Dynamic Loading of Human Engineered Heart Tissue Enhances Contractile Function and Drives Desmosome-linked Disease Phenotype

bioRxiv (Cold Spring Harbor Laboratory)

Abstract

ABSTRACT The role 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 in the heart. However, most EHT systems are unable to 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 fractional shortening of >10%. To do this, 3D EHTs are integrated with an elastic polydimethylsiloxane (PDMS) strip that provides mechanical pre- and afterload to the tissue in addition to enabling contractile force measurements based on strip bending. Our results demonstrate in wild-type EHTs that dynamic loading is beneficial based on the magnitude of the forces, leading to improved alignment, conduction velocity, and contractility. For disease modeling, we use hiPSC–derived cardiomyocytes from a patient with arrhythmogenic cardiomyopathy (ACM) due to mutations in desmoplakin. We demonstrate that manifestation of this desmosome-linked disease state requires the dyn-EHT conditioning and that it cannot be induced using 2D or standard 3D EHT approaches. Thus, dynamic loading strategy is necessary to provoke a disease phenotype (diastolic lengthening, reduction of desmosome counts, and reduced contractility), which are akin to primary endpoints of clinical disease, such as chamber thinning and reduced cardiac output. Single Sentence Summary Development of a dynamic mechanical loading platform to improve contractile function of engineered heart tissues and study cardiac disease progression.

Authors 23

1. Jacqueline M. Bliley

   Carnegie Mellon University

   Affiliation as printed

   Regenerative Biomaterials and Therapeutics Group, Department of Biomedical Engineering, Carnegie Mellon University

   Regenerative Biomaterials and Therapeutics Group, Department of Biomedical Engineering, Carnegie Mellon University, Pittsburgh, PA

2. Mathilde C. S. C. Vermeer

   University Medical Center Groningen · University of Groningen

   Affiliation as printed

   Department of Cardiology, University of Groningen, University Medical Center Groningen

   Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands

3. Rebecca M. Duffy

   Carnegie Mellon University

   Affiliation as printed

   Regenerative Biomaterials and Therapeutics Group, Department of Biomedical Engineering, Carnegie Mellon University

   Regenerative Biomaterials and Therapeutics Group, Department of Biomedical Engineering, Carnegie Mellon University, Pittsburgh, PA

4. Ivan Batalov

   Carnegie Mellon University

   Affiliation as printed

   Regenerative Biomaterials and Therapeutics Group, Department of Biomedical Engineering, Carnegie Mellon University

   Regenerative Biomaterials and Therapeutics Group, Department of Biomedical Engineering, Carnegie Mellon University, Pittsburgh, PA

5. Duco Kramer

   University Medical Center Groningen · University of Groningen

   Affiliation as printed

   Department of Dermatology, University of Groningen, University Medical Center Groningen

   Department of Dermatology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands

6. Joshua W. Tashman

   Carnegie Mellon University

   Affiliation as printed

   Regenerative Biomaterials and Therapeutics Group, Department of Biomedical Engineering, Carnegie Mellon University

   Regenerative Biomaterials and Therapeutics Group, Department of Biomedical Engineering, Carnegie Mellon University, Pittsburgh, PA

7. Daniel John Shiwarski

   Carnegie Mellon University

   Affiliation as printed

   Regenerative Biomaterials and Therapeutics Group, Department of Biomedical Engineering, Carnegie Mellon University

   Regenerative Biomaterials and Therapeutics Group, Department of Biomedical Engineering, Carnegie Mellon University, Pittsburgh, PA

8. Andrew R. Lee

   Carnegie Mellon University

   Affiliation as printed

   Regenerative Biomaterials and Therapeutics Group, Department of Biomedical Engineering, Carnegie Mellon University

   Regenerative Biomaterials and Therapeutics Group, Department of Biomedical Engineering, Carnegie Mellon University, Pittsburgh, PA

9. Alexander S Teplenin Aachen Department of Cardiology, Heart Lung Center Leiden

   Leiden University Medical Center

   Affiliation as printed

   Department of Cardiology, Heart Lung Center Leiden, Leiden University Medical Center

   Department of Cardiology, Heart Lung Center Leiden, Leiden University Medical Center, Leiden, The Netherlands

10. Linda Volkers Aachen Department of Cardiology, Heart Lung Center Leiden

    Leiden University Medical Center

    Affiliation as printed

    Department of Cardiology, Heart Lung Center Leiden, Leiden University Medical Center

    Department of Cardiology, Heart Lung Center Leiden, Leiden University Medical Center, Leiden, The Netherlands

11. Brian D. Coffin

    Carnegie Mellon University

    Affiliation as printed

    Regenerative Biomaterials and Therapeutics Group, Department of Biomedical Engineering, Carnegie Mellon University

    Regenerative Biomaterials and Therapeutics Group, Department of Biomedical Engineering, Carnegie Mellon University, Pittsburgh, PA

12. Martijn F. Hoes

    University Medical Center Groningen · University of Groningen

    Affiliation as printed

    Department of Cardiology, University of Groningen, University Medical Center Groningen

    Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands

13. Anna Kalmykov

    Carnegie Mellon University

    Affiliation as printed

    Regenerative Biomaterials and Therapeutics Group, Department of Biomedical Engineering, Carnegie Mellon University

    Regenerative Biomaterials and Therapeutics Group, Department of Biomedical Engineering, Carnegie Mellon University, Pittsburgh, PA

14. Rachelle N. Palchesko

    Carnegie Mellon University

    Affiliation as printed

    Regenerative Biomaterials and Therapeutics Group, Department of Biomedical Engineering, Carnegie Mellon University

    Regenerative Biomaterials and Therapeutics Group, Department of Biomedical Engineering, Carnegie Mellon University, Pittsburgh, PA

15. Yan Sun

    Carnegie Mellon University

    Affiliation as printed

    Regenerative Biomaterials and Therapeutics Group, Department of Biomedical Engineering, Carnegie Mellon University

    Regenerative Biomaterials and Therapeutics Group, Department of Biomedical Engineering, Carnegie Mellon University, Pittsburgh, PA

16. Jan D.H. Jongbloed

    University Medical Center Groningen · University of Groningen

    Affiliation as printed

    Department of Genetics, University of Groningen, University Medical Center Groningen

    Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands

17. Nils Bömer

    University Medical Center Groningen · University of Groningen

    Affiliation as printed

    Department of Cardiology, University of Groningen, University Medical Center Groningen

    Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands

18. Rudolf A. de Boer

    University Medical Center Groningen · University of Groningen

    Affiliation as printed

    Department of Cardiology, University of Groningen, University Medical Center Groningen

    Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands

19. Albert J.H. Suurmeijer

    University Medical Center Groningen · University of Groningen

    Affiliation as printed

    Department of Pathology, University of Groningen, University Medical Center Groningen

    Department of Pathology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands

20. Daniël A. Pijnappels Aachen Department of Cardiology, Heart Lung Center Leiden

    Leiden University Medical Center

    Affiliation as printed

    Department of Cardiology, Heart Lung Center Leiden, Leiden University Medical Center

    Department of Cardiology, Heart Lung Center Leiden, Leiden University Medical Center, Leiden, The Netherlands

21. Maria C. Bolling

    University Medical Center Groningen · University of Groningen

    Affiliation as printed

    Department of Dermatology, University of Groningen, University Medical Center Groningen

    Department of Dermatology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands

22. 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

    Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands

23. Adam W. Feinberg corresponding

    Carnegie Mellon University

    Affiliation as printed

    Department of Materials Science and Engineering, Carnegie Mellon University

    Regenerative Biomaterials and Therapeutics Group, Department of Biomedical Engineering, Carnegie Mellon University

    Department of Materials Science and Engineering, Carnegie Mellon University, Pittsburgh, PA

    Regenerative Biomaterials and Therapeutics Group, Department of Biomedical Engineering, Carnegie Mellon University, Pittsburgh, PA