Dynamic loading of human engineered heart tissue enhances contractile function and drives a desmosome-linked disease phenotype
Science Translational Medicine, vol. 13
Abstract
The role that mechanical forces play in shaping the structure and function of the heart is critical to understanding heart formation and the etiology of disease but is challenging to study in patients. Engineered heart tissues (EHTs) incorporating human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes have the potential to provide insight into these adaptive and maladaptive changes. However, most EHT systems cannot model both preload (stretch during chamber filling) and afterload (pressure the heart must work against to eject blood). Here, we have developed a new dynamic EHT (dyn-EHT) model that enables us to tune preload and have unconstrained contractile shortening of >10%. To do this, three-dimensional (3D) EHTs were integrated with an elastic polydimethylsiloxane strip providing mechanical preload and afterload in addition to enabling contractile force measurements based on strip bending. Our results demonstrated that dynamic loading improves the function of wild-type EHTs on the basis of the magnitude of the applied force, leading to improved alignment, conduction velocity, and contractility. For disease modeling, we used hiPSC-derived cardiomyocytes from a patient with arrhythmogenic cardiomyopathy due to mutations in the desmoplakin gene. We demonstrated that manifestation of this desmosome-linked disease state required dyn-EHT conditioning and that it could not be induced using 2D or standard 3D EHT approaches. Thus, a dynamic loading strategy is necessary to provoke the disease phenotype of diastolic lengthening, reduction of desmosome counts, and reduced contractility, which are related to primary end points of clinical disease, such as chamber thinning and reduced cardiac output.
Authors 23
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Jacqueline M. Bliley corresponding
Affiliation as printed
Regenerative Biomaterials and Therapeutics Group, Department of Biomedical Engineering, Carnegie Mellon University, Pittsburgh, PA 15213, USA
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Mathilde C. S. C. Vermeer corresponding
University Medical Center Groningen · University of Groningen
Affiliation as printed
Department of Cardiology, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, Netherlands
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Affiliation as printed
Regenerative Biomaterials and Therapeutics Group, Department of Biomedical Engineering, Carnegie Mellon University, Pittsburgh, PA 15213, USA
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Affiliation as printed
Regenerative Biomaterials and Therapeutics Group, Department of Biomedical Engineering, Carnegie Mellon University, Pittsburgh, PA 15213, USA
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University Medical Center Groningen · University of Groningen
Affiliation as printed
Department of Dermatology, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, Netherlands
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Affiliation as printed
Regenerative Biomaterials and Therapeutics Group, Department of Biomedical Engineering, Carnegie Mellon University, Pittsburgh, PA 15213, USA
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Affiliation as printed
Regenerative Biomaterials and Therapeutics Group, Department of Biomedical Engineering, Carnegie Mellon University, Pittsburgh, PA 15213, USA
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Affiliation as printed
Regenerative Biomaterials and Therapeutics Group, Department of Biomedical Engineering, Carnegie Mellon University, Pittsburgh, PA 15213, USA
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Leiden University Medical Center
Affiliation as printed
Department of Cardiology, Heart Lung Center Leiden, Leiden University Medical Center, 2333 ZA Leiden, Netherlands
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Leiden University Medical Center
Affiliation as printed
Department of Cardiology, Heart Lung Center Leiden, Leiden University Medical Center, 2333 ZA Leiden, Netherlands
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Affiliation as printed
Department of Materials Science and Engineering, Carnegie Mellon University, Pittsburgh, PA 15213, USA
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University Medical Center Groningen · University of Groningen
Affiliation as printed
Department of Cardiology, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, Netherlands
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Affiliation as printed
Regenerative Biomaterials and Therapeutics Group, Department of Biomedical Engineering, Carnegie Mellon University, Pittsburgh, PA 15213, USA
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Affiliation as printed
Regenerative Biomaterials and Therapeutics Group, Department of Biomedical Engineering, Carnegie Mellon University, Pittsburgh, PA 15213, USA
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Affiliation as printed
Regenerative Biomaterials and Therapeutics Group, Department of Biomedical Engineering, Carnegie Mellon University, Pittsburgh, PA 15213, USA
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University Medical Center Groningen · University of Groningen
Affiliation as printed
Department of Genetics, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, Netherlands
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University Medical Center Groningen · University of Groningen
Affiliation as printed
Department of Cardiology, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, Netherlands
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University Medical Center Groningen · University of Groningen
Affiliation as printed
Department of Cardiology, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, Netherlands
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University Medical Center Groningen · University of Groningen
Affiliation as printed
Department of Pathology, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, Netherlands
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Leiden University Medical Center
Affiliation as printed
Department of Cardiology, Heart Lung Center Leiden, Leiden University Medical Center, 2333 ZA Leiden, Netherlands
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University Medical Center Groningen · University of Groningen
Affiliation as printed
Department of Dermatology, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, Netherlands
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Peter van der Meer corresponding
University Medical Center Groningen · University of Groningen
Affiliation as printed
Department of Cardiology, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, Netherlands
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Adam W. Feinberg corresponding
Affiliation as printed
Department of Materials Science and Engineering, Carnegie Mellon University, Pittsburgh, PA 15213, USA
Regenerative Biomaterials and Therapeutics Group, Department of Biomedical Engineering, Carnegie Mellon University, Pittsburgh, PA 15213, USA
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