Author + information
- Received December 6, 2018
- Revision received March 11, 2019
- Accepted March 13, 2019
- Published online August 26, 2019.
- Lorenzo R. Sewanan, MSa,∗,
- Jonas Schwan, PhDa,∗,
- Jonathan Kluger, BSEa,
- Jinkyu Park, PhDb,e,
- Daniel L. Jacoby, MDb,
- Yibing Qyang, PhDb,c,d,e and
- Stuart G. Campbell, PhDa,f,∗ ()
- aDepartment of Biomedical Engineering, Yale University, New Haven, Connecticut
- bYale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut
- cYale Stem Cell Center, Yale University, New Haven, Connecticut
- dDepartment of Pathology, Yale University, New Haven, Connecticut
- eVascular Biology and Therapeutics Program, Yale School of Medicine, New Haven, Connecticut
- fDepartment of Cellular and Molecular Physiology, Yale School of Medicine, New Haven, Connecticut
- ↵∗Address for correspondence:
Dr. Stuart G. Campbell, Department of Biomedical Engineering, Yale University, 55 Prospect Street, MEC 211, New Haven, Connecticut 06511.
• The goal of this study was to examine the effects of diseased extracellular matrix on the behavior of healthy heart cells.
• Myocardium was harvested from a genetically engineered miniature pig carrying the hypertrophic cardiomyopathy mutation MYH7 R403Q and from a wild-type littermate.
• Engineered heart tissues were created by seeding healthy human induced pluripotent stem cell–derived cardiomyocytes onto thin strips of decellularized porcine myocardium.
• Engineered heart tissues made from the extracellular matrix of hypertrophic cardiomyopathy hearts exhibit increased stiffness, impaired relaxation, and increased force development.
• This suggests that diseased extracellular matrix can provoke abnormal contractile behavior in otherwise healthy cardiomyocytes.
Hypertrophic cardiomyopathy (HCM) is often caused by single sarcomeric gene mutations that affect muscle contraction. Pharmacological correction of mutation effects prevents but does not reverse disease in mouse models. Suspecting that diseased extracellular matrix is to blame, we obtained myocardium from a miniature swine model of HCM, decellularized thin slices of the tissue, and re-seeded them with healthy human induced pluripotent stem cell–derived cardiomyocytes. Compared with cardiomyocytes grown on healthy extracellular matrix, those grown on the diseased matrix exhibited prolonged contractions and poor relaxation. This outcome suggests that extracellular matrix abnormalities must be addressed in therapies targeting established HCM.
- diastolic dysfunction
- engineered heart tissue
- hypertrophic cardiomyopathy
- iPSC-derived cardiomyocyte
- MYH7 mutation
↵∗ Mr. Sewanan and Dr. Schwan contributed equally to this work and are joint first authors.
This research was supported by National Institutes of Health grants R01 HL136590 (to Dr. Campbell) and R01 HL131940 (to Dr. Qyang), DOD 11959515 (to Dr. Qyang), an American Heart Association Predoctoral Fellowship (to Dr. Schwan), and a P.D. Soros Fellowship for New Americans (to Mr. Sewanan). Mr. Sewanan was also supported by a National Institutes of Health/National Institute of General Medical Sciences Medical Scientist Training Program Grant (T32GM007205). Drs. Schwan and Campbell have equity ownership in Propria LLC, which has licensed technology used in the research reported in this publication. This arrangement has been reviewed and approved by the Yale University Conflict of Interest Office. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
All authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: Basic to Translational Science author instructions page.
- Received December 6, 2018.
- Revision received March 11, 2019.
- Accepted March 13, 2019.
- 2019 The Authors