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.

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Review: Tissue Engineering of Small-Diameter Vascular Grafts and Their In Vivo Evaluation in Large Animals and Humans

Cells ◽

10.3390/cells10030713 ◽

2021 ◽

Vol 10 (3) ◽

pp. 713

Author(s):

Shu Fang ◽

Ditte Gry Ellman ◽

Ditte Caroline Andersen

Keyword(s):

Animal Models ◽

Vascular Grafts ◽

Small Diameter ◽

Large Animal ◽

Large Animal Models ◽

Graft Outcome ◽

Limited Success ◽

Large Animals

To date, a wide range of materials, from synthetic to natural or a mixture of these, has been explored, modified, and examined as small-diameter tissue-engineered vascular grafts (SD-TEVGs) for tissue regeneration either in vitro or in vivo. However, very limited success has been achieved due to mechanical failure, thrombogenicity or intimal hyperplasia, and improvements of the SD-TEVG design are thus required. Here, in vivo studies investigating novel and relative long (10 times of the inner diameter) SD-TEVGs in large animal models and humans are identified and discussed, with emphasis on graft outcome based on model- and graft-related conditions. Only a few types of synthetic polymer-based SD-TEVGs have been evaluated in large-animal models and reflect limited success. However, some polymers, such as polycaprolactone (PCL), show favorable biocompatibility and potential to be further modified and improved in the form of hybrid grafts. Natural polymer- and cell-secreted extracellular matrix (ECM)-based SD-TEVGs tested in large animals still fail due to a weak strength or thrombogenicity. Similarly, native ECM-based SD-TEVGs and in-vitro-developed hybrid SD-TEVGs that contain xenogeneic molecules or matrix seem related to a harmful graft outcome. In contrast, allogeneic native ECM-based SD-TEVGs, in-vitro-developed hybrid SD-TEVGs with allogeneic banked human cells or isolated autologous stem cells, and in-body tissue architecture (IBTA)-based SD-TEVGs seem to be promising for the future, since they are suitable in dimension, mechanical strength, biocompatibility, and availability.

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Sphingosine 1-phosphate in inflammation

Journal of Clinical and Nursing Research ◽

10.26689/jcnr.v4i6.1610 ◽

2020 ◽

Vol 4 (6) ◽

Author(s):

Lijuan Li ◽

Lixia An ◽

Lifang Li ◽

Yongjuan Zhao

Keyword(s):

Plasma Membrane ◽

Drug Targets ◽

Therapeutic Potential ◽

Cell Types ◽

In Vivo Models ◽

Integral Role ◽

Sphingosine 1 Phosphate ◽

And Migration

Sphingolipids are formed via the metabolism of sphingomyelin, aconstituent of the plasma membrane, or by denovosynthesis. Enzymatic pathways result in the formation of several different lipid mediators, which are known to have important roles in many cellular processes, including proliferation, apoptosis and migration. Several studies now suggest that these sphingolipid mediators, including ceramide, ceramide 1-phosphate and sphingosine 1-phosphate (S1P), are likely to have an integral role in in?ammation. This can involve, for example, activation of pro-in?ammatory transcription factors in different cell types and induction of cyclooxygenase-2, leading to production of pro-in?ammatory prostaglandins. The mode of action of each sphingolipid is different. Increased ceramide production leads to the formation of ceramide-rich areas of the membrane, which may assemble signalling complexes, whereas S1P acts via high-af?nity G-protein-coupled S1P receptors on the plasma membrane. Recent studies have demonstrated that in vitro effects of sphingolipids on in?ammation can translate into in vivo models. This review will highlight the areas of research where sphingolipids are involved in in?ammation and the mechanisms of action of each mediator. In addition, the therapeutic potential of drugs that alter sphingolipid actions will be examined with reference to disease states, such as asthma and in?ammatory bowel disease, which involve important in?ammatory components. A signi?cant body of research now indicates that sphingolipids are intimately involved in the in?ammatory process and recent studies have demonstrated that these lipids, together with associated enzymes and receptors, can provide effective drug targets for the treatment of pathological in?ammation.

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Defining stem cell types: understanding the therapeutic potential of ESCs, ASCs, and iPS cells

Journal of Molecular Endocrinology ◽

10.1530/jme-12-0072 ◽

2012 ◽

Vol 49 (2) ◽

pp. R89-R111 ◽

Cited By ~ 41

Author(s):

Clara V Alvarez ◽

Montserrat Garcia-Lavandeira ◽

Maria E R Garcia-Rendueles ◽

Esther Diaz-Rodriguez ◽

Angela R Garcia-Rendueles ◽

...

Keyword(s):

Therapeutic Potential ◽

Main Property ◽

Cell Types ◽

Functional Behavior ◽

Dna Alterations ◽

Human Therapy ◽

Induced Pluripotent ◽

Models Of Disease

Embryonic, adult, artificially reprogrammed, and cancer…– there are various types of cells associated with stemness. Do they have something fundamental in common? Are we applying a common name to very different entities? In this review, we will revisit the characteristics that define ‘pluripotency’, the main property of stem cells (SCs). For each main type of physiological (embryonic and adult) or synthetic (induced pluripotent) SCs, markers and functional behavior in vitro and in vivo will be described. We will review the pioneering work that has led to obtaining human SC lines, together with the problems that have arisen, both in a biological context (DNA alterations, heterogeneity, tumors, and immunogenicity) and with regard to ethical concerns. Such problems have led to proposals for new operative procedures for growing human SCs of sufficiently high quality for use as models of disease and in human therapy. Finally, we will review the data from the first clinical trials to use various types of SCs.

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Comparative Analysis of Methods to Induce Myocardial Infarction in a Closed-Chest Rabbit Model

BioMed Research International ◽

10.1155/2015/893051 ◽

2015 ◽

Vol 2015 ◽

pp. 1-9 ◽

Cited By ~ 6

Author(s):

Marc-Antoine Isorni ◽

Amaury Casanova ◽

Julie Piquet ◽

Valérie Bellamy ◽

Charly Pignon ◽

...

Keyword(s):

Myocardial Infarction ◽

Animal Models ◽

Rabbit Model ◽

Left Ventricular ◽

Balloon Occlusion ◽

Gelatin Sponge ◽

Large Animal ◽

Alcohol Injection ◽

Closed Chest ◽

Large Animal Models

Objective.To develop a rabbit model of closed-chest catheter-induced myocardial infarction.Background.Limitations of rodent and large animal models justify the search for clinically relevant alternatives.Methods.Microcatheterization of the heart was performed in 47 anesthetized 3-4 kg New Zealand rabbits to test five techniques of myocardial ischemia: free coils (n=4), interlocking coils (n=4), thrombogenic gelatin sponge (n=4), balloon occlusion (n=4), and alcohol injection (n=8). In order to limit ventricular fibrillation, an antiarrhythmic protocol was implemented, with beta-blockers/amiodarone before and xylocaine infusion during the procedure. Clinical, angiographic, and echographic data were gathered. End points included demonstration of vessel occlusion (TIMI flow grades 0 and 1 on the angiogram), impairment of left ventricular function at 2 weeks after procedure (by echocardiography), and pathologically confirmed myocardial infarction.Results.The best arterial access was determined to be through the right carotid artery. The internal mammary guiding catheter 4-Fr was selected as the optimal device for selective intracoronary injection. Free coils deployed prematurely and tended to prolapse into the aorta. Interlocking coils did not deploy completely and failed to provide reliable results. Gelatin sponge was difficult to handle, adhered to the catheter, and could not be clearly visualized by fluoroscopy. Balloon occlusion yielded inconsistent results. Alcohol injection was the most efficient and reproducible method for inducing myocardial infarction (4 out of 6 animals), the extent of which could be fine-tuned by using a coaxial balloon catheter as a microcatheter (0.52 mm) to achieve a superselective injection of 0.2 mL of alcohol. This approach resulted in a 20% decrease in LVEF and infarcted myocardium was confirmed histologically.Conclusions.By following a stepwise approach, a minimally invasive, effective, and reproducible rabbit model of catheter-induced myocardial infarction has been developed which addresses the limitations of rodent experiments while avoiding the logistical and cost issues associated with large animal models.

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Consequences of mitral valve prolapse on chordal tension: Ex vivo and in vivo studies in large animal models

Journal of Thoracic and Cardiovascular Surgery ◽

10.1016/j.jtcvs.2011.08.035 ◽

2011 ◽

Vol 142 (6) ◽

pp. 1585-1587 ◽

Cited By ~ 13

Author(s):

Mathieu Granier ◽

Morten O. Jensen ◽

Jesper L. Honge ◽

Alain Bel ◽

Philippe Menasché ◽

...

Keyword(s):

Mitral Valve ◽

Animal Models ◽

Mitral Valve Prolapse ◽

Ex Vivo ◽

In Vivo Studies ◽

Large Animal ◽

Large Animal Models

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Translational failure of anti-inflammatory compounds for myocardial infarction: a meta-analysis of large animal models

Cardiovascular Research ◽

10.1093/cvr/cvv239 ◽

2015 ◽

Vol 109 (2) ◽

pp. 240-248 ◽

Cited By ~ 22

Author(s):

Gerardus P. J. van Hout ◽

Sanne J. Jansen of Lorkeers ◽

Kimberly E. Wever ◽

Emily S. Sena ◽

Lisanne H. J. A. Kouwenberg ◽

...

Keyword(s):

Myocardial Infarction ◽

Animal Models ◽

Meta Analysis ◽

Large Animal ◽

Large Animal Models ◽

Anti Inflammatory

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Adult Canine Intestinal Derived Organoids: A Novel In Vitro System for Translational Research in Comparative Gastroenterology

10.1101/466409 ◽

2018 ◽

Cited By ~ 1

Author(s):

Lawrance Chandra ◽

Dana C Borcherding ◽

Dawn Kingsbury ◽

Todd Atherly ◽

Yoko M Ambrosini ◽

...

Keyword(s):

Animal Models ◽

Translational Research ◽

Three Dimensional ◽

Metabolic Imaging ◽

Large Animal ◽

Large Animal Models ◽

Molecular Features ◽

Naturally Occurring

AbstractBackgroundLarge animal models, such as the dog, are increasingly being used over rodent models for studying naturally occurring diseases including gastrointestinal (GI) disorders. Dogs share similar environmental, genomic, anatomical, and intestinal physiologic features with humans. To bridge the gap between currently used animal models (e.g. mouse) and humans, and expand the translational potential of the dog model, we developed a three dimensional (3D) canine GI organoid (enteroid and colonoid) system. Organoids have recently gained interest in translational research as this model system better recapitulates the physiological and molecular features of the tissue environment in comparison with two-dimensional cultures.ResultsOrganoids were propagated from isolation of adult intestinal stem cells (ISC) from whole jejunal tissue as well as endoscopically obtained duodenal, ileal and colonic biopsy samples of healthy dogs and GI cases, including inflammatory bowel disease (IBD) and intestinal carcinomas. Intestinal organoids were comprehensively characterized using histology, immunohistochemistry, RNA in situ hybridization and transmission electron microscopy, and organoids mimicked the in vivo tissue environment. Physiological relevance of the enteroid system was defined using functional assays such as Optical Metabolic Imaging (OMI), the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) function assay, and Exosome-Like Vesicles (EV) uptake assay, as a basis for wider applications of this technology in basic, preclinical and translational GI research.ConclusionsIn summary, our findings establish the canine GI organoid systems as a novel model to study naturally occurring intestinal diseases in dogs and humans. Furthermore, canine organoid systems will help to elucidate host-pathogen interactions contributing to GI disease pathogenesis.

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Preclinical and Clinical Development of Noncoding RNA Therapeutics for Cardiovascular Disease

Circulation Research ◽

10.1161/circresaha.119.315856 ◽

2020 ◽

Vol 126 (5) ◽

pp. 663-678 ◽

Cited By ~ 12

Author(s):

Cheng-Kai Huang ◽

Sabine Kafert-Kasting ◽

Thomas Thum

Keyword(s):

Cardiovascular Disease ◽

Animal Models ◽

Noncoding Rna ◽

Ex Vivo ◽

Human Cells ◽

Large Animal ◽

Cardiovascular Research ◽

In Vivo Models ◽

Large Animal Models ◽

Promising Therapeutic Approach

RNA modulation has become a promising therapeutic approach for the treatment of several types of disease. The emerging field of noncoding RNA-based therapies has now come to the attention of cardiovascular research, in which it could provide valuable advancements in comparison to current pharmacotherapy such as small molecule drugs or antibodies. In this review, we focus on noncoding RNA-based studies conducted mainly in large-animal models, including pigs, rabbits, dogs, and nonhuman primates. The obstacles and promises of targeting long noncoding RNAs and circRNAs as therapeutic modalities in humans are specifically discussed. We also describe novel ex vivo methods based on human cells and tissues, such as engineered heart tissues and living myocardial slices that could help bridging the gap between in vivo models and clinical applications in the future. Finally, we summarize antisense oligonucleotide drugs that have already been approved by the Food and Drug Administration for targeting mRNAs and discuss the progress of noncoding RNA-based drugs in clinical trials. Additional factors, such as drug chemistry, drug formulations, different routes of administration, and the advantages of RNA-based drugs, are also included in the present review. Recently, first therapeutic miRNA-based inhibitory strategies have been tested in heart failure patients as well as healthy volunteers to study effects on wound healing (NCT04045405; NCT03603431). In summary, a combination of novel therapeutic RNA targets, large-animal models, ex vivo studies with human cells/tissues, and new delivery techniques will likely lead to significant progress in the development of noncoding RNA-based next-generation therapeutics for cardiovascular disease.

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