Journal articles on the topic 'Engineered Heart Muscle Tissues'
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Sheehy, Sean P., Anna Grosberg, Pu Qin, David J. Behm, John P. Ferrier, Mackenzie A. Eagleson, Alexander P. Nesmith, et al. "Toward improved myocardial maturity in an organ-on-chip platform with immature cardiac myocytes." Experimental Biology and Medicine 242, no. 17 (March 26, 2017): 1643–56. http://dx.doi.org/10.1177/1535370217701006.
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In vitro studies of cardiac physiology and drug response have traditionally been performed on individual isolated cardiomyocytes or isotropic monolayers of cells that may not mimic desired physiological traits of the laminar adult myocardium. Recent studies have reported a number of advances to Heart-on-a-Chip platforms for the fabrication of more sophisticated engineered myocardium, but cardiomyocyte immaturity remains a challenge. In the anisotropic musculature of the heart, interactions between cardiac myocytes, the extracellular matrix (ECM), and neighboring cells give rise to changes in cell shape and tissue architecture that have been implicated in both development and disease. We hypothesized that engineered myocardium fabricated from cardiac myocytes cultured in vitro could mimic the physiological characteristics and gene expression profile of adult heart muscle. To test this hypothesis, we fabricated engineered myocardium comprised of neonatal rat ventricular myocytes with laminar architectures reminiscent of that observed in the mature heart and compared their sarcomere organization, contractile performance characteristics, and cardiac gene expression profile to that of isolated adult rat ventricular muscle strips. We found that anisotropic engineered myocardium demonstrated a similar degree of global sarcomere alignment, contractile stress output, and inotropic concentration–response to the β-adrenergic agonist isoproterenol. Moreover, the anisotropic engineered myocardium exhibited comparable myofibril related gene expression to muscle strips isolated from adult rat ventricular tissue. These results suggest that tissue architecture serves an important developmental cue for building in vitro model systems of the myocardium that could potentially recapitulate the physiological characteristics of the adult heart. Impact statement With the recent focus on developing in vitro Organ-on-Chip platforms that recapitulate tissue and organ-level physiology using immature cells derived from stem cell sources, there is a strong need to assess the ability of these engineered tissues to adopt a mature phenotype. In the present study, we compared and contrasted engineered tissues fabricated from neonatal rat ventricular myocytes in a Heart-on-a-Chip platform to ventricular muscle strips isolated from adult rats. The results of this study support the notion that engineered tissues fabricated from immature cells have the potential to mimic mature tissues in an Organ-on-Chip platform.
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He, Feng, Hailan Yao, Jianmin Wang, Zonghui Xiao, Le Xin, Zhuo Liu, Xiaolin Ma, Juan Sun, Qi Jin, and Zhewei Liu. "Coxsackievirus B3 Engineered To Contain MicroRNA Targets for Muscle-Specific MicroRNAs Displays Attenuated Cardiotropic Virulence in Mice." Journal of Virology 89, no. 2 (October 22, 2014): 908–16. http://dx.doi.org/10.1128/jvi.02933-14.
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ABSTRACTCoxsackievirus B3 (CVB3) is trophic for cardiac tissue and is a major causative agent for viral myocarditis, where local viral replication in the heart may lead to heart failure or even death. Recent studies show that inserting microRNA target sequences into the genomes of certain viruses can eradicate these viruses within local host tissues that specifically express the cognate microRNA. Here, we demonstrated bothin vitroandin vivothat incorporating target sequences for miRNA-133 and -206 into the 5′ untranslated region of the CVB3 genome ameliorated CVB3 virulence in skeletal muscle and myocardial cells that specifically expressed the cognate cellular microRNAs. Compared to wild-type CVB3, viral replication of the engineered CVB3 was attenuated in human TE671 (rhabdomyosarcoma) and L6 (skeletal muscle) cell linesin vitrothat expressed high levels of miRNA-206. In thein vivomurine CVB3-infection model, viral replication of the engineered CVB3 was attenuated specifically in the heart that expressed high levels of both miRNAs, but not in certain tissues, which allowed the host to retain the ability to induce a strong and protective humoral immune response against CVB3. The results of this study suggest that a microRNA-targeting strategy to control CVB3 tissue tropism and pathogenesis may be useful for viral attenuation and vaccine development.IMPORTANCECoxsackievirus B3 (CVB3) is a major causative agent for viral myocarditis, and viral replication in the heart may lead to heart failure or even death. Limiting CVB3 replication within the heart may be a promising strategy to decrease CVB3 pathogenicity. miRNAs are ∼21-nucleotide-long, tissue-specific endogenous small RNA molecules that posttranscriptionally regulate gene expression by imperfectly binding to the 3′ untranslated region (UTR), the 5′ UTR, or the coding region within a gene. In our study, muscle-specific miRNA targets (miRT) were incorporated into the CVB3 genome. Replication of the engineered viruses was restricted in the important heart tissue of infected mice, which reduced cardiac pathology and increased mouse survival. Meanwhile, replication ability was retained in other tissues, thus inducing a strong humoral immune response and providing long-term protection against CVB3 rechallenge. This study suggests that a microRNA-targeting strategy can potentially control CVB3 tissue tropism and pathogenesis and may be useful for viral attenuation and vaccine development.
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Schmitt, Phillip R., Kiera D. Dwyer, Alicia J. Minor, and Kareen L. K. Coulombe. "Wet-Spun Polycaprolactone Scaffolds Provide Customizable Anisotropic Viscoelastic Mechanics for Engineered Cardiac Tissues." Polymers 14, no. 21 (October 28, 2022): 4571. http://dx.doi.org/10.3390/polym14214571.
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Myocardial infarction is a leading cause of death worldwide and has severe consequences including irreversible damage to the myocardium, which can lead to heart failure. Cardiac tissue engineering aims to re-engineer the infarcted myocardium using tissues made from human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) to regenerate heart muscle and restore contractile function via an implantable epicardial patch. The current limitations of this technology include both biomanufacturing challenges in maintaining tissue integrity during implantation and biological challenges in inducing cell alignment, maturation, and coordinated electromechanical function, which, when overcome, may be able to prevent adverse cardiac remodeling through mechanical support in the injured heart to facilitate regeneration. Polymer scaffolds serve to mechanically reinforce both engineered and host tissues. Here, we introduce a novel biodegradable, customizable scaffold composed of wet-spun polycaprolactone (PCL) microfibers to strengthen engineered tissues and provide an anisotropic mechanical environment to promote engineered tissue formation. We developed a wet-spinning process to produce consistent fibers which are then collected on an automated mandrel that precisely controls the angle of intersection of fibers and their spacing to generate mechanically anisotropic scaffolds. Through optimization of the wet-spinning process, we tuned the fiber diameter to 339 ± 31 µm and 105 ± 9 µm and achieved a high degree of fidelity in the fiber structure within the scaffold (fiber angle within 1.8° of prediction). Through degradation and mechanical testing, we demonstrate the ability to maintain scaffold mechanical integrity as well as tune the mechanical environment of the scaffold through structure (Young’s modulus of 120.8 ± 1.90 MPa for 0° scaffolds, 60.34 ± 11.41 MPa for 30° scaffolds, 73.59 ± 3.167 MPa for 60° scaffolds, and 49.31 ± 6.90 MPa for 90° scaffolds), while observing decreased hysteresis in angled vs. parallel scaffolds. Further, we embedded the fibrous PCL scaffolds in a collagen hydrogel mixed with hiPSC-CMs to form engineered cardiac tissue with high cell survival, tissue compaction, and active contractility of the hiPSC-CMs. Through this work, we develop and optimize a versatile biomanufacturing process to generate customizable PCL fibrous scaffolds which can be readily utilized to guide engineered tissue formation and function.
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Naito, H. "Optimizing Engineered Heart Tissue for Therapeutic Applications as Surrogate Heart Muscle." Circulation 114, no. 1_suppl (July 4, 2006): I—72—I—78. http://dx.doi.org/10.1161/circulationaha.105.001560.
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Porzionato, Andrea, Elena Stocco, Silvia Barbon, Francesca Grandi, Veronica Macchi, and Raffaele De Caro. "Tissue-Engineered Grafts from Human Decellularized Extracellular Matrices: A Systematic Review and Future Perspectives." International Journal of Molecular Sciences 19, no. 12 (December 18, 2018): 4117. http://dx.doi.org/10.3390/ijms19124117.
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Tissue engineering and regenerative medicine involve many different artificial and biologic materials, frequently integrated in composite scaffolds, which can be repopulated with various cell types. One of the most promising scaffolds is decellularized allogeneic extracellular matrix (ECM) then recellularized by autologous or stem cells, in order to develop fully personalized clinical approaches. Decellularization protocols have to efficiently remove immunogenic cellular materials, maintaining the nonimmunogenic ECM, which is endowed with specific inductive/differentiating actions due to its architecture and bioactive factors. In the present paper, we review the available literature about the development of grafts from decellularized human tissues/organs. Human tissues may be obtained not only from surgery but also from cadavers, suggesting possible development of Human Tissue BioBanks from body donation programs. Many human tissues/organs have been decellularized for tissue engineering purposes, such as cartilage, bone, skeletal muscle, tendons, adipose tissue, heart, vessels, lung, dental pulp, intestine, liver, pancreas, kidney, gonads, uterus, childbirth products, cornea, and peripheral nerves. In vitro recellularizations have been reported with various cell types and procedures (seeding, injection, and perfusion). Conversely, studies about in vivo behaviour are poorly represented. Actually, the future challenge will be the development of human grafts to be implanted fully restored in all their structural/functional aspects.
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Skopenkova, Victoria V., Tatiana V. Egorova, and Maryana V. Bardina. "Muscle-Specific Promoters for Gene Therapy." Acta Naturae 13, no. 1 (March 15, 2021): 47–58. http://dx.doi.org/10.32607/actanaturae.11063.
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Many genetic diseases that are responsible for muscular disorders have been described to date. Gene replacement therapy is a state-of-the-art strategy used to treat such diseases. In this approach, the functional copy of a gene is delivered to the affected tissues using viral vectors. There is an urgent need for the design of short, regulatory sequences that would drive a high and robust expression of a therapeutic transgene in skeletal muscles, the diaphragm, and the heart, while exhibiting limited activity in non-target tissues. This review focuses on the development and improvement of muscle-specific promoters based on skeletal muscle -actin, muscle creatine kinase, and desmin genes, as well as other genes expressed in muscles. The current approaches used to engineer synthetic muscle-specific promoters are described. Other elements of the viral vectors that contribute to tissue-specific expression are also discussed. A special feature of this review is the presence of up-to-date information on the clinical and preclinical trials of gene therapy drug candidates that utilize muscle-specific promoters.
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Birla, Ravi K., Gregory H. Borschel, and Robert G. Dennis. "In Vivo Conditioning of Tissue-engineered Heart Muscle Improves Contractile Performance." Artificial Organs 29, no. 11 (November 2005): 866–75. http://dx.doi.org/10.1111/j.1525-1594.2005.00148.x.
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Santos, Gabriela Leão, Svenja Hartmann, Wolfram-Hubertus Zimmermann, Anne Ridley, and Susanne Lutz. "Inhibition of Rho-associated kinases suppresses cardiac myofibroblast function in engineered connective and heart muscle tissues." Journal of Molecular and Cellular Cardiology 134 (September 2019): 13–28. http://dx.doi.org/10.1016/j.yjmcc.2019.06.015.
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Buckner, Frederick S., Aaron J. Wilson, and Wesley C. Van Voorhis. "Detection of Live Trypanosoma cruzi in Tissues of Infected Mice by Using Histochemical Stain for β-Galactosidase." Infection and Immunity 67, no. 1 (January 1, 1999): 403–9. http://dx.doi.org/10.1128/iai.67.1.403-409.1999.
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ABSTRACT The pathogenesis of tissue damage in chronic Trypanosoma cruzi infection has been a subject of long-standing debate. Conventional staining methods reveal a paucity of parasites in tissues from chronically infected individuals, which has led to the theory that the pathologic findings may be primarily autoimmune in origin. Immunostaining for T. cruzi antigens or in situ PCR methods show evidence for parasite components in chronic tissues; however, these methods do not address whether the stained material represents parasite debris or live organisms. An improved method for detecting intact T. cruzi in tissues was developed by making a genetically engineered strain that expresses Escherichia coli β-galactosidase. The expression of this enzyme allows the detection of T. cruzi in tissues by using the histochemical stain 5-bromo-4-chloro-3-indolyl-β-d-galactopyranoside (X-Gal). The technique was used to monitor tissue parasitism and its relation to pathologic findings in the mouse model of Chagas’ disease. Parasites were easily visible as bright blue structures in skeletal muscle, heart, bladder, peripheral nerve, liver, spleen, adrenal gland, brain, and adipose tissue in acutely infected mice. The number of viable parasites diminished >100-fold when tissues from 3-week-infected mice were compared with those from 10-month-infected mice. However, even at the lower level, parasites were clearly recognizable in sections of skeletal muscle and bladder at the 10-month time point. Inflammation remained robust in skeletal muscle, bladder, and sciatic nerve despite the near disappearance of parasites, suggesting three possibilities: exuberant host reactions to the few remaining parasites, autoimmune inflammation, or reactions to retained parasite antigens in the tissues.
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Bremner, Samantha B., Christian J. Mandrycky, Andrea Leonard, Ruby M. Padgett, Alan R. Levinson, Ethan S. Rehn, J. Manuel Pioner, Nathan J. Sniadecki, and David L. Mack. "Full-length dystrophin deficiency leads to contractile and calcium transient defects in human engineered heart tissues." Journal of Tissue Engineering 13 (January 2022): 204173142211196. http://dx.doi.org/10.1177/20417314221119628.
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Cardiomyopathy is currently the leading cause of death for patients with Duchenne muscular dystrophy (DMD), a severe neuromuscular disorder affecting young boys. Animal models have provided insight into the mechanisms by which dystrophin protein deficiency causes cardiomyopathy, but there remains a need to develop human models of DMD to validate pathogenic mechanisms and identify therapeutic targets. Here, we have developed human engineered heart tissues (EHTs) from CRISPR-edited, human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) expressing a truncated dystrophin protein lacking part of the actin-binding domain. The 3D EHT platform enables direct measurement of contractile force, simultaneous monitoring of Ca2+ transients, and assessment of myofibril structure. Dystrophin-mutant EHTs produced less contractile force as well as delayed kinetics of force generation and relaxation, as compared to isogenic controls. Contractile dysfunction was accompanied by reduced sarcomere length, increased resting cytosolic Ca2+ levels, delayed Ca2+ release and reuptake, and increased beat rate irregularity. Transcriptomic analysis revealed clear differences between dystrophin-deficient and control EHTs, including downregulation of genes related to Ca2+ homeostasis and extracellular matrix organization, and upregulation of genes related to regulation of membrane potential, cardiac muscle development, and heart contraction. These findings indicate that the EHT platform provides the cues necessary to expose the clinically-relevant, functional phenotype of force production as well as mechanistic insights into the role of Ca2+ handling and transcriptomic dysregulation in dystrophic cardiac function, ultimately providing a powerful platform for further studies in disease modeling and drug discovery.
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Scherbak, S. G., D. G. Lisovets, A. M. Sarana, S. V. Makarenko, T. A. Kamilova, A. S. Golota, and M. A. Snegirev. "CELL AND TISSUE THERAPY OF HEART." Physical and rehabilitation medicine, medical rehabilitation 1, no. 2 (June 15, 2019): 77–84. http://dx.doi.org/10.36425/2658-6843-19191.
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The strategy of heart tissue engineering is simple enough: first remove all the cells from a organ then take the protein scaffold left behind and repopulate it with stem cells immunologically matched to the patient in need. While various successful methods for decellularization have been developed, and the feasibility of using decellularized whole hearts and extracellular matrix to support cells has been demonstrated, the reality of creating whole hearts for transplantation and of clinical application of decellularized extracellular matrix-based scaffolds will require much more research. For example, further investigations into how lineage-restricted progenitors repopulate the decellularized heart and differentiate in a site-specific manner into different populations of the native heart would be essential. The scaffold heart does not have to be human. Pig hearts carries all the essential components of the extracellular matrix. Through trial and error, scaling up the concentration, timing and pressure of the detergents, researchers have refined the decellularization process on hundreds of hearts and other organs, but this is only the first step. Further, the framework must be populated with human cells. Most researchers in the field use a mixture of two or more cell types, such as endothelial precursor cells to line blood vessels and muscle progenitors to seed the walls of the chambers. The final challenge is one of the hardest: vascularization, placing a engineered heart into a living animal, integration with the recipient tissue, and keeping it beating for a long time. Much remains to be done before a bioartificial heart is available for transplantation in humans.
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Lechuga-Vieco, Ana Victoria, Ana Latorre-Pellicer, Enrique Calvo, Carlos Torroja, Juan Pellico, Rebeca Acín-Pérez, María Luisa García-Gil, et al. "Heteroplasmy of Wild-Type Mitochondrial DNA Variants in Mice Causes Metabolic Heart Disease With Pulmonary Hypertension and Frailty." Circulation 145, no. 14 (April 5, 2022): 1084–101. http://dx.doi.org/10.1161/circulationaha.121.056286.
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Background: In most eukaryotic cells, the mitochondrial DNA (mtDNA) is transmitted uniparentally and present in multiple copies derived from the clonal expansion of maternally inherited mtDNA. All copies are therefore near-identical, or homoplasmic. The presence of >1 mtDNA variant in the same cytoplasm can arise naturally or result from new medical technologies aimed at preventing mitochondrial genetic diseases and improving fertility. The latter is called divergent nonpathologic mtDNA heteroplasmy (DNPH). We hypothesized that DNPH is maladaptive and usually prevented by the cell. Methods: We engineered and characterized DNPH mice throughout their lifespan using transcriptomic, metabolomic, biochemical, physiologic, and phenotyping techniques. We focused on in vivo imaging techniques for noninvasive assessment of cardiac and pulmonary energy metabolism. Results: We show that DNPH impairs mitochondrial function, with profound consequences in critical tissues that cannot resolve heteroplasmy, particularly cardiac and skeletal muscle. Progressive metabolic stress in these tissues leads to severe pathology in adulthood, including pulmonary hypertension and heart failure, skeletal muscle wasting, frailty, and premature death. Symptom severity is strongly modulated by the nuclear context. Conclusions: Medical interventions that may generate DNPH should address potential incompatibilities between donor and recipient mtDNA.
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Naderi, Hojjat, Maryam M. Matin, and Ahmad Reza Bahrami. "Review paper: Critical Issues in Tissue Engineering: Biomaterials, Cell Sources, Angiogenesis, and Drug Delivery Systems." Journal of Biomaterials Applications 26, no. 4 (September 16, 2011): 383–417. http://dx.doi.org/10.1177/0885328211408946.
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Tissue engineering is a newly emerging biomedical technology, which aids and increases the repair and regeneration of deficient and injured tissues. It employs the principles from the fields of materials science, cell biology, transplantation, and engineering in an effort to treat or replace damaged tissues. Tissue engineering and development of complex tissues or organs, such as heart, muscle, kidney, liver, and lung, are still a distant milestone in twenty-first century. Generally, there are four main challenges in tissue engineering which need optimization. These include biomaterials, cell sources, vascularization of engineered tissues, and design of drug delivery systems. Biomaterials and cell sources should be specific for the engineering of each tissue or organ. On the other hand, angiogenesis is required not only for the treatment of a variety of ischemic conditions, but it is also a critical component of virtually all tissue-engineering strategies. Therefore, controlling the dose, location, and duration of releasing angiogenic factors via polymeric delivery systems, in order to ultimately better mimic the stem cell niche through scaffolds, will dictate the utility of a variety of biomaterials in tissue regeneration. This review focuses on the use of polymeric vehicles that are made of synthetic and/or natural biomaterials as scaffolds for three-dimensional cell cultures and for locally delivering the inductive growth factors in various formats to provide a method of controlled, localized delivery for the desired time frame and for vascularized tissue-engineering therapies.
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Sewanan, Lorenzo R., Shi Shen, and Stuart G. Campbell. "Mavacamten preserves length-dependent contractility and improves diastolic function in human engineered heart tissue." American Journal of Physiology-Heart and Circulatory Physiology 320, no. 3 (March 1, 2021): H1112—H1123. http://dx.doi.org/10.1152/ajpheart.00325.2020.
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We applied innovative methods to comprehensively characterize the length and load-dependent behaviors of engineered human cardiac muscle when treated with the cardiac β-myosin specific inhibitor mavacamten, a drug on the verge of clinical implementation for hypertrophic cardiomyopathy. We find mechanistic support for the role of mavacamten in improving diastolic function of cardiac tissue and note novel effects on work and power.
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Birla, R. K., Y. C. Huang, and R. G. Dennis. "Development of a Novel Bioreactor for the Mechanical Loading of Tissue-Engineered Heart Muscle." Tissue Engineering 13, no. 9 (September 2007): 2239–48. http://dx.doi.org/10.1089/ten.2006.0359.
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Trombino, Sonia, Federica Curcio, Roberta Cassano, Manuela Curcio, Giuseppe Cirillo, and Francesca Iemma. "Polymeric Biomaterials for the Treatment of Cardiac Post-Infarction Injuries." Pharmaceutics 13, no. 7 (July 7, 2021): 1038. http://dx.doi.org/10.3390/pharmaceutics13071038.
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Cardiac regeneration aims to reconstruct the heart contractile mass, preventing the organ from a progressive functional deterioration, by delivering pro-regenerative cells, drugs, or growth factors to the site of injury. In recent years, scientific research focused the attention on tissue engineering for the regeneration of cardiac infarct tissue, and biomaterials able to anatomically and physiologically adapt to the heart muscle have been proposed as valuable tools for this purpose, providing the cells with the stimuli necessary to initiate a complete regenerative process. An ideal biomaterial for cardiac tissue regeneration should have a positive influence on the biomechanical, biochemical, and biological properties of tissues and cells; perfectly reflect the morphology and functionality of the native myocardium; and be mechanically stable, with a suitable thickness. Among others, engineered hydrogels, three-dimensional polymeric systems made from synthetic and natural biomaterials, have attracted much interest for cardiac post-infarction therapy. In addition, biocompatible nanosystems, and polymeric nanoparticles in particular, have been explored in preclinical studies as drug delivery and tissue engineering platforms for the treatment of cardiovascular diseases. This review focused on the most employed natural and synthetic biomaterials in cardiac regeneration, paying particular attention to the contribution of Italian research groups in this field, the fabrication techniques, and the current status of the clinical trials.
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Crane, Andrew T., Rajagopal N. Aravalli, Atsushi Asakura, Andrew W. Grande, Venkatramana D. Krishna, Daniel F. Carlson, Maxim C. J. Cheeran, et al. "Interspecies Organogenesis for Human Transplantation." Cell Transplantation 28, no. 9-10 (August 19, 2019): 1091–105. http://dx.doi.org/10.1177/0963689719845351.
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Blastocyst complementation combined with gene editing is an emerging approach in the field of regenerative medicine that could potentially solve the worldwide problem of organ shortages for transplantation. In theory, blastocyst complementation can generate fully functional human organs or tissues, grown within genetically engineered livestock animals. Targeted deletion of a specific gene(s) using gene editing to cause deficiencies in organ development can open a niche for human stem cells to occupy, thus generating human tissues. Within this review, we will focus on the pancreas, liver, heart, kidney, lung, and skeletal muscle, as well as cells of the immune and nervous systems. Within each of these organ systems, we identify and discuss (i) the common causes of organ failure; (ii) the current state of regenerative therapies; and (iii) the candidate genes to knockout and enable specific exogenous organ development via the use of blastocyst complementation. We also highlight some of the current barriers limiting the success of blastocyst complementation.
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Zolk, Oliver, Sven Engmann, Felix Münzel, and Rasti Krajcik. "Chronic cardiotrophin-1 stimulation impairs contractile function in reconstituted heart tissue." American Journal of Physiology-Endocrinology and Metabolism 288, no. 6 (June 2005): E1214—E1221. http://dx.doi.org/10.1152/ajpendo.00261.2004.
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Cardiotrophin-1 (CT-1) is known to promote survival but also to induce an elongated morphology of isolated cardiac myocytes, leading to the hypothesis that CT-1, which is chronically augmented in human heart failure, might induce eccentric cardiac hypertrophy and contractile failure. To address this, we used heart tissues reconstituted from neonatal rat cardiac myocytes (engineered heart tissue, EHT) as multicellular in vitro test systems. CT-1 dose-dependently affected contractile function in EHTs. After treatment with 0.1 nM CT-1 (corresponds to plasma levels in humans) for 10 days, twitch tension significantly decreased to 0.30 ± 0.04 mN ( n = 15) vs. 0.45 ± 0.04 mN ( n = 16) in controls. Furthermore, positive inotropic effects of cumulative concentrations of Ca2+ and isoprenaline were significantly diminished. Maximum isoprenaline-induced increase in twitch tension amounted to 0.27 ± 0.04 mN ( n = 15) vs. 0.47 ± 0.06 mN ( n = 16) in controls ( P < 0.001). When EHTs were treated for only 5 days, qualitatively similar results were obtained but changes were less pronounced. Immunostaining of whole mount EHT preparations revealed that after CT-1 treatment, the number of nonmyocytes significantly increased by 98% (1 nM, 10 days), and myocytes did not form compact, longitudinally oriented muscle bundles. Interestingly, expression of the Ca2+-handling protein calsequestrin was markedly reduced (69 ± 7% of control) by treatment with CT-1 (0.1 nM, 10 days). In summary, long-term exposure to CT-1 induces contractile dysfunction in EHTs. Structural changes due to impaired differentiation and/or remodeling of heart tissue may play an important role.
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Venugopal, Jayarama Reddy, Molamma P. Prabhakaran, Shayanti Mukherjee, Rajeswari Ravichandran, Kai Dan, and Seeram Ramakrishna. "Biomaterial strategies for alleviation of myocardial infarction." Journal of The Royal Society Interface 9, no. 66 (April 13, 2011): 1–19. http://dx.doi.org/10.1098/rsif.2011.0301.
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World Health Organization estimated that heart failure initiated by coronary artery disease and myocardial infarction (MI) leads to 29 per cent of deaths worldwide. Heart failure is one of the leading causes of death in industrialized countries and is expected to become a global epidemic within the twenty-first century. MI, the main cause of heart failure, leads to a loss of cardiac tissue impairment of left ventricular function. The damaged left ventricle undergoes progressive ‘remodelling’ and chamber dilation, with myocyte slippage and fibroblast proliferation. Repair of diseased myocardium with in vitro -engineered cardiac muscle patch/injectable biopolymers with cells may become a viable option for heart failure patients. These events reflect an apparent lack of effective intrinsic mechanism for myocardial repair and regeneration. Motivated by the desire to develop minimally invasive procedures, the last 10 years observed growing efforts to develop injectable biomaterials with and without cells to treat cardiac failure. Biomaterials evaluated include alginate, fibrin, collagen, chitosan, self-assembling peptides, biopolymers and a range of synthetic hydrogels. The ultimate goal in therapeutic cardiac tissue engineering is to generate biocompatible, non-immunogenic heart muscle with morphological and functional properties similar to natural myocardium to repair MI. This review summarizes the properties of biomaterial substrates having sufficient mechanical stability, which stimulates the native collagen fibril structure for differentiating pluripotent stem cells and mesenchymal stem cells into cardiomyocytes for cardiac tissue engineering.
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Walton, Kelly L., Justin L. Chen, Quinn Arnold, Emily Kelly, Mylinh La, Louis Lu, George Lovrecz, et al. "Activin A–Induced Cachectic Wasting Is Attenuated by Systemic Delivery of Its Cognate Propeptide in Male Mice." Endocrinology 160, no. 10 (July 19, 2019): 2417–26. http://dx.doi.org/10.1210/en.2019-00257.
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Abstract In cancer, elevated activin levels promote cachectic wasting of muscle, irrespective of tumor progression. In excess, activins A and B use the myostatin signaling pathway in muscle, triggering a decrease in protein synthesis and an increase in protein degradation, which ultimately leads to atrophy. Recently, we demonstrated that local delivery of engineered activin and myostatin propeptides (natural inhibitors of these growth factors) could induce profound muscle hypertrophy in healthy mice. Additionally, the expression of these propeptides effectively attenuated localized muscle wasting in models of dystrophy and cancer cachexia. In this study, we examined whether a systemically administered recombinant propeptide could reverse activin A–induced cachectic wasting in mice. Chinese hamster ovary cells stably expressing activin A were transplanted into the quadriceps of nude mice and caused an 85-fold increase in circulating activin A levels within 12 days. Elevated activin A induced a rapid reduction in body mass (−16%) and lean mass (−10%). In agreement with previous findings, we demonstrated that adeno-associated virus–mediated delivery of activin propeptide to the tibialis anterior muscle blocked activin-induced wasting. In addition, despite massively elevated levels of activin A in this model, systemic delivery of the propeptide significantly reduced activin-induced changes in lean and body mass. Specifically, recombinant propeptide reversed activin-induced wasting of skeletal muscle, heart, liver, and kidneys. This is the first study to demonstrate that systemic administration of recombinant propeptide therapy effectively attenuates tumor-derived activin A insult in multiple tissues.
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Schwan, Jonas, and Stuart G. Campbell. "Article Commentary: Prospects for In Vitro Myofilament Maturation in Stem Cell-Derived Cardiac Myocytes." Biomarker Insights 10s1 (January 2015): BMI.S23912. http://dx.doi.org/10.4137/bmi.s23912.
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Cardiomyocytes derived from human stem cells are quickly becoming mainstays of cardiac regenerative medicine, in vitro disease modeling, and drug screening. Their suitability for such roles may seem obvious, but assessments of their contractile behavior suggest that they have not achieved a completely mature cardiac muscle phenotype. This could be explained in part by an incomplete transition from fetal to adult myofilament protein isoform expression. In this commentary, we review evidence that supports this hypothesis and discuss prospects for ultimately generating engineered heart tissue specimens that behave similarly to adult human myocardium. We suggest approaches to better characterize myofilament maturation level in these in vitro systems, and illustrate how new computational models could be used to better understand complex relationships between muscle contraction, myofilament protein isoform expression, and maturation.
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Riaz, Muhammad, Jinkyu Park, Lorenzo R. Sewanan, Yongming Ren, Jonas Schwan, Subhash K. Das, Pawel T. Pomianowski, et al. "Muscle LIM Protein Force-Sensing Mediates Sarcomeric Biomechanical Signaling in Human Familial Hypertrophic Cardiomyopathy." Circulation 145, no. 16 (April 19, 2022): 1238–53. http://dx.doi.org/10.1161/circulationaha.121.056265.
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Background: Familial hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disease and is typically caused by mutations in genes encoding sarcomeric proteins that regulate cardiac contractility. HCM manifestations include left ventricular hypertrophy and heart failure, arrythmias, and sudden cardiac death. How dysregulated sarcomeric force production is sensed and leads to pathological remodeling remains poorly understood in HCM, thereby inhibiting the efficient development of new therapeutics. Methods: Our discovery was based on insights from a severe phenotype of an individual with HCM and a second genetic alteration in a sarcomeric mechanosensing protein. We derived cardiomyocytes from patient-specific induced pluripotent stem cells and developed robust engineered heart tissues by seeding induced pluripotent stem cell–derived cardiomyocytes into a laser-cut scaffold possessing native cardiac fiber alignment to study human cardiac mechanobiology at both the cellular and tissue levels. Coupled with computational modeling for muscle contraction and rescue of disease phenotype by gene editing and pharmacological interventions, we have identified a new mechanotransduction pathway in HCM, shown to be essential in modulating the phenotypic expression of HCM in 5 families bearing distinct sarcomeric mutations. Results: Enhanced actomyosin crossbridge formation caused by sarcomeric mutations in cardiac myosin heavy chain ( MYH7 ) led to increased force generation, which, when coupled with slower twitch relaxation, destabilized the MLP (muscle LIM protein) stretch-sensing complex at the Z-disc. Subsequent reduction in the sarcomeric muscle LIM protein level caused disinhibition of calcineurin–nuclear factor of activated T-cells signaling, which promoted cardiac hypertrophy. We demonstrate that the common muscle LIM protein–W4R variant is an important modifier, exacerbating the phenotypic expression of HCM, but alone may not be a disease-causing mutation. By mitigating enhanced actomyosin crossbridge formation through either genetic or pharmacological means, we alleviated stress at the Z-disc, preventing the development of hypertrophy associated with sarcomeric mutations. Conclusions: Our studies have uncovered a novel biomechanical mechanism through which dysregulated sarcomeric force production is sensed and leads to pathological signaling, remodeling, and hypertrophic responses. Together, these establish the foundation for developing innovative mechanism-based treatments for HCM that stabilize the Z-disc MLP-mechanosensory complex.
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Yost, Michael, Robert Price, David Simpson, and Louis Terracio. "Artificial Myocardium: Design Principles and Substratum." Microscopy and Microanalysis 7, S2 (August 2001): 138–39. http://dx.doi.org/10.1017/s1431927600026763.
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Death and disability due to cardiovascular disease and congenital anomalies remains a significant health problem in the United States. Despite improvements in detection, patient management, surgery and preventative medicine, the quality of life for people who suffer from cardiovascular dysfunction has a major impact on our society. The intact heart is an elaborate three-dimensional structure that insures the orderly propagation of electrical signals coordinating the contraction and relaxation of the ventricular wall. Localized loss of muscular tissue as a result of congenital defect or disease process alters this structural arrangement and impairs overall cardiac function. Conventional surgical techniques cannot begin to adequately restore the subtle structural and functional relationships in the heart. The ability to construct a tissue-engineered prosthesis composed of cardiac muscle cells in a collagen-based scaffold may potentially offer a superior alternative to currently available surgical techniques.A tissue engineered myocardium must have the following components: First, it must develop and maintain the correct cellular phenotype as well as a functioning contractile apparatus of parallel myofibrils, Second it must be able to form gap junctions within itself and with the native tissue and these gap junctions must be competent at conducting electrical pacing as well as other biochemical signals, and Third, it must be capable of participating in and contributing to the rhythmic contraction of normal myocardium as well as accommodate the changes in contraction frequency ubiquitous in the cardiac environment
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Krishnamurthy, Gaurav, Daniel B. Ennis, Akinobu Itoh, Wolfgang Bothe, Julia C. Swanson, Matts Karlsson, Ellen Kuhl, D. Craig Miller, and Neil B. Ingels. "Material properties of the ovine mitral valve anterior leaflet in vivo from inverse finite element analysis." American Journal of Physiology-Heart and Circulatory Physiology 295, no. 3 (September 2008): H1141—H1149. http://dx.doi.org/10.1152/ajpheart.00284.2008.
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We measured leaflet displacements and used inverse finite-element analysis to define, for the first time, the material properties of mitral valve (MV) leaflets in vivo. Sixteen miniature radiopaque markers were sewn to the MV annulus, 16 to the anterior MV leaflet, and 1 on each papillary muscle tip in 17 sheep. Four-dimensional coordinates were obtained from biplane videofluoroscopic marker images (60 frames/s) during three complete cardiac cycles. A finite-element model of the anterior MV leaflet was developed using marker coordinates at the end of isovolumic relaxation (IVR; when the pressure difference across the valve is ∼0), as the minimum stress reference state. Leaflet displacements were simulated during IVR using measured left ventricular and atrial pressures. The leaflet shear modulus ( Gcirc-rad) and elastic moduli in both the commisure-commisure ( Ecirc) and radial ( Erad) directions were obtained using the method of feasible directions to minimize the difference between simulated and measured displacements. Group mean (±SD) values (17 animals, 3 heartbeats each, i.e., 51 cardiac cycles) were as follows: Gcirc-rad= 121 ± 22 N/mm2, Ecirc= 43 ± 18 N/mm2, and Erad= 11 ± 3 N/mm2( Ecirc> Erad, P < 0.01). These values, much greater than those previously reported from in vitro studies, may result from activated neurally controlled contractile tissue within the leaflet that is inactive in excised tissues. This could have important implications, not only to our understanding of mitral valve physiology in the beating heart but for providing additional information to aid the development of more durable tissue-engineered bioprosthetic valves.
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Cooper, Paige E., Monica Sala-Rabanal, Sun Joo Lee, and Colin G. Nichols. "Differential mechanisms of Cantú syndrome–associated gain of function mutations in the ABCC9 (SUR2) subunit of the KATP channel." Journal of General Physiology 146, no. 6 (November 30, 2015): 527–40. http://dx.doi.org/10.1085/jgp.201511495.
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Cantú syndrome (CS) is a rare disease characterized by congenital hypertrichosis, distinct facial features, osteochondrodysplasia, and cardiac defects. Recent genetic analysis has revealed that the majority of CS patients carry a missense mutation in ABCC9, which codes for the sulfonylurea receptor SUR2. SUR2 subunits couple with Kir6.x, inwardly rectifying potassium pore-forming subunits, to form adenosine triphosphate (ATP)-sensitive potassium (KATP) channels, which link cell metabolism to membrane excitability in a variety of tissues including vascular smooth muscle, skeletal muscle, and the heart. The functional consequences of multiple uncharacterized CS mutations remain unclear. Here, we have focused on determining the functional consequences of three documented human CS-associated ABCC9 mutations: human P432L, A478V, and C1043Y. The mutations were engineered in the equivalent position in rat SUR2A (P429L, A475V, and C1039Y), and each was coexpressed with mouse Kir6.2. Using macroscopic rubidium (86Rb+) efflux assays, we show that KATP channels formed with P429L, A475V, or C1039Y mutants enhance KATP activity compared with wild-type (WT) channels. We used inside-out patch-clamp electrophysiology to measure channel sensitivity to ATP inhibition and to MgADP activation. For P429L and A475V mutants, sensitivity to ATP inhibition was comparable to WT channels, but activation by MgADP was significantly greater. C1039Y-dependent channels were significantly less sensitive to inhibition by ATP or by glibenclamide, but MgADP activation was comparable to WT. The results indicate that these three CS mutations all lead to overactive KATP channels, but at least two mechanisms underlie the observed gain of function: decreased ATP inhibition and enhanced MgADP activation.
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Leal-Marin, Sara, Glynn Gallaway, Kai Höltje, Alex Lopera-Sepulveda, Birgit Glasmacher, and Oleksandr Gryshkov. "Scaffolds with Magnetic Nanoparticles for Tissue Stimulation." Current Directions in Biomedical Engineering 7, no. 2 (October 1, 2021): 460–63. http://dx.doi.org/10.1515/cdbme-2021-2117.
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Abstract Magnetic nanoparticles (MNPs) have been used in several medical applications, including targeted hyperthermia, resonance tomography, diagnostic sensors, and localized drug delivery. Further applications of magnetic field manipulation through MNPs in tissue engineering have been described. The current study aims to develop tissue-engineered polymeric scaffolds with incorporated MNPs for applications that require stimulation of the tissues such as nerves, muscles, or heart. Electrospun scaffolds were obtained using 14%w/v polycaprolactone (PCL) in 2,2,2-Trifluoroethanol (TFE) at concentrations of 5% & 7.5%w/v of dispersed MNPs (iron oxide, Fe3O4, or cobalt iron oxide, CoFe2O4). Scaffolds were analyzed using scanning electron microscopy (SEM), energy dispersive x-ray spectroscopy, uniaxial tensile testing, and cell seeding for biocompatibility. Human bone marrow mesenchymal stem cells (bmMSCs) were seeded on the scaffolds. Biocompatibility was assessed by metabolic activity with Resazurin reduction assay on day 1, 3, 7, 10. Cell-cell and cell-scaffold interactions were analyzed by SEM. Electrospun scaffolds containing MNPs showed a decrease in fiber diameter as compared to scaffolds of pure PCL. The maximum force increases with the inclusion of MNPs, with higher values revealed for iron oxide. The metabolic activity decreased with MNPs, especially for cobalt iron oxide at a higher concentration. On the other hand, the cells developed good cell-scaffold and cell-cell interactions, making the proposed scaffolds good prospects for potential use in tissue stimulation.
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Bullard, Tara A., Tricia L. Protack, Frédérick Aguilar, Suveer Bagwe, H. Todd Massey, and Burns C. Blaxall. "Identification of Nogo as a novel indicator of heart failure." Physiological Genomics 32, no. 2 (January 2008): 182–89. http://dx.doi.org/10.1152/physiolgenomics.00200.2007.
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Numerous genetically engineered animal models of heart failure (HF) exhibit multiple characteristics of human HF, including aberrant β-adrenergic signaling. Several of these HF models can be rescued by cardiac-targeted expression of the Gβγ inhibitory carboxy-terminus of the β-adrenergic receptor kinase (βARKct). We recently reported microarray analysis of gene expression in multiple animal models of HF and their βARKct rescue, where we identified gene expression patterns distinct and predictive of HF and rescue. We have further investigated the muscle LIM protein knockout model of HF (MLP−/−), which closely parallels human dilated cardiomyopathy disease progression and aberrant β-adrenergic signaling, and their βARKct rescue. A group of known and novel genes was identified and validated by quantitative real-time PCR whose expression levels predicted phenotype in both the larger HF group and in the MLP−/− subset. One of these novel genes is herein identified as Nogo, a protein widely studied in the nervous system, where it plays a role in regeneration. Nogo expression is altered in HF and normalized with rescue, in an isoform-specific manner, using left ventricular tissue harvested from both animal and human subjects. To investigate cell type-specific expression of Nogo in the heart, immunofluorescence and confocal microscopy were utilized. Nogo expression appears to be most clearly associated with cardiac fibroblasts. To our knowledge, this is the first report to demonstrate the relationship between Nogo expression and HF, including cell-type specificity, in both mouse and human HF and phenotypic rescue.
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Kiss, Eva, Carolin Fischer, Jan-Mischa Sauter, Jinmeng Sun, and Nina D. Ullrich. "The Structural and the Functional Aspects of Intercellular Communication in iPSC-Cardiomyocytes." International Journal of Molecular Sciences 23, no. 8 (April 18, 2022): 4460. http://dx.doi.org/10.3390/ijms23084460.
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Recent advances in the technology of producing novel cardiomyocytes from induced pluripotent stem cells (iPSC-cardiomyocytes) fuel new hope for future clinical applications. The use of iPSC-cardiomyocytes is particularly promising for the therapy of cardiac diseases such as myocardial infarction, where these cells could replace scar tissue and restore the functionality of the heart. Despite successful cardiogenic differentiation, medical applications of iPSC-cardiomyocytes are currently limited by their pronounced immature structural and functional phenotype. This review focuses on gap junction function in iPSC-cardiomyocytes and portrays our current understanding around the structural and the functional limitations of intercellular coupling and viable cardiac graft formation involving these novel cardiac muscle cells. We further highlight the role of the gap junction protein connexin 43 as a potential target for improving cell–cell communication and electrical signal propagation across cardiac tissue engineered from iPSC-cardiomyocytes. Better insight into the mechanisms that promote functional intercellular coupling is the foundation that will allow the development of novel strategies to combat the immaturity of iPSC-cardiomyocytes and pave the way toward cardiac tissue regeneration.
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Li, J., K. C. Liu, F. Jin, M. M. Lu, and J. A. Epstein. "Transgenic rescue of congenital heart disease and spina bifida in Splotch mice." Development 126, no. 11 (June 1, 1999): 2495–503. http://dx.doi.org/10.1242/dev.126.11.2495.
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Pax3-deficient Splotch mice display neural tube defects and an array of neural crest related abnormalities including defects in the cardiac outflow tract, dorsal root ganglia and pigmentation. Pax3 is expressed in neural crest cells that emerge from the dorsal neural tube. Pax3 is also expressed in the somites, through which neural crest cells migrate, where it is required for hypaxial muscle development. Homozygous mutant Splotch embryos die by embryonic day 14. We have utilized the proximal 1.6 kb Pax3 promoter and upstream regulatory elements to engineer transgenic mice reproducing endogenous Pax3 expression in neural tube and neural crest, but not the somite. Over expression of Pax3 in these tissues reveals no discernible phenotype. Breeding of transgenic mice onto a Splotch background demonstrates that neural tube and neural crest expression of Pax3 is sufficient to rescue neural tube closure, cardiac development and other neural crest related defects. Transgenic Splotch mice survive until birth at which time they succumb to respiratory failure secondary to absence of a muscular diaphragm. Limb muscles are also absent. These results indicate that regulatory elements sufficient for functional expression of Pax3 required for cardiac development and neural tube closure are contained within the region 1.6 kb upstream of the Pax3 transcriptional start site. In addition, the single Pax3 isoform used for this transgene is sufficient to execute these developmental processes. Although the extracellular matrix and the environment of the somites through which neural crest migrates is known to influence neural crest behavior, our results indicate that Pax3-deficient somites are capable of supporting proper neural crest migration and function suggesting a cell autonomous role for Pax3 in neural crest.
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Ploeg, Meike C., Chantal Munts, Tayeba Seddiqi, Tim J. L. ten Brink, Jonathan Breemhaar, Lorenzo Moroni, Frits W. Prinzen, and Frans A. van Nieuwenhoven. "Culturing of Cardiac Fibroblasts in Engineered Heart Matrix Reduces Myofibroblast Differentiation but Maintains Their Response to Cyclic Stretch and Transforming Growth Factor β1." Bioengineering 9, no. 10 (October 14, 2022): 551. http://dx.doi.org/10.3390/bioengineering9100551.
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Isolation and culturing of cardiac fibroblasts (CF) induces rapid differentiation toward a myofibroblast phenotype, which is partly mediated by the high substrate stiffness of the culture plates. In the present study, a 3D model of Engineered Heart Matrix (EHM) of physiological stiffness (Youngs modulus ~15 kPa) was developed using primary adult rat CF and a natural hydrogel collagen type 1 matrix. CF were equally distributed, viable and quiescent for at least 13 days in EHM and the baseline gene expression of myofibroblast-markers alfa-smooth muscle actin (Acta2), and connective tissue growth factor (Ctgf) was significantly lower, compared to CF cultured in 2D monolayers. CF baseline gene expression of transforming growth factor-beta1 (Tgfβ1) and brain natriuretic peptide (Nppb) was higher in EHM-fibers compared to the monolayers. EHM stimulation by 10% cyclic stretch (1 Hz) increased the gene expression of Nppb (3.0-fold), Ctgf (2.1-fold) and Tgfβ1 (2.3-fold) after 24 h. Stimulation of EHM with TGFβ1 (1 ng/mL, 24 h) induced Tgfβ1 (1.6-fold) and Ctgf (1.6-fold). In conclusion, culturing CF in EHM of physiological stiffness reduced myofibroblast marker gene expression, while the CF response to stretch or TGFβ1 was maintained, indicating that our novel EHM structure provides a good physiological model to study CF function and myofibroblast differentiation.
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Ratner, B. D., M. Allan, J. Angello, P. Bornstein, K. D. Hauch, S. D. Hauschka, A. S. Hoffman, et al. "TO TISSUE ENGINEER HEART MUSCLE." ASAIO Journal 49, no. 2 (March 2003): 219. http://dx.doi.org/10.1097/00002480-200303000-00312.
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Posner, Mason, Kelly L. Murray, Matthew S. McDonald, Hayden Eighinger, Brandon Andrew, Amy Drossman, Zachary Haley, Justin Nussbaum, Larry L. David, and Kirsten J. Lampi. "The zebrafish as a model system for analyzing mammalian and native α-crystallin promoter function." PeerJ 5 (November 27, 2017): e4093. http://dx.doi.org/10.7717/peerj.4093.
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Previous studies have used the zebrafish to investigate the biology of lens crystallin proteins and their roles in development and disease. However, little is known about zebrafish α-crystallin promoter function, how it compares to that of mammals, or whether mammalian α-crystallin promoter activity can be assessed using zebrafish embryos. We injected a variety of α-crystallin promoter fragments from each species combined with the coding sequence for green fluorescent protein (GFP) into zebrafish zygotes to determine the resulting spatiotemporal expression patterns in the developing embryo. We also measured mRNA levels and protein abundance for all three zebrafish α-crystallins. Our data showed that mouse and zebrafish αA-crystallin promoters generated similar GFP expression in the lens, but with earlier onset when using mouse promoters. Expression was also found in notochord and skeletal muscle in a smaller percentage of embryos. Mouse αB-crystallin promoter fragments drove GFP expression primarily in zebrafish skeletal muscle, with less common expression in notochord, lens, heart and in extraocular regions of the eye. A short fragment containing only a lens-specific enhancer region increased lens and notochord GFP expression while decreasing muscle expression, suggesting that the influence of mouse promoter control regions carries over into zebrafish embryos. The two paralogous zebrafish αB-crystallin promoters produced subtly different expression profiles, with the aBa promoter driving expression equally in notochord and skeletal muscle while the αBb promoter resulted primarily in skeletal muscle expression. Messenger RNA for zebrafish αA increased between 1 and 2 days post fertilization (dpf), αBa increased between 4 and 5 dpf, but αBb remained at baseline levels through 5 dpf. Parallel reaction monitoring (PRM) mass spectrometry was used to detect αA, aBa, and αBb peptides in digests of zebrafish embryos. In whole embryos, αA-crystallin was first detected by 2 dpf, peaked in abundance by 4–5 dpf, and was localized to the eye. αBa was detected in whole embryo at nearly constant levels from 1–6 dpf, was also localized primarily to the eye, and its abundance in extraocular tissues decreased from 4–7 dpf. In contrast, due to its low abundance, no αBb protein could be detected in whole embryo, or dissected eye and extraocular tissues. Our results show that mammalian α-crystallin promoters can be efficiently screened in zebrafish embryos and that their controlling regions are well conserved. An ontogenetic shift in zebrafish aBa-crystallin promoter activity provides an interesting system for examining the evolution and control of tissue specificity. Future studies that combine these promoter based approaches with the expanding ability to engineer the zebrafish genome via techniques such as CRISPR/Cas9 will allow the manipulation of protein expression to test hypotheses about lens crystallin function and its relation to lens biology and disease.
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Ferrari, Margaret Rose, Jeffrey Jacot, Michael Di Maria, Damon Pool, Mallory Lennon, and Dillon Jarrell. "3212 Development of a Contractile Fontan Circuit to Decrease Central Venous Pressures in Single Ventricle Patients." Journal of Clinical and Translational Science 3, s1 (March 2019): 7–8. http://dx.doi.org/10.1017/cts.2019.22.
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OBJECTIVES/SPECIFIC AIMS: Children born with a single ventricle congenital heart defect requires three invasive open-heart surgeries in the first three years of life. The third operation, the Fontan procedure, includes connection of the vena cava (VC) to the pulmonary artery (PA) using a bio-inert conduit to reduce work required by the right ventricle (RV). While this operation greatly extends the lives of HLHS patients, the Fontan circuit eventually fails, and the only solution is a scarcely available donor heart. This failed circuit is explained by the “Fontan paradox” where central venous pressures build up over time, causing increased systemic resistance and congestion. The absence of the sub-pulmonary ventricle leads to abnormal hemodynamics associated with life-threatening complications. We believe that decreasing central venous pressures through the use of a tissue engineered contractile, patient specific conduit will decrease the amount and severity of complications caused by the “Fontan paradox.” We will use amniotic fluid derived induced pluripotent stem cells (AF-iPSCs) differentiated into cardiomyocytes (CMs) to generate flow within a biodegradable conduit. Additionally, AF-iPSC will be differentiated into structural support cells (SSCs), including cardiac fibroblasts and epicardium. Several studies suggest advanced contraction and structure of CMs in specific ratios with SSCs, particularly mouse and human fetal fibroblasts. In combination, these cells have shown advanced tissue organization and function through mechanically and electrically aligned junctions. This allows them to have a magnitude higher contractile force than CMs alone, making them ideal for increasing pressure within a tissue engineered construct. This poster focuses on the differentiation and selection of SSCs. METHODS/STUDY POPULATION: AF-iPSCs differentiation began at roughly 80% confluency. Mesoderm formation occurred via WNT pathway modulation by supplementing RPMI+insulin media with 0.5 ng/mL BMP4 at day 0, followed by 3 ng/mL BMP4, 2 ng/mL Activin A, and 5 ng/mL BFGF for four days. Then, RPMI+insulin media was supplemented with 10 ng/mL of BMP4 until day fifteen for epicardial formation. Cells were lifted to induce epithelial-to-mesenchymal transition (EMT) and RPMI-insulin media was supplemented with 10 ng/mL BFGF for cardiac fibroblasts. They were then harvested and characterized using immunofluorescence. Planned experiments include RT-qPCR for further characterization of cardiac fibroblasts. Additionally, a fibroblast isolation plating technique will be utilized to obtain cardiac fibroblast from AF-iPSC CMs and AF-iPSC epicardium. Commercially obtained human cardiac fibroblasts will be utilized as a control for all studies. RESULTS/ANTICIPATED RESULTS: Immunofluorescence (IF) revealed positive expression of vimentin and α-SMA indicating a fibroblast and vascular smooth muscle phenotype after supplementation with 10 ng/mL of BMP4 after EMT induction. It is expected that IF of epicardial formation at day 15 will show positive expression of WT1, a well-known epicardial marker. We also suspect RT-qPCR will reveal high expression of cardiac fibroblast specific markers COL1A1, PDGFA, TCF21, and THSB1. We expect to yield a higher number of cardiac fibroblast from the small molecule AF-iPSC differentiation compared to a timed plating technique of AF-iPSC CMs and AF-iPSC epicardium (separately plated). Results will be quantified and compared using the aforementioned techniques. DISCUSSION/SIGNIFICANCE OF IMPACT: Discussion/significance of impact: Although fibroblasts make up a large portion of cells in the heart and greatly enhance CM function, they are poorly characterized in the literature and not easily obtained. This study will provide an efficiency comparison on the best method for acquiring cardiac fibroblast for cardiac tissue engineering applications as we move forward with translational cardiac pediatric research.
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Cho, Nathan, Shadi E. Razipour, and Megan L. McCain. "Featured Article: TGF-β1 dominates extracellular matrix rigidity for inducing differentiation of human cardiac fibroblasts to myofibroblasts." Experimental Biology and Medicine 243, no. 7 (March 4, 2018): 601–12. http://dx.doi.org/10.1177/1535370218761628.
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Cardiac fibroblasts and their activated derivatives, myofibroblasts, play a critical role in wound healing after myocardial injury and often contribute to long-term pathological outcomes, such as excessive fibrosis. Thus, defining the microenvironmental factors that regulate the phenotype of cardiac fibroblasts and myofibroblasts could lead to new therapeutic strategies. Both chemical and biomechanical cues have previously been shown to induce myofibroblast differentiation in many organs and species. For example, transforming growth factor beta 1, a cytokine secreted by neutrophils, and rigid extracellular matrix environments have both been shown to promote differentiation. However, the relative contributions of transforming growth factor beta 1 and extracellular matrix rigidity, two hallmark cues in many pathological myocardial microenvironments, to the phenotype of human cardiac fibroblasts are unclear. We hypothesized that transforming growth factor beta 1 and rigid extracellular matrix environments would potentially have a synergistic effect on the differentiation of human cardiac fibroblasts to myofibroblasts. To test this, we seeded primary human adult cardiac fibroblasts onto coverslips coated with polydimethylsiloxane of various elastic moduli, introduced transforming growth factor beta 1, and longitudinally quantified cell phenotype by measuring expression of α-smooth muscle actin, the most robust indicator of myofibroblasts. Our data indicate that, although extracellular matrix rigidity influenced differentiation after one day of transforming growth factor beta 1 treatment, ultimately transforming growth factor beta 1 superseded extracellular matrix rigidity as the primary regulator of myofibroblast differentiation. We also measured expression of POSTN, FAP, and FSP1, proposed secondary indicators of fibroblast/myofibroblast phenotypes. Although these genes partially trended with α-smooth muscle actin expression, they were relatively inconsistent. Finally, we demonstrated that activated myofibroblasts incompletely revert to a fibroblast phenotype after they are re-plated onto new surfaces without transforming growth factor beta 1, suggesting differentiation is partially reversible. Our results provide new insights into how microenvironmental cues affect human cardiac fibroblast differentiation in the context of myocardial pathology, which is important for identifying effective therapeutic targets and dictating supporting cell phenotypes for engineered human cardiac disease models. Impact statement Heart disease is the leading cause of death worldwide. Many forms of heart disease are associated with fibrosis, which increases extracellular matrix (ECM) rigidity and compromises cardiac output. Fibrotic tissue is synthesized primarily by myofibroblasts differentiated from fibroblasts. Thus, defining the cues that regulate myofibroblast differentiation is important for understanding the mechanisms of fibrosis. However, previous studies have focused on non-human cardiac fibroblasts and have not tested combinations of chemical and mechanical cues. We tested the effects of TGF-β1, a cytokine secreted by immune cells after injury, and ECM rigidity on the differentiation of human cardiac fibroblasts to myofibroblasts. Our results indicate that differentiation is initially influenced by ECM rigidity, but is ultimately superseded by TGF-β1. This suggests that targeting TGF-β signaling pathways in cardiac fibroblasts may have therapeutic potential for attenuating fibrosis, even in rigid microenvironments. Additionally, our approach can be leveraged to engineer more precise multi-cellular human cardiac tissue models.
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Au, Sam H. "Squeezing inspiration from embryonic hearts." Science Translational Medicine 11, no. 477 (January 30, 2019): eaaw5317. http://dx.doi.org/10.1126/scitranslmed.aaw5317.
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Tijsen, Anke J., Lucía Cócera Ortega, Yolan J. Reckman, Xiaolei Zhang, Ingeborg van der Made, Simona Aufiero, Jiuru Li, et al. "Titin Circular RNAs Create a Back-Splice Motif Essential for SRSF10 Splicing." Circulation 143, no. 15 (April 13, 2021): 1502–12. http://dx.doi.org/10.1161/circulationaha.120.050455.
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Background: TTN (Titin), the largest protein in humans, forms the molecular spring that spans half of the sarcomere to provide passive elasticity to the cardiomyocyte. Mutations that disrupt the TTN transcript are the most frequent cause of hereditary heart failure. We showed before that TTN produces a class of circular RNAs (circRNAs) that depend on RBM20 to be formed. In this study, we show that the back-splice junction formed by this class of circRNAs creates a unique motif that binds SRSF10 to enable it to regulate splicing. Furthermore, we show that one of these circRNAs (cTTN1) distorts both localization of and splicing by RBM20. Methods: We calculated genetic constraint of the identified motif in 125 748 exomes collected from the gnomAD database. Furthermore, we focused on the highest expressed RBM20-dependent circRNA in the human heart, which we named cTTN1. We used shRNAs directed to the back-splice junction to induce selective loss of cTTN1 in human induced pluripotent stem cell–derived cardiomyocytes. Results: Human genetics suggests reduced genetic tolerance of the generated motif, indicating that mutations in this motif might lead to disease. RNA immunoprecipitation confirmed binding of circRNAs with this motif to SRSF10. Selective loss of cTTN1 in human induced pluripotent stem cell–derived cardiomyocytes induced structural abnormalities, apoptosis, and reduced contractile force in engineered heart tissue. In line with its SRSF10 binding, loss of cTTN1 caused abnormal splicing of important cardiomyocyte SRSF10 targets such as MEF2A and CASQ2 . Strikingly, loss of cTTN1 also caused abnormal splicing of TTN itself. Mechanistically, we show that loss of cTTN1 distorts both localization of and splicing by RBM20. Conclusions: We demonstrate that circRNAs formed from the TTN transcript are essential for normal splicing of key muscle genes by enabling splice regulators RBM20 and SRSF10. This shows that the TTN transcript also has regulatory roles, besides its well-known signaling and structural function. In addition, we demonstrate that the specific sequence created by the back-splice junction of these circRNAs has important functions. This highlights the existence of functionally important sequences that cannot be recognized as such in the human genome but provides an as-yet unrecognized source for functional sequence variation.
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McSpadden, Luke C., Robert D. Kirkton, and Nenad Bursac. "Electrotonic loading of anisotropic cardiac monolayers by unexcitable cells depends on connexin type and expression level." American Journal of Physiology-Cell Physiology 297, no. 2 (August 2009): C339—C351. http://dx.doi.org/10.1152/ajpcell.00024.2009.
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Understanding how electrotonic loading of cardiomyocytes by unexcitable cells alters cardiac impulse conduction may be highly relevant to fibrotic heart disease. In this study, we optically mapped electrical propagation in confluent, aligned neonatal rat cardiac monolayers electrotonically loaded with cardiac fibroblasts, control human embryonic kidney (HEK-293) cells, or HEK-293 cells genetically engineered to overexpress the gap junction proteins connexin-43 or connexin-45. Gap junction expression and function were assessed by immunostaining, immunoblotting, and fluorescence recovery after photobleaching and were correlated with the optically mapped propagation of action potentials. We found that neonatal rat ventricular fibroblasts negative for the myofibroblast marker smooth muscle α-actin expressed connexin-45 rather than connexin-43 or connexin-40, weakly coupled to cardiomyocytes, and, without significant depolarization of cardiac resting potential, slowed cardiac conduction to 75% of control only at high (>60%) coverage densities, similar to loading effects found from HEK-293 cells expressing similar levels of connexin-45. In contrast, HEK-293 cells with connexin-43 expression similar to that of cardiomyocytes significantly decreased cardiac conduction velocity and maximum capture rate to as low as 22% and 25% of control values, respectively, while increasing cardiac action potential duration to 212% of control and cardiac resting potential from −71.6 ± 4.9 mV in controls to −65.0 ± 3.8 mV. For all unexcitable cell types and coverage densities, velocity anisotropy ratio remained unchanged. Despite the induced conduction slowing, none of the loading cell types increased the proportion of spontaneously active monolayers. These results signify connexin isoform and expression level as important contributors to potential electrical interactions between unexcitable cells and myocytes in cardiac tissue.
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Zhang, Donghui, and William T. Pu. "Exercising engineered heart muscle to maturity." Nature Reviews Cardiology 15, no. 7 (May 24, 2018): 383–84. http://dx.doi.org/10.1038/s41569-018-0032-x.
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Apa, Ludovica, Marianna Cosentino, Flavia Forconi, Antonio Musarò, Emanuele Rizzuto, and Zaccaria Del Prete. "The Development of an Innovative Embedded Sensor for the Optical Measurement of Ex-Vivo Engineered Muscle Tissue Contractility." Sensors 22, no. 18 (September 12, 2022): 6878. http://dx.doi.org/10.3390/s22186878.
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Tissue engineering is a multidisciplinary approach focused on the development of innovative bioartificial substitutes for damaged organs and tissues. For skeletal muscle, the measurement of contractile capability represents a crucial aspect for tissue replacement, drug screening and personalized medicine. To date, the measurement of engineered muscle tissues is rather invasive and not continuous. In this context, we proposed an innovative sensor for the continuous monitoring of engineered-muscle-tissue contractility through an embedded technique. The sensor is based on the calibrated deflection of one of the engineered tissue’s supporting pins, whose movements are measured using a noninvasive optical method. The sensor was calibrated to return force values through the use of a step linear motor and a micro-force transducer. Experimental results showed that the embedded sensor did not alter the correct maturation of the engineered muscle tissue. Finally, as proof of concept, we demonstrated the ability of the sensor to capture alterations in the force contractility of the engineered muscle tissues subjected to serum deprivation.
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Smith, Alec ST, Shawn M. Luttrell, Jean-Baptiste Dupont, Kevin Gray, Daniel Lih, Jacob W. Fleming, Nathan J. Cunningham, et al. "High-throughput, real-time monitoring of engineered skeletal muscle function using magnetic sensing." Journal of Tissue Engineering 13 (January 2022): 204173142211221. http://dx.doi.org/10.1177/20417314221122127.
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Engineered muscle tissues represent powerful tools for examining tissue level contractile properties of skeletal muscle. However, limitations in the throughput associated with standard analysis methods limit their utility for longitudinal study, high throughput drug screens, and disease modeling. Here we present a method for integrating 3D engineered skeletal muscles with a magnetic sensing system to facilitate non-invasive, longitudinal analysis of developing contraction kinetics. Using this platform, we show that engineered skeletal muscle tissues derived from both induced pluripotent stem cell and primary sources undergo improvements in contractile output over time in culture. We demonstrate how magnetic sensing of contractility can be employed for simultaneous assessment of multiple tissues subjected to different doses of known skeletal muscle inotropes as well as the stratification of healthy versus diseased functional profiles in normal and dystrophic muscle cells. Based on these data, this combined culture system and magnet-based contractility platform greatly broadens the potential for 3D engineered skeletal muscle tissues to impact the translation of novel therapies from the lab to the clinic.
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Kim, Byung-Soo, and David J. Mooney. "Scaffolds for Engineering Smooth Muscle Under Cyclic Mechanical Strain Conditions." Journal of Biomechanical Engineering 122, no. 3 (February 6, 2000): 210–15. http://dx.doi.org/10.1115/1.429651.
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Cyclic mechanical strain has been demonstrated to enhance the development and function of engineered smooth muscle (SM) tissues, but appropriate scaffolds for engineering tissues under conditions of cyclic strain are currently lacking. These scaffolds must display elastic behavior, and be capable of inducing an appropriate smooth muscle cell (SMC) phenotype in response to mechanical signals. In this study, we have characterized several scaffold types commonly utilized in tissue engineering applications in order to select scaffolds that exhibit elastic properties under appropriate cyclic strain conditions. The ability of the scaffolds to promote an appropriate SMC phenotype in engineered SM tissues under cyclic strain conditions was subsequently analyzed. Poly(L-lactic acid)-bonded polyglycolide fiber-based scaffolds and type I collagen sponges exhibited partially elastic mechanical properties under cyclic strain conditions, although the synthetic polymer scaffolds demonstrated significant permanent deformation after extended times of cyclic strain application. SM tissues engineered with type I collagen sponges subjected to cyclic strain were found to contain more elastin than control tissues, and the SMCs in these tissues exhibited a contractile phenotype. In contrast, SMCs in control tissues exhibited a structure more consistent with the nondifferentiated, synthetic phenotype. These studies indicate the appropriate choice of a scaffold for engineering tissues in a mechanically dynamic environment is dependent on the time frame of the mechanical stimulation, and elastic scaffolds allow for mechanically directed control of cell phenotype in engineered tissues. [S0148-0731(00)00103-5]
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Alfonso, Abraham R., Sasmita Rath, Parvin Rafiee, Mario Hernandez-Espino, Mahreen Din, Florence George, and Sharan Ramaswamy. "Glycosaminoglycan entrapment by fibrin in engineered heart valve tissues." Acta Biomaterialia 9, no. 9 (September 2013): 8149–57. http://dx.doi.org/10.1016/j.actbio.2013.06.009.
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Ng, Ronald, Lorenzo R. Sewanan, Allison L. Brill, Paul Stankey, Xia Li, Yibing Qyang, Barbara E. Ehrlich, and Stuart G. Campbell. "Contractile work directly modulates mitochondrial protein levels in human engineered heart tissues." American Journal of Physiology-Heart and Circulatory Physiology 318, no. 6 (June 1, 2020): H1516—H1524. http://dx.doi.org/10.1152/ajpheart.00055.2020.
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In this work, we present a novel bioreactor that allows for active length control of engineered heart tissues during extended tissue culture. Specific length transients were designed so that engineered heart tissues generated complete cardiac work loops. Chronic culture with various work loops suggests that mitochondrial mass and biogenesis are directly regulated by work output.
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Cho, Seung-Woo, Il-Kwon Kim, Sang Hyun Lim, Dong-Ik Kim, Sun-Woong Kang, Soo Hyun Kim, Young Ha Kim, Eun Yeol Lee, Cha Yong Choi, and Byung-Soo Kim. "Smooth muscle-like tissues engineered with bone marrow stromal cells." Biomaterials 25, no. 15 (July 2004): 2979–86. http://dx.doi.org/10.1016/j.biomaterials.2003.09.068.
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Kim, Byung-Soo, Janeta Nikolovski, Jeffrey Bonadio, Elizabeth Smiley, and David J. Mooney. "Engineered Smooth Muscle Tissues: Regulating Cell Phenotype with the Scaffold." Experimental Cell Research 251, no. 2 (September 1999): 318–28. http://dx.doi.org/10.1006/excr.1999.4595.
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McSweeney, Sara J., and Michael D. Schneider. "Virgin birth: engineered heart muscle from parthenogenetic stem cells." Journal of Clinical Investigation 123, no. 3 (February 22, 2013): 1010–13. http://dx.doi.org/10.1172/jci67961.
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Geisse, Nicholas, Bonnie Berry, Kevin Gray, Samir Kharoufeh, Shawn M. Luttrell, Jesse Macadangdang, and Christal Worthen. "Abstract P1131: Modeling Contractile Diseases Using Scalable 3D Engineered Heart Tissues For Drug Discovery." Circulation Research 131, Suppl_1 (August 5, 2022). http://dx.doi.org/10.1161/res.131.suppl_1.p1131.
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Model systems that accurately recapitulate healthy and diseased function in a dish are critical for the development of novel therapeutics. For cardiac diseases, direct assessment of contractile output constitutes the most reliable metric with which to assess overall tissue function, as other ‘proxy’ measurements are poor predictors of muscle strength. 3D engineered muscle tissues (EMTs) derived from iPSCs hold great potential for modeling contractile function. Here, we have developed a platform and device that utilizes 3D EMTs in conjunction with a label-free magnetic sensing array. The platform enables facile and reproducible fabrication of 3D EMTs using virtually any cell source and is coupled with a highly parallel direct measurement of contractile strength. This approach enables the stratification of healthy and diseased phenotypes and facilitates compound safety and efficacy screening for evaluation of a drug’s effect on contractile output. We will present data from a drug (BMS-986094) that failed clinical trials due to unanticipated cardiotoxicity. We go on to show both the acute and chronic effects of doxorubicin in cardiac EMTs. Contractile force decreased in a dose dependent-like manner when the drug was applied continuously. Interestingly, a single 1uM bolus induced a transient effect that could be washed out over time. A repeat bolus, however, irreversibly abolished contraction, suggesting that repeat dosing may have a cardiotoxic effect on the muscle. These data demonstrate a first-and-only commercial platform for high-throughput assessment of 3D cardiac muscle contraction with potential for widespread adoption within the drug development field.
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Biermann, Daniel, Michael Didié, Bijoy Chandapillai Karikkineth, Claudia Lange, Thomas Eschenhagen, and Wolfram H. Zimmermann. "Abstract 1855: Transmural Myocardial Repair with Engineered Heart Tissue Grafts." Circulation 116, suppl_16 (October 16, 2007). http://dx.doi.org/10.1161/circ.116.suppl_16.ii_397.
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Engineered Heart Tissue (EHT) can be utilized to partially repair infarcted myocardium in rats. Here, we investigated the feasibility of EHT-grafts as transmural wall replacement in a heterotopic transplantation model. Methods: EHTs (diameter: 15 mm, thickness: 1– 4 mm) were generated from 12.5 ×10 6 neonatal rat heart cells, collagen type I, and matrigel. Similarly, non-contractile constructs were generated from rat cardiac fibroblasts (FB) and mesenchymal stem cells (MSC). Grafts were surgically inserted into large transmural defects (diameter: 6 mm) in the left ventricle of explanted donor hearts. Subsequently, “treated” hearts were transplanted into weight-matched (308±12 g; n=14), immune suppressed (cyclosporine, azathioprine, prednisolone) Wistar rats in heterotopic position. All transmural defects were also covered with an aortic patch to prevent bleeding from the ventricles. Sham surgeries included aortic patch implantations only. Heterotopic hearts were harvested after 28 days and subjected to morphological analyses by confocal laser scanning microscopy (CLSM). Results: Heart transplant weight at the time of implantation was 1.1±0.02 g (n=14). Heterotopic heart weight increased substantially in Sham (2.4±0.3 g, n=3) and FB-graft (2.1±0.1 g, n=3) animals, whereas MSC- (1.7±0.2 g, n=4) and EHT-graft (1.3±0.1 g, n=4; p<0.05 vs. Sham) animals showed a smaller or no increase in weight, respectively. EHT grafts remained contractile throughout the observation period. CLSM revealed that EHT-grafts established oriented muscle bundles (actin and actinin staining) inside the transmural defects and were strongly vascularized (CD31 and smooth muscle actin staining; lectin labeling) leading to partial reconstitution of the myocardial continuity. This was not observed in animals with FB- and MSC-grafts. However, MSC-grafts, but not FB-grafts, contained newly formed vessels with a markedly larger diameter than observed in EHT-grafts (21±6 vs. 5±0.7 μm; p<0.05). Conclusion: EHTs can be utilized as myocardial tissue grafts to reconstruct and prevent pathological enlargement of the left ventricle. This study constitutes a first step to establish a novel transmural myocardial repair technology involving fully bioengineered heart muscle.
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Dickerson, Darryl A. "Advancing Engineered Heart Muscle Tissue Complexity with Hydrogel Composites." Advanced Biology, August 23, 2022, 2200067. http://dx.doi.org/10.1002/adbi.202200067.
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Batalov, Ivan, Quentin Jallerat, and Adam W. Feinberg. "Abstract 153: Using the Embryonic Heart as an Instructive Template for Cardiac Tissue Engineering." Circulation Research 117, suppl_1 (July 17, 2015). http://dx.doi.org/10.1161/res.117.suppl_1.153.
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The engineering of highly aligned cardiomyocytes into functional heart muscle remains a primary challenge in cardiac tissue engineering. Researchers have shown that micropatterned topography and chemistry as well as mechanical and electrical gradients are all effective at inducing some degree of alignment. However, which approach works best in terms of electromechanical function of the engineered cardiac muscle is still an active area of research. Because formation of new heart muscle in mammals primarily occurs during cardiogenesis, we asked whether the embryonic heart could be used as an instructive template for the design of more effective cardiac tissue engineering scaffolds. Specifically, we hypothesized that micropatterns of fibronectin based on fibronectin fibril size and architecture in embryonic myocardium could improve cardiomyocyte alignment relative to 20 μm wide, 20 μm spaced fibronectin lines, a control pattern used widely in the literature. To test this, we first imaged the fibronectin matrix in the ventricles of day-5 embryonic chick hearts and imaged this in 3D using a multiphoton microscope. This fibronectin structure was then converted into a photomask for photolithography and subsequent patterning of fibronectin onto cover slips using microcontact printing. Samples with the biomimetic patterns or control patterns were seeded with embryonic chick cardiomyocytes, cultured for 3 days and then stained and imaged to visualize the myofibrils. Image analysis to quantify alignment showed that the ability of the biomimetic pattern to induce cardiomyocyte alignment increased with cell density, suggesting that cell-cell interactions play an important role in the formation of aligned embryonic myocardium. Disruption of the cadherins junctions using blocking antibodies confirmed this conclusion. In the future we will use human induced pluripotent stem cell-derived cardiomyocytes to engineer more clinically-relevant human heart muscle and analyze electromechanical function of the tissues including contractile force and action potential propagation.