from heart tissue obtained from children undergoing heart transplantation due to severe heart failure. We processed heart tissue from 6 children with DCM (EF: 18.67±2.11%) of an age of 0.5, 0.75, 5, 6, 12 and 13 years (y). After snRNA-seq, unsupervised clustering was performed identifying 8 major cell types, including cardiomyocytes (CM), fibroblasts (FB), endothelial cells, leukocytes, pericytes, smooth muscle cells, neuronal-like cells and an endothelial-fibroblast-like cluster. Relative numbers of FB clusters correlated with increasing age of the children which was clinically validated by measuring late enhancement (LE) with cardiac magnetic resonance imaging in 68 pediatric DCM patients. The mean age of patients with LE was 5.86±0.53y vs. 2.36±0.53y in patients without LE (p Together, these data demonstrate an age-dependent decrease in CM numbers concomitant with increased FBs in pediatric DCM. FBs of Funding Acknowledgement Type of funding source: Public grant(s) – EU funding. Main funding source(s): Dr. Rolf M. Schwiete Stiftung, DZHK

Acute injuries to the heart, like myocardial infarction (MI), contribute to the development and pathology of heart failure (HF). Reperfusion of the ischemic heart greatly increases survival but results in reperfusion injury that can account for up to 50% of the final infarct size. The inflammatory response to MI-induced myocardial injury is thought to be responsible for the propagation of reperfusion injury into the infarct border zone, expanding myocardial damage. We have previously shown in a swine model of MI that intramyocardial injections of cortical bone-derived stem cells (CBSCs) into the infarct border zone has no acute cardioprotective effect but reduces scar size by half and prevents the decline of ejection fraction and LV dilation 3 months after MI. Our new preliminary data show that CBSCs have potent immunoregulatory capabilities. Therefore, we hypothesize that CBSC treatment has an effect on the immune response to MI that improves the wound healing response to myocardial injury and mitigates LV remodeling and infarct size 3 months later. To test this hypothesis, we characterized the effects of CBSC paracrine factors on macrophages in vitro and found that CBSC-treated macrophages express higher levels of CD206, produce more IL-1RA and IL-10, and phagocytose apoptotic myocytes more efficiently. In addition, macrophages were increased in CBSC-treated swine hearts 7 days after MI compared to controls with a corresponding increase in IL-1RA and TIMP-2. Apoptosis was decreased overall and in macrophages specifically in CBSC-treated animals. From these data we conclude CBSCs may exert an acute pro-reparative effect on the immune response after MI, reducing reperfusion injury and adverse remodeling resulting in improved functional outcomes at later time points.

Type-II diabetes (T2D) patients affected by underlying hyperglycemic (high glucose/blood sugar) conditions often suffer from cardiac atrophy, resulting in tissue mass reduction and debilitating cardiac health. To understand pathophysiological mechanisms during progression of cardiac atrophy, a 3D bioprinted organoid platform was developed from a mixture of hydrogels containing human cardiac cells, including cardiomyocytes (CM), fibroblasts (CF) and endothelial cells (EC), to mimic the functionality of the in-vivo tissue. The organoids were cultured using normoglycemic- or hyperglycemic-conditions. The expression of essential biomarkers in these organoids, for myocardin (Myocd), troponin-I (TRP-I), fibroblast protein-1 (FSP-1) and endothelin-1 (ET-1) was confirmed. To assess the physiological cellular connections during hyperglycemia, the presence of Connexin-43 (CX-43) was assessed in the presence of a CX-43 blocker, gap26. Epigenomic tools were used to simultaneously interrogate histone-modifications by histone 3 lysine 9 mono-methylation (H3K9me1) along with the co-regulation of inflammatory mediators, such as the high mobility group box 1 (HMGB1) and toll like receptor 4 (TLR4) in the cardiac organoids cultured using normal versus hyperglycemic conditions. Organoids exposed to high glucose showed an increased expression of H3K9me1 as well as inflammatory mediators HMGB1 and TLR4. Hyperglycemia also exhibited alterations in expression of Myocd and FSP-1 in the organoids, compared to normoglycemic conditions. Treatment with gap26 affected the CX-43 expression significantly, in organoids cultured under hyperglycemia suggesting that high glucose conditions associated with prolonged diabetes may lead to compromised CM-CF coupling, essential for maintenance of cardiac functionality. Increased levels of H3K9me1 suggest decreased expression of Myocd, which may lead to CM degeneration. Epigenetic modifications including alterations in histone methylation in regulation of the myocardial genes and gap junction proteins under hyperglycemic conditions, may lead to cardiac atrophy. We expect to establish an actual T2D patient iPSC cell derived cardiac platform, to offer new therapeutic opportunities within the field.

Although the initial clinical trials of cardiac cell therapy have failed to demonstrate unequivocal clinical benefits, the accumulation of preclinical data gathered in parallel can now help us to understand the main causes of failures, while providing mechanistic insights that may be leveraged to improve the outcomes of subsequent clinical studies using cells or their secreted products. This review briefly describes the current status of clinical trials, discusses the potential mechanisms of action of the grafted cells, and the impact of this knowledge on the design of future studies, and finally draws some perspectives.

Background CardioChimeras produced by fusion of murine c‐kit + cardiac interstitial cells with mesenchymal stem cells promote superior structural and functional recovery in a mouse model of myocardial infarction compared with either precursor cell alone or in combination. Creation of human CardioChimeras ( hCCs ) represents the next step in translational development of this novel cell type, but new challenges arise when working with c‐kit + cardiac interstitial cells isolated and expanded from human heart tissue samples. The objective of the study was to establish a reliable cell fusion protocol for consistent optimized creation of hCC s and characterize fundamental hCC properties. Methods and Results Cell fusion was induced by incubating human c‐kit + cardiac interstitial cells and mesenchymal stem cells at a 2:1 ratio with inactivated Sendai virus. Hybrid cells were sorted into 96‐well microplates for clonal expansion to derive unique cloned hCC s, which were then characterized for various cellular and molecular properties. hCC s exhibited enhanced survival relative to the parent cells and promoted cardiomyocyte survival in response to serum deprivation in vitro. Conclusions The generation of hCC is demonstrated and validated in this study, representing the next step toward implementation of a novel cell product for therapeutic development. Feasibility of creating human hybrid cells prompts consideration of multiple possibilities to create novel chimeric cells derived from cells with desirable traits to promote healing in pathologically damaged myocardium.

Some of the most significant leaps in the history of modern civilization-the development of article in China, the steam engine, which led to the European industrial revolution, and the era of computers-have occurred when science converged with engineering. Recently, the convergence of human pluripotent stem cell technology with biomaterials and bioengineering have launched a new medical innovation: functional human engineered tissue, which promises to revolutionize the treatment of failing organs including most critically, the heart. This compendium covers recent, state-of-the-art developments in the fields of cardiovascular tissue engineering, as well as the needs and challenges associated with the clinical use of these technologies. We have not attempted to provide an exhaustive review in stem cell biology and cardiac cell therapy; many other important and influential reports are certainly merit but already been discussed in several recent reviews. Our scope is limited to the engineered tissues that have been fabricated to repair or replace components of the heart (eg, valves, vessels, contractile tissue) that have been functionally compromised by diseases or developmental abnormalities. In particular, we have focused on using an engineered myocardial tissue to mitigate deficiencies in contractile function. (Circ Res. 2018;123:244–265. DOI: 10.1161/CIRCRESAHA.118.311213.)

Stem cell therapy is a promising strategy for tissue regeneration. The therapeutic benefits of cell therapy are mediated by both direct and indirect mechanisms. However, the application of stem cell therapy in the clinic is hampered by several limitations. This concise review provides a brief introduction into stem cell therapies for ischemic heart disease. It summarizes cell-based and cell-free paradigms, their limitations, and the benefits of using them to target disease.

Transplantations of various stem cells or their progeny have repeatedly improved cardiac performance in animal models of myocardial injury; however, the benefits observed in clinical trials have been generally less consistent. Some of the recognized challenges are poor engraftment of implanted cells and, in the case of human cardiomyocytes, functional immaturity and lack of electrical integration, leading to limited contribution to the heart’s contractile activity and increased arrhythmogenic risks. Advances in tissue and genetic engineering techniques are expected to improve the survival and integration of transplanted cells, and to support structural, functional, and bioenergetic recovery of the recipient hearts. Specifically, application of a prefabricated cardiac tissue patch to prevent dilation and to improve pumping efficiency of the infarcted heart offers a promising strategy for making stem cell therapy a clinical reality.

Cardiac cell-based therapy has emerged as a novel therapeutic option for patients dealing with untreatable refractory angina (RA). However, after more than a decade of controlled studies, no definitive consensus has been reached regarding clinical efficacy. Although positive results in terms of surrogate endpoints have been suggested by early and phase II clinical studies as well as by meta-analyses, the more recent reports lacked the provision of definitive response in terms of hard clinical endpoints. Regrettably, pivotal trials designed to conclusively determine the efficacy of cell-based therapeutics in such a challenging clinical condition are therefore still missing. Considering this, a comprehensive reappraisal of cardiac cell-based therapy role in RA seems warranted and timely, since a number of crucial cell- and patient-related aspects need to be systematically analysed. As an example, the large variability in efficacy endpoint selection appears to be a limiting factor for the advancement of cardiac cell-based therapy in the field. This review will provide an overview of the key elements that may have influenced the results of cell-based trials in the context of RA, focusing in particular on the understanding at which the extent of angina-related endpoints may predict cell-based therapeutic efficacy.

Cardiac injury due to any cause leads to cardiac cell damage and thereby to ventricular dysfunction. Unlike current medical therapy, cardiac regeneration by stem cell therapy is a promising approach which has a potential to reverse left ventricular dysfunction. It is conceived to complement and potentially transform available therapeutic armamentarium. Early experience in clinical studies support the safety and feasibility of cell therapy and as adjuvants to established practice. This review discusses type of stem cells used, its therapeutic indications, and its current status.

Cardiotoxicity is one of the major adverse effects of pharmaceuticals and new methods are sought for measuring cell properties with high-throughput. Here we report a flexible diffraction grating device fabricated from polydimethylsiloxane coated with platinum to make optically responsive cell culturing substrates. Cardiomyocytes from neonatal Sprague-Dawley rats were isolated and seeded upon the surface of the PDMS diffraction grating using fibronectin as the binding protein. On this substrate the cells formed a confluent layer and continued beating synchronously. By measuring the optical change of the PDMS substrate, the beating of the confluent layer could be monitored. Epinephrine was introduced to the cell environment and the change in beating frequency was measured and visualized. This flexible diffraction grating substrate provides a new way for remotely measuring cell beating properties during high-throughput testing and within miniaturized or confined device architectures.

Ischemic heart diseases like myocardial infarction are the largest contributors to cardiovascular disease world-wide. The resulting cardiac cell death impairs function of the heart and can lead to heart failure and death. Re-perfusion of the ischemic tissue is necessary but causes damage to the surrounding tissue by re-perfusion injury and initiates a sterile inflammatory response. Cortical bone stem cells (CBSCs) have been shown to increase pump function and decrease scar size in a large animal swine model of myocardial infarction. To explore the potential cause of these changes, we hypothesized that CBSCs were altering the inflammatory response after re-perfusion thereby changing the wound healing process. To test this, we performed serial immune cell analysis of the blood and tissue from Gottingen mini-swine that underwent 90 minutes of lateral anterior descending coronary artery ischemia followed by 7 days of re-perfusion to assess changes in immune cell recruitment and phenotype. Our findings indicate that CBSCs modify the cytokines released by immune cells in the infarct, decrease macrophage infiltration of the infarct 3 days after MI, and increase the recruitment of CD4+ T-cells to the infarct zone 7 days after MI. In addition, these changes reflect a pro-healing inflammatory environment. From this data, we conclude that CBSCs are influencing immune cell recruitment dynamics and phenotype, and these changes may contribute to the decreased scar size and increased pump function seen in CBSC-treated animals.

One of the most common causes of heart failure is ischaemia. In this disease, the heart muscles die due to the lack or insufficiency of the blood in the cardiac veins. As a result of such a phenomenon, the action potential in that part of the heart would fade. In this article, using the electric model of the cardiac cell and the mechanism of producing an ECG signal in the heart, the process of producing cardiac electrical potential has been modelled. In this regard, the basic constituent signals of the ECG are generated. Afterward, by accumulating these signals, the final ECG is reproduced. In addition, by variation of the presented model parameters, the cardiac ischaemic signal is simulated in a way that the influence of ventricle ischaemia on the ventricular tissues is considered. The results of such a simulation demonstrate a sufficient match between the model output and the reported changes of the cardiac arrhythmia including ischaemic failures. Here, we report the 91% match between the simulated signal and the considered clinical data.

The myocardium is composed of various cell types including cardiomyocytes, fibroblasts, endothelial cells, and leukocytes. Although cardiomyocytes count for up to 85% of a heart’s volume, the actual cell number of cardiomyocytes account for just 30–40% of all cardiac cells. Non-cardiomyocytes constitute 60–70% of a cardiac cell and approximately 90% of these non-cardiomyocytes represent fibroblasts (1,2). Previously, the function and viability of cardiomyocytes have been treated as a primary research interest area, while fibrosis was considered as a secondary effect from the changes in cardiomyocytes. However, recent studies have suggested an influence of fibroblasts over cardiomyocytes (3,4).

© 2019 Elsevier B.V. Patient deaths resulting from cardiovascular diseases are increasing across the globe, posing the greatest risk to patients in developed countries. Myocardial infarction, as a result of inadequate blood flow to the myocardium, results in irreversible loss of cardiomyocytes which can lead to heart failure. A sequela of myocardial infarction is scar formation that can alter the normal myocardial architecture and result in arrhythmias. Over the past decade, a myriad of tissue engineering approaches has been developed to fabricate engineered scaffolds for repairing cardiac tissue. This paper highlights the recent application of electrically conductive nanomaterials (carbon and gold-based nanomaterials, and electroactive polymers) to the development of scaffolds for cardiac tissue engineering. Moreover, this work summarizes the effects of these nanomaterials on cardiac cell behavior such as proliferation and migration, as well as cardiomyogenic differentiation in stem cells.