Activation of a GPCR, ORL1 Receptor: A Novel Therapy to Prevent Heart Failure Progression.

The number of ischemic heart failure (HF) patients is growing dramatically worldwide. However, there are at present no preventive treatments for HF. Our previous study showed that Gata4 overexpression improved cardiac function after myocardial infarction in rat hearts.

Sall4 and Gata4 induce cardiac fibroblast transition towards a partially multipotent state with cardiogenic potential.

Cardiac cellular fate transition holds remarkable promise for the treatment of ischemic heart disease. We report that overexpressing two transcription factors, Sall4 and Gata4, which play distinct and overlapping roles in both pluripotent stem cell reprogramming and embryonic heart development, induces a fraction of stem-like cells in rodent cardiac fibroblasts that exhibit unlimited ex vivo expandability with clonogenicity. Transcriptomic and phenotypic analyses reveal that around 32 ± 6.

Activation of a GPCR, ORL1 receptor: A novel therapy to prevent heart failure progression.

Purpose: The number of ischemic heart failure (HF) patients is growing dramatically worldwide. However, there are at present no preventive treatments for HF. Our previous study showed that Gata4 overexpression improved cardiac function after myocardial infarction in the rat heart.

Direct cardiac reprogramming: A new technology for cardiac repair.

Cardiovascular disease is one of the leading causes of morbidity and mortality worldwide, with myocardial infarctions being amongst the deadliest manifestations. Reduced blood flow to the heart can result in the death of cardiac tissue, leaving affected patients susceptible to further complications and recurrent disease. Further, contemporary management typically involves a pharmacopeia to manage the metabolic conditions contributing to atherosclerotic and hypertensive heart disease, rather than regeneration of the damaged myocardium.

p63 silencing induces epigenetic modulation to enhance human cardiac fibroblast to cardiomyocyte-like differentiation.

Direct cell reprogramming represents a promising new myocardial regeneration strategy involving in situ transdifferentiation of cardiac fibroblasts into induced cardiomyocytes. Adult human cells are relatively resistant to reprogramming, however, likely because of epigenetic restraints on reprogramming gene activation. We hypothesized that modulation of the epigenetic regulator gene p63 could improve the efficiency of human cell cardio-differentiation.

Hippo Pathway Effector Tead1 Induces Cardiac Fibroblast to Cardiomyocyte Reprogramming.

Background The conversion of fibroblasts into induced cardiomyocytes may regenerate myocardial tissue from cardiac scar through in situ cell transdifferentiation. The efficiency transdifferentiation is low, especially for human cells. We explored the leveraging of Hippo pathway intermediates to enhance induced cardiomyocyte generation.

Fibroblast transition to an endothelial "trans" state improves cell reprogramming efficiency.

Fibroblast reprogramming offers the potential for myocardial regeneration via in situ cell transdifferentiation. We explored a novel strategy leveraging endothelial cell plasticity to enhance reprogramming efficiency. Rat cardiac endothelial cells and fibroblasts were treated with Gata4, Mef2c, and Tbx5 (GMT) to assess the cardio-differentiation potential of these cells.

Immune-modulatory alginate protects mesenchymal stem cells for sustained delivery of reparative factors to ischemic myocardium.

Paracrine factors secreted by mesenchymal stem cells (MSCs) have been previously shown to improve cardiac function following acute myocardial infarction (MI). However, cell therapy activates the innate immune response, leading to the rapid elimination of transplanted cells and only short-term therapeutic delivery. Herein, we describe a new strategy to deliver sustained paracrine-mediated MSC therapy to ischemic myocardium.

Enhanced Generation of Induced Cardiomyocytes Using a Small-Molecule Cocktail to Overcome Barriers to Cardiac Cellular Reprogramming.

Background Given known inefficiencies in reprogramming of fibroblasts into mature induced cardiomyocytes (iCMs), we sought to identify small molecules that would overcome these barriers to cardiac cell transdifferentiation. Methods and Results We screened alternative combinations of compounds known to impact cell reprogramming using morphologic and functional cell differentiation assays in vitro. After screening 6 putative reprogramming factors, we found that a combination of the histone deacetylase inhibitor sodium butyrate, the WNT inhibitor ICG-001, and the cardiac growth regulator retinoic acid (RA) maximally enhanced iCM generation from primary rat cardiac fibroblasts when combined with administration of the cardiodifferentiating transcription factors Gata4, Mef2C, and Tbx5 (GMT) compared with GMT administration alone (23±1.

p63 Silencing induces reprogramming of cardiac fibroblasts into cardiomyocyte-like cells.

Objective: Reprogramming of fibroblasts into induced cardiomyocytes represents a potential new therapy for heart failure. We hypothesized that inactivation of p63, a p53 gene family member, may help overcome human cell resistance to reprogramming.

Methods: p63 Knockout () and knockdown murine embryonic fibroblasts (MEFs), p63 adult murine cardiac fibroblasts, and human cardiac fibroblasts were assessed for cardiomyocyte-specific feature changes, with or without treatment by the cardiac transcription factors Hand2-Myocardin (HM).

The stem cell factor SALL4 is an essential transcriptional regulator in mixed lineage leukemia-rearranged leukemogenesis.

Background: The stem cell factor spalt-like transcription factor 4 (SALL4) plays important roles in normal hematopoiesis and also in leukemogenesis. We previously reported that SALL4 exerts its effect by recruiting important epigenetic factors such as DNA methyltransferases DNMT1 and lysine-specific demethylase 1 (LSD1/KDM1A). Both of these proteins are critically involved in mixed lineage leukemia (MLL)-rearranged (MLL-r) leukemia, which has a very poor clinical prognosis.

Cardiac reprogramming factor Gata4 reduces postinfarct cardiac fibrosis through direct repression of the profibrotic mediator snail.

Objective: The administration of a variety of reprogramming factor cocktails has now been shown to reprogram cardiac fibroblasts into induced cardiomyocyte-like cells. However, reductions in ventricular fibrosis observed after reprogramming factor administration seem to far exceed the extent of induced cardiomyocyte-like cell generation in vivo. We investigated whether reprogramming factor administration might primarily play a role in activating antifibrotic molecular pathways.

MiR-590 Promotes Transdifferentiation of Porcine and Human Fibroblasts Toward a Cardiomyocyte-Like Fate by Directly Repressing Specificity Protein 1.

Background: Reprogramming of cardiac fibroblasts into induced cardiomyocyte-like cells represents a promising potential new therapy for treating heart disease, inducing significant improvements in postinfarct ventricular function in rodent models. Because reprogramming factors effective in transdifferentiating rodent cells are not sufficient to reprogram human cells, we sought to identify reprogramming factors potentially applicable to human studies.

Methods And Results: Lentivirus vectors expressing Gata4, Mef2c, and Tbx5 (GMT); Hand2 (H), Myocardin (My), or microRNA (miR)-590 were administered to rat, porcine, and human cardiac fibroblasts in vitro.

In situ reprogramming to transdifferentiate fibroblasts into cardiomyocytes using adenoviral vectors: Implications for clinical myocardial regeneration.

Objective: The reprogramming of cardiac fibroblasts into induced cardiomyocyte-like cells improves ventricular function in myocardial infarction models. Only integrating persistent expression vectors have thus far been used to induce reprogramming, potentially limiting its clinical applicability. We therefore tested the reprogramming potential of nonintegrating, acute expression adenoviral (Ad) vectors.

Direct Cardiac Cellular Reprogramming for Cardiac Regeneration.

Direct cardiac cellular reprogramming of endogenous cardiac fibroblasts directly into induced cardiomyocytes is a highly feasible, promising therapeutic option for patients with advanced heart failure. The most successful cardiac reprogramming strategy will likely be a multimodal approach involving an optimal combination of cardio-differentiating factors, suppression of fibroblast gene expression, and induction of angiogenic factors.

"Triplet" polycistronic vectors encoding Gata4, Mef2c, and Tbx5 enhances postinfarct ventricular functional improvement compared with singlet vectors.

Objective: The in situ reprogramming of cardiac fibroblasts into induced cardiomyocytes by the administration of gene transfer vectors encoding Gata4 (G), Mef2c (M), and Tbx5 (T) has been shown to improve ventricular function in myocardial infarction models. The efficacy of this strategy could, however, be limited by the need for fibroblast targets to be infected 3 times--once by each of the 3 transgene vectors. We hypothesized that a polycistronic "triplet" vector encoding all 3 transgenes would enhance postinfarct ventricular function compared with use of "singlet" vectors.

In vivo cardiac cellular reprogramming efficacy is enhanced by angiogenic preconditioning of the infarcted myocardium with vascular endothelial growth factor.

Background: In situ cellular reprogramming offers the possibility of regenerating functional cardiomyocytes directly from scar fibroblasts, obviating the challenges of cell implantation. We hypothesized that pretreating scar with gene transfer of the angiogenic vascular endothelial growth factor (VEGF) would enhance the efficacy of this strategy.

Methods And Results: Gata4, Mef2c, and Tbx5 (GMT) administration via lentiviral transduction was demonstrated to transdifferentiate rat fibroblasts into (induced) cardiomyocytes in vitro by cardiomyocyte marker studies.

A clinically relevant large-animal model for evaluation of tissue-engineered cardiac surgical patch materials.

Extracellular matrix (ECM) scaffolds may be useful as a tissue engineering approach toward myocardial regeneration in the infarcted heart. An appropriate large-animal model for testing the utility of biologically derived ECM in this application is needed. The purpose of this study was to develop such a model for optimal procedural success during and after patch implantation surgery.

Extracellular matrix scaffold for cardiac repair.

Background: Heart failure remains a significant problem. Tissue-engineered cardiac patches offer potential to treat severe heart failure. We studied an extracellular matrix scaffold for repairing the infarcted left ventricle.

Implications of problematic access in transluminal endografting of abdominal aortic aneurysm.

Purpose: Despite careful preoperative assessment, problematic access to the abdominal aorta for transluminal endografting (TE) of abdominal aortic aneurysm (AAA) is sometimes encountered. This study identifies preoperative risk factors predictive of problematic access and determines the impact of problematic access on outcomes.

Materials And Methods: Three hundred twenty-one consecutive TE procedures for AAA were divided into two groups: group A, which had access problems (n = 74), and group B, which had none (n = 247).