IPSC Therapy for Myocardial Infarction in Large Animal Models: Land of Hope and Dreams

Myocardial infarction is the main driver of heart failure due to ischemia and subsequent cell death, and cell-based strategies have emerged as promising therapeutic methods to replace dead tissue in cardiovascular diseases. Research in this field has been dramatically advanced by the development of laboratory-induced pluripotent stem cells (iPSCs) that harbor the capability to become any cell type. Like other experimental strategies, stem cell therapy must meet multiple requirements before reaching the clinical trial phase, and in vivo models are indispensable for ensuring the safety of such novel therapies. Specifically, translational studies in large animal models are necessary to fully evaluate the therapeutic potential of this approach; to empirically determine the optimal combination of cell types, supplementary factors, and delivery methods to maximize efficacy; and to stringently assess safety. In the present review, we summarize the main strategies employed to generate iPSCs and differentiate them into cardiomyocytes in large animal species; the most critical differences between using small versus large animal models for cardiovascular studies; and the strategies that have been pursued regarding implanted cells' stage of differentiation, origin, and technical application

Idiopathic Dilated Cardiomyopathy: Molecular Basis and Distilling Complexity to Advance

Cardiomyopathies are heterogeneous diseases of the myocardium associated with abnormal findings of chamber size, wall thickness, and/or functional contractility. In particular, dilated cardiomyopathy (DCM) is mainly characterized by ventricular chamber enlargement with systolic dysfunction and normal left ventricular (LV) wall thickness. Although DCM is thought to be induced mainly by genetic or environmental factors, in the majority of cases, the cause is unknown. With an estimated prevalence of 1:2500 and an incidence of 1:18,000 per year in adults, DCM is the most frequent indication for heart transplantation, which represents an enormous cost burden on healthcare systems. These figures warrant greater accuracy in patient diagnosis and prognosis and further insight into the underlying basis of DCM. Here, we discuss past and recent findings on the molecular mechanisms involved in DCM. Dilated cardiomyopathy has been linked to the overactivation of extracellular signal-regulated kinase (ERK1/2), which in turn is related to activation of low-density lipoprotein receptor–related protein-1 (LRP-1). Moreover, a redistribution of LRP-1 into cholesterol-enriched plasma membrane domains (lipid rafts) and alterations in cardiac DNA methylation have been reported in failing hearts. In conclusion, more comprehensive analyses of myocardial lipid rafts and epigenetic mechanisms may advance our understanding of DCM causes and progression. In turn, this understanding may promote the development of innovative treatments

Mechanisms governing the therapeutic effect of mesenchymal stromal cell-derived extracellular vesicles: A scoping review of preclinical evidence

Compelling evidence supports the therapeutic benefit of extracellular vesicles (EVs). EVs are nanostructures with a lipid bilayer membrane that are secreted by multiple cells, including mesenchymal stromal cells (MSCs), as means of cellular communication. MSC-EVs, resembling their MSC origin, carry protected immunomodulatory and pro-regenerative cargoes to targeted neighboring or distant cells and tissues. Though treatments focused on MSC-EVs have emerged as greatly versatile approaches to modulate multiple inflammatory-related conditions, crucial concerns, including the possibility of increasing therapeutic outcomes by pre-conditioning parental MSCs or engineering derived EVs and clarification of the most relevant mechanisms of action, remain. Here, we summarize the large amount of preclinical research surrounding the modulation of beneficial effects by MSC-EVs

Transitioning From Preclinical Evidence to Advanced Therapy Medicinal Product: A Spanish Experience

A systematic and ordered product development program, in compliance with current quality and regulatory standards, increases the likelihood of yielding a successful advanced therapy medicinal product (ATMP) for clinical use as safe and effective therapy. As this is a novel field, little accurate information is available regarding the steps to be followed, and the information to be produced to support the development and use of an ATMP. Notably, successful clinical translation can be somewhat cumbersome for academic researchers. In this article, we have provided a summary of the available information, supported by our experience in Spain throughout the development of an ATMP for myocardial infarction, from the pre-clinical stage to phase I clinical trial approval

Resonance-Based microwave technique for body implant sensing

There is an increasing need for safe and simple techniques for sensing devices and prostheses implanted inside the human body. Microwave wireless inspection may be an appropriate technique for it. The implanted device may have specific characteristics that allow to distinguish it from its environment. A new sensing technique based on the principle of differential resonance is proposed and its basic parameters are discussed. This technique allows to use the implant as a signal scattering device and to detect changes produced in the implant based on the corresponding change in its scattering signature. The technique is first tested with a canonic human phantom and then applied to a real in vivo clinical experiment to detect coronary stents implanted in swine animalsPeer ReviewedPostprint (published version

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. Swine transcriptome hits were mapped to their human equivalents using Reciprocal Best (blast) Hits, Gene Name Correspondence, and InParanoid database. Heart failure remodeling was studied using public data available in gene expression omnibus (accession GSE57345, subseries GSE57338), processed using the GEO2R tool. Using the Therapeutic Performance Mapping System technology, dedicated mathematical models trained to fit a set of molecular criteria, defining both pathologies and including all the information available on Sacubitril/Valsartan, were generated. All relationships incorporated into the biological network were drawn from public resources (including KEGG, REACTOME, INTACT, BIOGRID, and MINT). An artificial neural network analysis revealed that Sacubitril/Valsartan acts synergistically against cardiomyocyte cell death and left ventricular extracellular matrix remodeling via eight principal synergistic nodes. When studying each pathway independently, Valsartan was found to improve cardiac remodeling by inhibiting members of the guanine nucleotide-binding protein family, while Sacubitril attenuated cardiomyocyte cell death, hypertrophy, and impaired myocyte contractility by inhibiting PTEN. The complex molecular mechanisms of action of Sacubitril/Valsartan upon post-myocardial infarction and heart failure cardiac remodeling were delineated using a systems biology approach. Further, this dataset provides pathophysiological rationale for the use of Sacubitril/Valsartan to prevent post-infarct remodeling. The new wonder drug in heart failure management, Sacubitril/Valsartan, rejuvenates the heart by preventing its dilation. Using data from myocardial infarction and heart failure samples, we generated a mathematical model to better understand how Sacubitril/Valsartan modulates pathological heart resize and the combined effect of the drug. Our analysis revealed that Sacubitril/Valsartan mainly acts by blocking both, cell death and the pathological makeover of the outer-membrane of the cardiac cells. These two major processes occur after a heart attack. Most importantly, we discovered a core of 8 proteins that emerge as key players in this process. A better understanding of the mechanism of novel cardiovascular drugs at the most basic level may help decipher future therapies and indications

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. Cardiac function was evaluated noninvasively by using magnetic resonance imaging (MRI). Scar healing was evaluated by using the EIS system within the implanted graft. Additionally, infarct size, fibrosis, and inflammation were explored by histopathology. Upon sacrifice 1 month after the intervention, MRI detected a significant improvement in left ventricular ejection fraction (7.5%64.9% vs. 1.4%63.7%; p = .038) and stroke volume (11.565.9 ml vs. 364.5 ml; p = .019) in EBIG-treated animals. Noninvasive EIS data analysis showed differences in both impedance magnitude ratio (20.02 6 0.04 per day vs. 20.48 6 0.07 per day; p = .002) and phase angle slope (20.18°60.24° per day vs.23.52°60.84° per day; p = .004) in EBIG compared with control animals. Moreover, in EBIG-treated animals, the infarct size was 48% smaller (3.4%60.6% vs. 6.5%61%; p = .015), less inflammation was found by means of CD25+ lymphocytes (0.65 6 0.12 vs. 1.26 6 0.2; p = .006), and a lower collagen I/III ratio was detected (0.4960.06 vs. 1.6660.5; p = .019). An EBIG composed of acellular pericardium refilled with pATPCs significantly reduced infarct size and improved cardiac function in a preclinical model of MI. Noninvasive EIS monitoring was useful for tracking differential scar healing in EBIG-treated animals, which was confirmed by less inflammation and altered collagen deposit.Peer ReviewedPostprint (published version

Telomere attrition in heart failure : a flow-FISH longitudinal analysis of circulating monocytes

Altres ajuts: AB-G was supported by Grants from the Ministerio de Educación y Ciencia (SAF2014-59892), Fundació La MARATÓ de TV3 (201502, 201516), CIBER Cardiovascular (CB16/11/00403), and AdvanceCat with the support of ACCIÓ [Catalonia Trade & Investment; Generalitat de Catalunya] under the Catalonian ERDF [European Regional Development Fund] operational program, 2014-2020.Cross-sectional investigations report shorter telomeres in patients with heart failure (HF); however, no studies describe telomere length (TL) trajectory and its relationship with HF progression. Here we aimed to investigate telomere shortening over time and its relationship to outcomes. Our study cohort included 101 ambulatory patients with HF. Blood samples were collected at baseline (n = 101) and at the 1-year follow-up (n = 54). Using flow-FISH analysis of circulating monocytes, we simultaneously measured three monocyte subsets-classical (CD14 ++ CD16 −), intermediate (CD14 ++ CD16 +), and nonclassical (CD14 + CD16 ++)-and their respective TLs based on FITC-labeled PNA probe hybridization. The primary endpoints were all-cause death and the composite of all-cause death or HF-related hospitalization, assessed at 2.3 ± 0.6 years. All statistical analyses were executed by using the SPSS 15.0 software, and included Student's t test and ANOVA with post hoc Scheffe analysis, Pearson or Spearman rho correlation and univariate Cox regression when applicable. We found high correlations between TL values of different monocyte subsets: CD14 ++ CD16 + vs. CD14 ++ CD16 −, R = 0.95, p 0.1). Cox regression analyses did not indicate that TL or ΔTL was associated with all-cause death or the composite endpoint. Overall, this longitudinal study demonstrated a ~ 22% reduction of TL in monocytes from ambulatory patients with HF within 1 year. TL and ΔTL were not related to outcomes over long-term follow-up. The online version of this article (10.1186/s12967-018-1412-z) contains supplementary material, which is available to authorized users

Physiological conditioning by electric field stimulation promotes cardiomyogenic gene expression in human cardiomyocyte progenitor cells

The optimal cell lineage for cardiac-regeneration approaches remains mysterious. Additionally, electrical stimulation promotes cardiomyogenic differentiation of stimulated cells. Therefore, we hypothesized that electrical conditioning of cardiomyocyte progenitor cells (CMPCs) might enrich their cardiovascular potential. CMPCs were isolated from human adult atrial appendages, characterized, and electrically stimulated for 7 and 14 days. Electrical stimulation modulated CMPCs gene and protein expression, increasing all cardiac markers. GATA-binding protein 4 (GATA4) early transcription factor was significantly overexpressed (P = 0.008), but also its coactivator myocyte enhancer factor 2A (MEF2A) was upregulated (P = 0.073) under electrical stimulation. Moreover, important structural proteins and calcium handling-related genes were enhanced. The cardioregeneration capability of CMPCs is improved by electrical field stimulation. Consequently, short-term electrical stimulation should be a valid biophysical approach to modify cardiac progenitor cells toward a cardiogenic phenotype, and can be incorporated into transdifferentiation protocols. Electrostimulated CMPCs may be best-equipped cells for myocardial integration after implantation.Peer ReviewedPostprint (published version