Personalized transcriptome signatures in a cardiomyopathy stem cell biobank.

Background: There is growing evidence that pathogenic mutations do not fully explain hypertrophic (HCM) or dilated (DCM) cardiomyopathy phenotypes. We hypothesized that if a patient's genetic background was influencing cardiomyopathy this should be detectable as signatures in gene expression. We built a cardiomyopathy biobank resource for interrogating personalized genotype phenotype relationships in human cell lines.

A deep learning platform to assess drug proarrhythmia risk.

Drug safety initiatives have endorsed human iPSC-derived cardiomyocytes (hiPSC-CMs) as an in vitro model for predicting drug-induced cardiac arrhythmia. However, the extent to which human-defined features of in vitro arrhythmia predict actual clinical risk has been much debated. Here, we trained a convolutional neural network classifier (CNN) to learn features of in vitro action potential recordings of hiPSC-CMs that are associated with lethal Torsade de Pointes arrhythmia.

Serine biosynthesis as a novel therapeutic target for dilated cardiomyopathy.

Aims: Genetic dilated cardiomyopathy (DCM) is a leading cause of heart failure. Despite significant progress in understanding the genetic aetiologies of DCM, the molecular mechanisms underlying the pathogenesis of familial DCM remain unknown, translating to a lack of disease-specific therapies. The discovery of novel targets for the treatment of DCM was sought using phenotypic sceening assays in induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) that recapitulate the disease phenotypes in vitro.

Unfolded Protein Response as a Compensatory Mechanism and Potential Therapeutic Target in PLN R14del Cardiomyopathy.

Background: Phospholamban (PLN) is a critical regulator of calcium cycling and contractility in the heart. The loss of arginine at position 14 in PLN (R14del) is associated with dilated cardiomyopathy with a high prevalence of ventricular arrhythmias. How the R14 deletion causes dilated cardiomyopathy is poorly understood, and there are no disease-specific therapies.

Small-molecule probe reveals a kinase cascade that links stress signaling to TCF/LEF and Wnt responsiveness.

Wnt signaling plays a central role in tissue maintenance and cancer. Wnt activates downstream genes through β-catenin, which interacts with TCF/LEF transcription factors. A major question is how this signaling is coordinated relative to tissue organization and renewal.

A Novel Recessive Mutation in SPEG Causes Early Onset Dilated Cardiomyopathy.

Dilated cardiomyopathy (DCM) is a common cause of heart failure and sudden cardiac death. It has been estimated that up to half of DCM cases are hereditary. Mutations in more than 50 genes, primarily autosomal dominant, have been reported.

Pharmacological Silencing of MicroRNA-152 Prevents Pressure Overload-Induced Heart Failure.

Background: MicroRNAs are small, noncoding RNAs that play a key role in gene expression. Accumulating evidence suggests that aberrant microRNA expression contributes to the heart failure (HF) phenotype; however, the underlying molecular mechanisms are not well understood. A better understanding of the mechanisms of action of microRNAs could potentially lead to targeted therapies that could halt the progression or even reverse HF.

Activation of PDGF pathway links LMNA mutation to dilated cardiomyopathy.

Lamin A/C (LMNA) is one of the most frequently mutated genes associated with dilated cardiomyopathy (DCM). DCM related to mutations in LMNA is a common inherited cardiomyopathy that is associated with systolic dysfunction and cardiac arrhythmias. Here we modelled the LMNA-related DCM in vitro using patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs).

Concise Review: Precision Matchmaking: Induced Pluripotent Stem Cells Meet Cardio-Oncology.

As common chemotherapeutic agents are associated with an increased risk of acute and chronic cardiovascular complications, a new clinical discipline, cardio-oncology, has recently emerged. At the same time, the development of preclinical human stem cell-derived cardiovascular models holds promise as a more faithful platform to predict the cardiovascular toxicity of common cancer therapies and advance our understanding of the underlying mechanisms contributing to the cardiotoxicity. In this article, we review the recent advances in preclinical cancer-related cardiotoxicity testing, focusing on new technologies, such as human induced pluripotent stem cell-derived cardiomyocytes and tissue engineering.

Recent Progress in Genome Editing Approaches for Inherited Cardiovascular Diseases.

Purpose Of Review: This review describes the recent progress in nuclease-based therapeutic applications for inherited heart diseases in vitro, highlights the development of the most recent genome editing technologies and discusses the associated challenges for clinical translation.

Recent Findings: Inherited cardiovascular disorders are passed from generation to generation. Over the past decade, considerable progress has been made in understanding the genetic basis of inherited heart diseases.

Head-to-head comparison of two engineered cardiac grafts for myocardial repair: From scaffold characterization to pre-clinical testing.

Cardiac tissue engineering, which combines cells and supportive scaffolds, is an emerging treatment for restoring cardiac function after myocardial infarction (MI), although, the optimal construct remains a challenge. We developed two engineered cardiac grafts, based on decellularized scaffolds from myocardial and pericardial tissues and repopulated them with adipose tissue mesenchymal stem cells (ATMSCs). The structure, macromechanical and micromechanical scaffold properties were preserved upon the decellularization and recellularization processes, except for recellularized myocardium micromechanics that was ∼2-fold stiffer than native tissue and decellularized scaffolds.

Author Correction: Unravelling the effects of mechanical physiological conditioning on cardiac adipose tissue-derived progenitor cells in vitro and in silico.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

Unravelling the effects of mechanical physiological conditioning on cardiac adipose tissue-derived progenitor cells in vitro and in silico.

Mechanical conditioning is incompletely characterized for stimulating therapeutic cells within the physiological range. We sought to unravel the mechanism of action underlying mechanical conditioning of adipose tissue-derived progenitor cells (ATDPCs), both in vitro and in silico. Cardiac ATDPCs, grown on 3 different patterned surfaces, were mechanically stretched for 7 days at 1 Hz.

Preclinical Safety Evaluation of Allogeneic Induced Pluripotent Stem Cell-Based Therapy in a Swine Model of Myocardial Infarction.

The combination of biomatrices and induced pluripotent stem cell (iPSC) derivatives to aid repair and myocardial scar formation may soon become a reality for cardiac regenerative medicine. However, the tumor risk associated with residual undifferentiated cells remains an important safety concern of iPSC-based therapies. This concern is not satisfactorily addressed in xenotransplantation, which requires immune suppression of the transplanted animal.

Mechanisms of action of sacubitril/valsartan on cardiac remodeling: a systems biology approach.

Sacubitril/Valsartan, proved superiority over other conventional heart failure management treatments, but its mechanisms of action remains obscure. In this study, we sought to explore the mechanistic details for Sacubitril/Valsartan in heart failure and post-myocardial infarction remodeling, using an in silico, systems biology approach. Myocardial transcriptome obtained in response to myocardial infarction in swine was analyzed to address post-infarction ventricular remodeling.

Electromechanical Conditioning of Adult Progenitor Cells Improves Recovery of Cardiac Function After Myocardial Infarction.

Cardiac cells are subjected to mechanical and electrical forces, which regulate gene expression and cellular function. Therefore, in vitro electromechanical stimuli could benefit further integration of therapeutic cells into the myocardium. Our goals were (a) to study the viability of a tissue-engineered construct with cardiac adipose tissue-derived progenitor cells (cardiac ATDPCs) and (b) to examine the effect of electromechanically stimulated cardiac ATDPCs within a myocardial infarction (MI) model in mice for the first time.

Noninvasive Assessment of an Engineered Bioactive Graft in Myocardial Infarction: Impact on Cardiac Function and Scar Healing.

Cardiac tissue engineering, which combines cells and biomaterials, is promising for limiting the sequelae of myocardial infarction (MI). We assessed myocardial function and scar evolution after implanting an engineered bioactive impedance graft (EBIG) in a swine MI model. The EBIG comprises a scaffold of decellularized human pericardium, green fluorescent protein-labeled porcine adipose tissue-derived progenitor cells (pATPCs), and a customized-design electrical impedance spectroscopy (EIS) monitoring system.

A Cell-Enriched Engineered Myocardial Graft Limits Infarct Size and Improves Cardiac Function: Pre-Clinical Study in the Porcine Myocardial Infarction Model.

Myocardial infarction (MI) remains a dreadful disease around the world, causing irreversible sequelae that shorten life expectancy and reduce quality of life despite current treatment. Here, the authors engineered a cell-enriched myocardial graft, composed of a decellularized myocardial matrix refilled with adipose tissue-derived progenitor cells (EMG-ATDPC). Once applied over the infarcted area in the swine MI model, the EMG-ATDPC improved cardiac function, reduced infarct size, attenuated fibrosis progression, and promoted neovascularization of the ischemic myocardium.

In vivo experience with natural scaffolds for myocardial infarction: the times they are a-changin'.

Treating a myocardial infarction (MI), the most frequent cause of death worldwide, remains one of the most exciting medical challenges in the 21st century. Cardiac tissue engineering, a novel emerging treatment, involves the use of therapeutic cells supported by a scaffold for regenerating the infarcted area. It is essential to select the appropriate scaffold material; the ideal one should provide a suitable cellular microenvironment, mimic the native myocardium, and allow mechanical and electrical coupling with host tissues.

Neoinnervation and neovascularization of acellular pericardial-derived scaffolds in myocardial infarcts.

Engineered bioimplants for cardiac repair require functional vascularization and innervation for proper integration with the surrounding myocardium. The aim of this work was to study nerve sprouting and neovascularization in an acellular pericardial-derived scaffold used as a myocardial bioimplant. To this end, 17 swine were submitted to a myocardial infarction followed by implantation of a decellularized human pericardial-derived scaffold.

Postinfarction Functional Recovery Driven by a Three-Dimensional Engineered Fibrin Patch Composed of Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells.

Considerable research has been dedicated to restoring myocardial cell slippage and limiting ventricular remodeling after myocardial infarction (MI). We examined the ability of a three-dimensional (3D) engineered fibrin patch filled with human umbilical cord blood-derived mesenchymal stem cells (UCBMSCs) to induce recovery of cardiac function after MI. The UCBMSCs were modified to coexpress luciferase and fluorescent protein reporters, mixed with fibrin, and applied as an adhesive, viable construct (fibrin-cell patch) over the infarcted myocardium in mice (MI-UCBMSC group).

In vitro comparative study of two decellularization protocols in search of an optimal myocardial scaffold for recellularization.

Introduction: Selection of a biomaterial-based scaffold that mimics native myocardial extracellular matrix (ECM) architecture can facilitate functional cell attachment and differentiation. Although decellularized myocardial ECM accomplishes these premises, decellularization processes may variably distort or degrade ECM structure.

Materials And Methods: Two decellularization protocols (DP) were tested on porcine heart samples (epicardium, mid myocardium and endocardium).

Preclinical evaluation of the immunomodulatory properties of cardiac adipose tissue progenitor cells using umbilical cord blood mesenchymal stem cells: a direct comparative study.

Cell-based strategies to regenerate injured myocardial tissue have emerged over the past decade, but the optimum cell type is still under scrutiny. In this context, human adult epicardial fat surrounding the heart has been characterized as a reservoir of mesenchymal-like progenitor cells (cardiac ATDPCs) with potential clinical benefits. However, additional data on the possibility that these cells could trigger a deleterious immune response following implantation are needed.