Contractile abnormalities and altered drug response in engineered heart tissue from Mybpc3-targeted knock-in mice

Stöhr, Andrea; Friedrich, Felix W.; Flenner, Frederik; Geertz, Birgit; Eder, Alexandra; Schaaf, Sebastian; Hirt, Marc N.; Uebeler, June; Schlossarek, Saskia; Carrier, Lucie; Hansen, Arne; Eschenhagen, Thomas

doi:10.1016/j.yjmcc.2013.07.011

Cited by 65 publications

(60 citation statements)

References 34 publications

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“…As shown earlier, KI EHTs exhibit higher sensitivity to external Ca 2 þ and higher mRNA levels of hypertrophic markers than WT EHTs 24 . As expected, force of contraction and velocity of both contraction and relaxation were higher in non-transduced KI than WT EHTs (Fig.…”

Section: Resultssupporting

confidence: 68%

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Mybpc3 gene therapy for neonatal cardiomyopathy enables long-term disease prevention in mice

et al. 2014

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Homozygous or compound heterozygous frameshift mutations in MYBPC3 encoding cardiac myosin-binding protein C (cMyBP-C) cause neonatal hypertrophic cardiomyopathy (HCM), which rapidly evolves into systolic heart failure and death within the first year of life. Here we show successful long-term Mybpc3 gene therapy in homozygous Mybpc3-targeted knock-in (KI) mice, which genetically mimic these human neonatal cardiomyopathies. A single systemic administration of adeno-associated virus (AAV9)-Mybpc3 in 1-day-old KI mice prevents the development of cardiac hypertrophy and dysfunction for the observation period of 34 weeks and increases Mybpc3 messenger RNA (mRNA) and cMyBP-C protein levels in a dose-dependent manner. Importantly, Mybpc3 gene therapy unexpectedly also suppresses accumulation of mutant mRNAs. This study reports the first successful long-term gene therapy of HCM with correction of both haploinsufficiency and production of poison peptides. In the absence of alternative treatment options except heart transplantation, gene therapy could become a realistic treatment option for severe neonatal HCM.

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Section: Resultssupporting

confidence: 68%

“…EHTs were generated from unpurified mouse cardiac cells 24 . In brief, isolated cells were resuspended at a density of 6.8 Â 10 6 cells ml À 1 in culture medium containing bovine fibrinogen (5 mg ml À 1 ), aprotinin (2.5 mg ml À 1 ) and 10% Matrigel (BD Bioscience).…”

Section: Discussionmentioning

confidence: 99%

Mybpc3 gene therapy for neonatal cardiomyopathy enables long-term disease prevention in mice

et al. 2014

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“…Previous studies reported that mutations in the MyBP-C gene frequently cause hypertrophic cardiomyopathy (43,44), whereas its absence (cMyBP-C null mice) significantly attenuated cardiac function (45). Contractile abnormalities were also found in myosinbinding protein C (Mybpc3)-targeted knock-in mice with significant reduction in the cardiac expression of cMyBP-C (46). Interestingly, in the present study, rapamycin treatment enhanced the expression of cMyBP-C and also a thin filament-FIGURE 9.…”

Section: D-dige Spotsupporting

confidence: 51%

Mammalian Target of Rapamycin (mTOR) Inhibition with Rapamycin Improves Cardiac Function in Type 2 Diabetic Mice

Das

Durrant

Koka

et al. 2014

Journal of Biological Chemistry

134

122

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Background: Elevated mammalian target of rapamycin (mTOR) signaling contributes to diabetic complications. Results: mTOR inhibitor, rapamycin, improves metabolic status and cardiac function, attenuates oxidative stress, and alters antioxidant and contractile protein expression in type 2 diabetic mice. Conclusion: Rapamycin may provide metabolic and cardiac benefits in diabetic mice. Significance: mTOR inhibition may be an attractive novel therapeutic strategy for diabetes-related complications.

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“…22,87 Similarly, EHTs from heterozygous cMyBP-C knock-in mice, a model that reflects human HCM most closely, were completely normal under baseline conditions but showed altered drug responses compatible with increased Ca 2+ sensitivity of the myofilaments. 88 The first results of hiPSCderived 3D engineered tissues are eagerly awaited.…”

Section: Regarding Target Validation and Functional Genomicsmentioning

confidence: 99%

Cardiac Tissue Engineering

Hirt

Hansen

Eschenhagen

2014

Circulation Research

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Abstract:The engineering of 3-dimensional (3D) heart muscles has undergone exciting progress for the past decade.Profound advances in human stem cell biology and technology, tissue engineering and material sciences, as well as prevascularization and in vitro assay technologies make the first clinical application of engineered cardiac tissues a realistic option and predict that cardiac tissue engineering techniques will find widespread use in the preclinical research and drug development in the near future. Tasks that need to be solved for this purpose include standardization of human myocyte production protocols, establishment of simple methods for the in vitro vascularization of 3D constructs and better maturation of myocytes, and, finally, thorough definition of the predictive value of these methods for preclinical safety pharmacology. The present article gives an overview of the present state of the art, bottlenecks, and perspectives of cardiac tissue engineering for cardiac repair and in vitro testing. ( Jeffrey Robbins, EditorOriginal received May 24, 2013; revision received July 12, 2013; accepted July 15, 2013. In November 2013, the average time from submission to first decision for all original research papers submitted to Circulation Research was 14.6 days.From the Department of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; and DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Hamburg, Germany.Correspondence to Thomas Eschenhagen, Department of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany. E-mail t.eschenhagen@uke.de by guest on May 9, 2018 http://circres.ahajournals.org/ Downloaded from Hirt et al Cardiac Tissue Engineering 355gyratory shaking of embryonic chicken cardiac myocytes in an Erlenmeyer flask induced the formation of spontaneously beating spheroids with improved functionality when compared with standard 2D-cultured myocytes. This selfassembly is still used in variations to generate cardiac microspheres. 5 Current cardiac tissue engineering methods embark on this endogenous capacity and use engineering techniques to make 3D constructs of the desired size, geometry, and orientation (Table). Hydrogel TechniqueThe hydrogel method has been pioneered in the 1980s as an advanced culture method for fibroblasts and skeletal muscle cells 6 and gave rise to the first successful cardiac tissue.7 It needs 3 factors: solutions of gelling natural products, such as collagen I, matrigel, fibrin, or mixtures of them; casting molds; and anchoring constructs. The hydrogel entraps cells in a 3D space during gelling, the mold gives the 3D form, and the anchors allow the growing tissue to fix and to develop mechanical tension between ≥2 anchor points. Important aspects of this technique are that the naturally occurring hydrogels stimulate cells to spread and form intercellular connections and that the cells compress the gel, reduce the w...

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Contractile abnormalities and altered drug response in engineered heart tissue from Mybpc3-targeted knock-in mice

Cited by 65 publications

References 34 publications

Mybpc3 gene therapy for neonatal cardiomyopathy enables long-term disease prevention in mice

Mybpc3 gene therapy for neonatal cardiomyopathy enables long-term disease prevention in mice

Mammalian Target of Rapamycin (mTOR) Inhibition with Rapamycin Improves Cardiac Function in Type 2 Diabetic Mice

Cardiac Tissue Engineering

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