22 results on '"Breckwoldt, K."'
Search Results
2. P778Physiological and pharmacological characterization of human engineered heart tissue
- Author
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Vollert, I, Schaaf, S, Neuber, C, Letuffe-Breniere, D, Breckwoldt, K, Shibamiya, A, Stimpel, D, Eder, A, Eschenhagen, T, and Hansen, A
- Published
- 2014
- Full Text
- View/download PDF
3. 287Human induced pluripotent stem cells for tissue-engineered cardiac repair
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Breckwoldt, K, Weinberger, F, Pecha, S, Geertz, B, Starbatty, J, Hansen, A, and Eschenhagen, T
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- 2014
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4. Implantation of Spontaneously Beating Human iPS Cell-Derived Engineered Heart Tissue Does Not Provoke Ventricular Arrhythmias in a Guinea Pig Infarction Model
- Author
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Pecha, S., primary, Breckwoldt, K., additional, Roehl, M., additional, Hansen, A., additional, Schwoerer, A., additional, Ehmke, H., additional, Reichenspurner, H., additional, and Eschenhagen, T., additional
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- 2017
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5. Implantation of Spontaneously Beating Human iPS Cell-Derived ENGINEERED HEART TISSUE Does Not Provoke Ventricular Arrhythmias in a Guinea Pig Infarction Model
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Pecha, S., additional, Breckwoldt, K., additional, Roehl, M., additional, Geertz, B., additional, Weinberger, F., additional, Hansen, A., additional, Schwoerer, A., additional, Reichenspurner, H., additional, and Eschenhagen, T., additional
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- 2017
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6. Electrophysiological Investigations of Human iPS Cell-Derived Engineered Heart Tissue in a Guinea Pig Infarction Model
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Pecha, S., primary, Weinberger, F., additional, Breckwoldt, K., additional, Hansen, A., additional, Reichenspurner, H., additional, and Eschenhagen, T., additional
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- 2016
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7. Human Induced Pluripotent Stem Cells for Tissue Engineered Cardiac Repair
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Pecha, S., primary, Weinberger, F., additional, Breckwoldt, K., additional, Geertz, B., additional, Starbatty, J., additional, Hansen, A., additional, Reichenspurner, H., additional, and Eschenhagen, T., additional
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- 2015
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8. Human iPS-cell-derived Engineered Heart Tissue for Cardiac Repair
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Pecha, S., primary, Weinberger, F., additional, Breckwoldt, K., additional, Geertz, B., additional, Starbatty, J., additional, Schulze, T., additional, Hansen, A., additional, Reichenspurner, H., additional, and Eschenhagen, T., additional
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- 2014
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9. (82) - Human Induced Pluripotent Stem Cells for Tissue Engineered Cardiac Repair
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Pecha, S., Weinberger, F., Breckwoldt, K., Geertz, B., Starbatty, J., Hansen, A., Reichenspurner, H., and Eschenhagen, T.
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- 2015
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10. (281) - Human iPS-cell-derived Engineered Heart Tissue for Cardiac Repair
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Pecha, S., Weinberger, F., Breckwoldt, K., Geertz, B., Starbatty, J., Schulze, T., Hansen, A., Reichenspurner, H., and Eschenhagen, T.
- Published
- 2014
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11. 287 Human induced pluripotent stem cells for tissue-engineered cardiac repair.
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Breckwoldt, K, Weinberger, F, Pecha, S, Geertz, B, Starbatty, J, Hansen, A, and Eschenhagen, T
- Subjects
- *
PLURIPOTENT stem cells , *TISSUE engineering , *MYOCARDIAL infarction treatment , *HEART cells , *CELL morphology , *LABORATORY swine - Abstract
Myocardial infarction causes unrecoverable loss of cardiomyocytes. Engineered heart tissue (EHT) is an in vitro model of three-dimensional, force generating cardiomyocyte network with morphological and functional similarity to native heart tissue. In this study we transplanted EHTs from human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (CM) on cryo-injured guinea pig hearts and investigated whether hiPSC-CM-EHTs support left ventricular function.Human iPSC were generated by retroviral reprogramming of dermal fibroblasts. Cardiac differentiation of hiPSC was performed by an embryoid body-based three-stage differentiation protocol. EHTs were created from hiPS-CM (5*10^6 cardiomyocytes and 2*10^6 GFP+-HUVECs per EHT) and cultivated for 3 weeks under auxotonic stretch between flexible silicone posts. Development of contractile force was monitored prior to transplantation. Left ventricular myocardial cryo-injury was induced in adult guinea pigs (n=21). 7 days after injury EHTs (2 per animal, n=12) or cell-free constructs (n=9) were implanted. Animals received ciclosporin and methylprednisolon for immunosuppression. Functional parameters were examined by echocardiography and histology at baseline, before and 28 days after transplantation.The cardiac differentiation protocol resulted in a cell population with ~50% cardiomyocytes, which was further enriched by lactate-based selection to >90% purity and directly used for EHT generation. HiPSC-CM-EHTs developed contractile force and displayed morphological properties of native heart tissue. Cryo-injury resulted in large transmural scars (~30% of ventricular wall) which were verified histologically. Immunohistochemical staining for dystrophin and MLC2v showed the formation of large islets of cross-striated muscle tissue in the scar. The human origin was demonstrated by fluorescent-in-situ-hybridization. The new myocardium was vascularized with endothelium partly being of human origin. Animals receiving cell-free constructs showed left ventricular dilatation 28 days after transplantation. The EHT-group showed less dilatation (8.12 mm ± 0.21 basal, 8.18 mm ± 0.23 7d post cryo-injury, 8.87 mm ± 0.41 28d EHT vs. 9.74 mm ± 0.72 28d control) and significantly better fractional area shortening (42.20% ± 1.92 basal, 26.07% ± 2.13 7d post cryo-injury, 41.98% ± 4.48 28d EHT vs. 23.00% ± 3.24 28d control).Transplantation of hiPSC-derived EHTs in a guinea pig cryo-injury model provides early evidence that human EHTs survive after transplantation and support cardiac function. [ABSTRACT FROM AUTHOR]
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- 2014
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12. P778 Physiological and pharmacological characterization of human engineered heart tissue.
- Author
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Vollert, I, Schaaf, S, Neuber, C, Letuffe-Breniere, D, Breckwoldt, K, Shibamiya, A, Stimpel, D, Eder, A, Eschenhagen, T, and Hansen, A
- Subjects
PHARMACOLOGY ,TISSUE engineering ,PLURIPOTENT stem cells ,CARDIOVASCULAR diseases ,CELL culture ,HEART cells - Abstract
Objective: Human induced pluripotent stem cell (iPS cell)-derived cardiomyocytes represent a valuable tool in cardiovascular research of tremendous potential. However, these cells are still immature and characterized by poor sarcomeric organization and cellular orientation in 2D cell culture. Therefore, the measurement of contractile force, the most important and best understood function of cardiomyocytes in vivo, is not established for these cells. This study describes the generation of three-dimensional, strip-format, force generating engineered heart tissues (EHTs) from human iPS cell-derived cardiomyocytes and presents a characterization of physiological and pharmacological parameters based on force development.Methods and results: Cardiomyocyte differentiation of human induced pluripotent cells was achieved by a growth factor-based three stage protocol. Strip-format EHTs were generated from dissociated cardiomyocytes in fibrin matrix between flexible silicone posts. Within two weeks after casting coherently beating human EHTs were formed and EHTs displayed a regular beating pattern for several weeks. Histological analysis revealed a high degree of sarcomeric organization and alignment of cardiomyocytes in EHTs. Functional analysis was performed by measuring force response to calcium concentration, pre-load, pacing frequency, beta-adrenergic and muscarinic agonists, modulators of sodium, calcium and potassium channels and revealed concentration-dependent effects. Comparison with native human heart tissue suggests an overall high level of similarity and minor differences.Conclusions: This study demonstrates feasibility to characterize human iPS cell-derived cardiomyocytes in EHTs by measuring contractile force. The analysis suggests high levels of similarity between EHTs and native human heart tissue. Human EHTs are a promising platform for automated toxicology screens in future drug development and for in vitro experiments on human cardiomyocytes in general. [ABSTRACT FROM AUTHOR]
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- 2014
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13. (480) - Electrophysiological Investigations of Human iPS Cell-Derived Engineered Heart Tissue in a Guinea Pig Infarction Model.
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Pecha, S., Weinberger, F., Breckwoldt, K., Hansen, A., Reichenspurner, H., and Eschenhagen, T.
- Subjects
- *
MYOCARDIAL infarction treatment , *INDUCED pluripotent stem cells , *CARDIAC regeneration , *TISSUE engineering , *ELECTROPHYSIOLOGY , *LABORATORY swine - Published
- 2016
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14. Author Correction: Differentiation of cardiomyocytes and generation of human engineered heart tissue.
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Breckwoldt K, Brenière-Letuffe D, Mannhardt I, Schulze T, Ulmer B, Werner T, Benzin A, Klampe B, Reinsch MC, Laufer S, Shibamiya A, Prondzynski M, Mearini G, Schade D, Fuchs S, Neuber C, Krämer E, Saleem U, Schulze ML, Rodriguez ML, Eschenhagen T, and Hansen A
- Abstract
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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- 2019
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15. Low Resting Membrane Potential and Low Inward Rectifier Potassium Currents Are Not Inherent Features of hiPSC-Derived Cardiomyocytes.
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Horváth A, Lemoine MD, Löser A, Mannhardt I, Flenner F, Uzun AU, Neuber C, Breckwoldt K, Hansen A, Girdauskas E, Reichenspurner H, Willems S, Jost N, Wettwer E, Eschenhagen T, and Christ T
- Subjects
- Heart Atria metabolism, Heart Atria physiopathology, Heart Ventricles metabolism, Heart Ventricles physiopathology, Humans, Induced Pluripotent Stem Cells metabolism, Induced Pluripotent Stem Cells physiology, Membrane Potentials physiology, Myocytes, Cardiac metabolism, Myocytes, Cardiac physiology, Potassium metabolism
- Abstract
Human induced pluripotent stem cell (hiPSC) cardiomyocytes (CMs) show less negative resting membrane potential (RMP), which is attributed to small inward rectifier currents (I
K1 ). Here, IK1 was measured in hiPSC-CMs (proprietary and commercial cell line) cultured as monolayer (ML) or 3D engineered heart tissue (EHT) and, for direct comparison, in CMs from human right atrial (RA) and left ventricular (LV) tissue. RMP was measured in isolated cells and intact tissues. IK1 density in ML- and EHT-CMs from the proprietary line was similar to LV and RA, respectively. IK1 density in EHT-CMs from the commercial line was 2-fold smaller than in the proprietary line. RMP in EHT of both lines was similar to RA and LV. Repolarization fraction and IK,ACh response discriminated best between RA and LV and indicated predominantly ventricular phenotype in hiPSC-CMs/EHT. The data indicate that IK1 is not necessarily low in hiPSC-CMs, and technical issues may underlie low RMP in hiPSC-CMs., (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)- Published
- 2018
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16. Human iPSC-derived cardiomyocytes cultured in 3D engineered heart tissue show physiological upstroke velocity and sodium current density.
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Lemoine MD, Mannhardt I, Breckwoldt K, Prondzynski M, Flenner F, Ulmer B, Hirt MN, Neuber C, Horváth A, Kloth B, Reichenspurner H, Willems S, Hansen A, Eschenhagen T, and Christ T
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- Action Potentials drug effects, Biophysical Phenomena, Cells, Cultured, Humans, Induced Pluripotent Stem Cells drug effects, Induced Pluripotent Stem Cells metabolism, Ion Channel Gating drug effects, Myocytes, Cardiac drug effects, Myocytes, Cardiac physiology, Protein Isoforms metabolism, Tetrodotoxin pharmacology, Heart physiology, Induced Pluripotent Stem Cells cytology, Myocytes, Cardiac cytology, Sodium Channels metabolism, Tissue Engineering methods
- Abstract
Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) are a promising tool for drug testing and modelling genetic disorders. Abnormally low upstroke velocity is a current limitation. Here we investigated the use of 3D engineered heart tissue (EHT) as a culture method with greater resemblance to human heart tissue in comparison to standard technique of 2D monolayer (ML) format. I
Na was measured in ML or EHT using the standard patch-clamp technique. INa density was ~1.8 fold larger in EHT (-18.5 ± 1.9 pA/pF; n = 17) than in ML (-10.3 ± 1.2 pA/pF; n = 23; p < 0.001), approaching densities reported for human CM. Inactivation kinetics, voltage dependency of steady-state inactivation and activation of INa did not differ between EHT and ML and were similar to previously reported values for human CM. Action potential recordings with sharp microelectrodes showed similar upstroke velocities in EHT (219 ± 15 V/s, n = 13) and human left ventricle tissue (LV, 253 ± 7 V/s, n = 25). EHT showed a greater resemblance to LV in CM morphology and subcellular NaV 1.5 distribution. INa in hiPSC-CM showed similar biophysical properties as in human CM. The EHT format promotes INa density and action potential upstroke velocity of hiPSC-CM towards adult values, indicating its usefulness as a model for excitability of human cardiac tissue.- Published
- 2017
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17. Differentiation of cardiomyocytes and generation of human engineered heart tissue.
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Breckwoldt K, Letuffe-Brenière D, Mannhardt I, Schulze T, Ulmer B, Werner T, Benzin A, Klampe B, Reinsch MC, Laufer S, Shibamiya A, Prondzynski M, Mearini G, Schade D, Fuchs S, Neuber C, Krämer E, Saleem U, Schulze ML, Rodriguez ML, Eschenhagen T, and Hansen A
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- Humans, Cell Differentiation, Induced Pluripotent Stem Cells physiology, Myocytes, Cardiac physiology, Tissue Engineering methods
- Abstract
Since the advent of the generation of human induced pluripotent stem cells (hiPSCs), numerous protocols have been developed to differentiate hiPSCs into cardiomyocytes and then subsequently assess their ability to recapitulate the properties of adult human cardiomyocytes. However, hiPSC-derived cardiomyocytes (hiPSC-CMs) are often assessed in single-cell assays. A shortcoming of these assays is the limited ability to characterize the physiological parameters of cardiomyocytes, such as contractile force, due to random orientations. This protocol describes the differentiation of cardiomyocytes from hiPSCs, which occurs within 14 d. After casting, cardiomyocytes undergo 3D assembly. This produces fibrin-based engineered heart tissues (EHTs)-in a strip format-that generate force under auxotonic stretch conditions. 10-15 d after casting, the EHTs can be used for contractility measurements. This protocol describes parallel expansion of hiPSCs; standardized generation of defined embryoid bodies, growth factor and small-molecule-based cardiac differentiation; and standardized generation of EHTs. To carry out the protocol, experience in advanced cell culture techniques is required.
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- 2017
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18. Cardiac repair in guinea pigs with human engineered heart tissue from induced pluripotent stem cells.
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Weinberger F, Breckwoldt K, Pecha S, Kelly A, Geertz B, Starbatty J, Yorgan T, Cheng KH, Lessmann K, Stolen T, Scherrer-Crosbie M, Smith G, Reichenspurner H, Hansen A, and Eschenhagen T
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- Animals, Cell Differentiation, Cell Proliferation, Cicatrix, Echocardiography, Female, Guinea Pigs, Heart Ventricles, Humans, Lung metabolism, Myocardium pathology, Myocytes, Cardiac cytology, Myocytes, Cardiac transplantation, Regeneration, Spleen metabolism, Cardiac Surgical Procedures, Heart physiology, Induced Pluripotent Stem Cells cytology, Tissue Engineering methods
- Abstract
Myocardial injury results in a loss of contractile tissue mass that, in the absence of efficient regeneration, is essentially irreversible. Transplantation of human pluripotent stem cell-derived cardiomyocytes has beneficial but variable effects. We created human engineered heart tissue (hEHT) strips from human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes and hiPSC-derived endothelial cells. The hEHTs were transplanted onto large defects (22% of the left ventricular wall, 35% decline in left ventricular function) of guinea pig hearts 7 days after cryoinjury, and the results were compared with those obtained with human endothelial cell patches (hEETs) or cell-free patches. Twenty-eight days after transplantation, the hearts repaired with hEHT strips exhibited, within the scar, human heart muscle grafts, which had remuscularized 12% of the infarct area. These grafts showed cardiomyocyte proliferation, vascularization, and evidence for electrical coupling to the intact heart tissue in a subset of engrafted hearts. hEHT strips improved left ventricular function by 31% compared to that before implantation, whereas the hEET or cell-free patches had no effect. Together, our study demonstrates that three-dimensional human heart muscle constructs can repair the injured heart., (Copyright © 2016, American Association for the Advancement of Science.)
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- 2016
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19. Ca(2+)-Currents in Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes Effects of Two Different Culture Conditions.
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Uzun AU, Mannhardt I, Breckwoldt K, Horváth A, Johannsen SS, Hansen A, Eschenhagen T, and Christ T
- Abstract
Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) provide a unique opportunity to study human heart physiology and pharmacology and repair injured hearts. The suitability of hiPSC-CM critically depends on how closely they share physiological properties of human adult cardiomyocytes (CM). Here we investigated whether a 3D engineered heart tissue (EHT) culture format favors maturation and addressed the L-type Ca(2+)-current (ICa,L) as a readout. The results were compared with hiPSC-CM cultured in conventional monolayer (ML) and to our previous data from human adult atrial and ventricular CM obtained when identical patch-clamp protocols were used. HiPSC-CM were two- to three-fold smaller than adult CM, independently of culture format [capacitance ML 45 ± 1 pF (n = 289), EHT 45 ± 1 pF (n = 460), atrial CM 87 ± 3 pF (n = 196), ventricular CM 126 ± 8 pF (n = 50)]. Only 88% of ML cells showed ICa, but all EHT. Basal ICa density was 10 ± 1 pA/pF (n = 207) for ML and 12 ± 1 pA/pF (n = 361) for EHT and was larger than in adult CM [7 ± 1 pA/pF (p < 0.05, n = 196) for atrial CM and 6 ± 1 pA/pF (p < 0.05, n = 47) for ventricular CM]. However, ML and EHT showed robust T-type Ca(2+)-currents (ICa,T). While (-)-Bay K 8644, that activates ICa,L directly, increased ICa,Lto the same extent in ML and EHT, β1- and β2-adrenoceptor effects were marginal in ML, but of same size as (-)-Bay K 8644 in EHT. The opposite was true for serotonin receptors. Sensitivity to β1 and β2-adrenoceptor stimulation was the same in EHT as in adult CM (-logEC50: 5.9 and 6.1 for norepinephrine (NE) and epinephrine (Epi), respectively), but very low concentrations of Rp-8-Br-cAMPS were sufficient to suppress effects (-logEC50: 5.3 and 5.3 respectively for NE and Epi). Taken together, hiPSC-CM express ICa,L at the same density as human adult CM, but, in contrast, possess robust ICa,T. Increased effects of catecholamines in EHT suggest more efficient maturation.
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- 2016
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20. Human Engineered Heart Tissue: Analysis of Contractile Force.
- Author
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Mannhardt I, Breckwoldt K, Letuffe-Brenière D, Schaaf S, Schulz H, Neuber C, Benzin A, Werner T, Eder A, Schulze T, Klampe B, Christ T, Hirt MN, Huebner N, Moretti A, Eschenhagen T, and Hansen A
- Subjects
- Cell Differentiation genetics, Humans, Mitochondria metabolism, Myocardial Contraction genetics, Myocardium cytology, Myocardium metabolism, Sarcomeres metabolism, Heart growth & development, Induced Pluripotent Stem Cells cytology, Myocytes, Cardiac cytology, Tissue Engineering
- Abstract
Analyzing contractile force, the most important and best understood function of cardiomyocytes in vivo is not established in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM). This study describes the generation of 3D, strip-format, force-generating engineered heart tissues (EHT) from hiPSC-CM and their physiological and pharmacological properties. CM were differentiated from hiPSC by a growth factor-based three-stage protocol. EHTs were generated and analyzed histologically and functionally. HiPSC-CM in EHTs showed well-developed sarcomeric organization and alignment, and frequent mitochondria. Systematic contractility analysis (26 concentration-response curves) reveals that EHTs replicated canonical response to physiological and pharmacological regulators of inotropy, membrane- and calcium-clock mediators of pacemaking, modulators of ion-channel currents, and proarrhythmic compounds with unprecedented precision. The analysis demonstrates a high degree of similarity between hiPSC-CM in EHT format and native human heart tissue, indicating that human EHTs are useful for preclinical drug testing and disease modeling., (Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2016
- Full Text
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21. Heart regeneration.
- Author
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Breckwoldt K, Weinberger F, and Eschenhagen T
- Subjects
- Animals, Cell Differentiation, Cell Proliferation, Heart Diseases metabolism, Heart Diseases pathology, Heart Diseases physiopathology, Humans, Myocytes, Cardiac metabolism, Myocytes, Cardiac pathology, Phenotype, Recovery of Function, Heart Diseases surgery, Myocardium pathology, Myocytes, Cardiac transplantation, Regeneration, Regenerative Medicine methods, Stem Cell Transplantation adverse effects, Tissue Engineering methods
- Abstract
Regenerating an injured heart holds great promise for millions of patients suffering from heart diseases. Since the human heart has very limited regenerative capacity, this is a challenging task. Numerous strategies aiming to improve heart function have been developed. In this review we focus on approaches intending to replace damaged heart muscle by new cardiomyocytes. Different strategies for the production of cardiomyocytes from human embryonic stem cells or human induced pluripotent stem cells, by direct reprogramming and induction of cardiomyocyte proliferation are discussed regarding their therapeutic potential and respective advantages and disadvantages. Furthermore, different methods for the transplantation of pluripotent stem cell-derived cardiomyocytes are described and their clinical perspectives are discussed. This article is part of a Special Issue entitled: Cardiomyocyte Biology: Integration of Developmental and Environmental Cues in the Heart edited by Marcus Schaub and Hughes Abriel., (Copyright © 2015 Elsevier B.V. All rights reserved.)
- Published
- 2016
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22. Development of Long Noncoding RNA-Based Strategies to Modulate Tissue Vascularization.
- Author
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Fiedler J, Breckwoldt K, Remmele CW, Hartmann D, Dittrich M, Pfanne A, Just A, Xiao K, Kunz M, Müller T, Hansen A, Geffers R, Dandekar T, Eschenhagen T, and Thum T
- Subjects
- Cells, Cultured, Human Umbilical Vein Endothelial Cells pathology, Humans, Sequence Analysis, RNA, Signal Transduction, Tissue Engineering methods, Cell Hypoxia genetics, Hypoxia-Inducible Factor 1, alpha Subunit genetics, Neovascularization, Pathologic genetics, Neovascularization, Pathologic pathology, RNA Interference, RNA, Long Noncoding genetics
- Abstract
Background: Long noncoding ribonucleic acids (lncRNAs) are a subclass of regulatory noncoding ribonucleic acids for which expression and function in human endothelial cells and angiogenic processes is not well studied., Objectives: The authors discovered hypoxia-sensitive human lncRNAs via next-generation ribonucleic acid sequencing and microarray approaches. To address their functional importance in angiogenic processes, several endothelial lncRNAs were characterized for their angiogenic characteristics in vitro and ex vivo., Methods: Ribonucleic acid sequencing and microarray-derived data showed specific endothelial lncRNA expression changes after hypoxia. Validation experiments confirmed strong hypoxia-dependent activation of 2 intergenic lncRNAs: LINC00323 and MIR503HG., Results: Silencing of these lncRNA transcripts led to angiogenic defects, including repression of growth factor signaling and/or the key endothelial transcription factor GATA2. Endothelial loss of these hypoxia-driven lncRNAs impaired cell-cycle control and inhibited capillary formation. The potential clinical importance of these endothelial lncRNAs to vascular structural integrity was demonstrated in an ex vivo model of human induced pluripotent stem cell-based engineered heart tissue., Conclusions: The authors report an expression atlas of human hypoxia-sensitive lncRNAs and identified 2 lncRNAs with important functions to sustain endothelial cell biology. LncRNAs hold great promise to serve as important future therapeutic targets of cardiovascular disease., (Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)
- Published
- 2015
- Full Text
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