Substrate mechanics unveil early structural and functional pathology in iPSC micro-tissue models of hypertrophic cardiomyopathy
Jingxuan Guo,
Huanzhu Jiang,
David Schuftan,
Jonathan D. Moreno,
Ghiska Ramahdita,
Lavanya Aryan,
Druv Bhagavan,
Jonathan Silva,
Nathaniel Huebsch
Affiliations
Jingxuan Guo
Department of Mechanical Engineering and Material Science, Washington University in Saint Louis, Saint Louis, MO 63130, USA
Huanzhu Jiang
Department of Biomedical Engineering, Washington University in Saint Louis, Saint Louis, MO 63130, USA
David Schuftan
Department of Biomedical Engineering, Washington University in Saint Louis, Saint Louis, MO 63130, USA
Jonathan D. Moreno
Division of Cardiology, Department of Medicine, Washington University in Saint Louis, Saint Louis, MO 63130, USA
Ghiska Ramahdita
Department of Mechanical Engineering and Material Science, Washington University in Saint Louis, Saint Louis, MO 63130, USA; NSF Science and Technology Center for Engineering Mechanobiology, Washington University in Saint Louis, Saint Louis, MO 63130, USA
Lavanya Aryan
Department of Biomedical Engineering, Washington University in Saint Louis, Saint Louis, MO 63130, USA
Druv Bhagavan
Department of Biomedical Engineering, Washington University in Saint Louis, Saint Louis, MO 63130, USA
Jonathan Silva
Department of Biomedical Engineering, Washington University in Saint Louis, Saint Louis, MO 63130, USA
Nathaniel Huebsch
Department of Biomedical Engineering, Washington University in Saint Louis, Saint Louis, MO 63130, USA; NSF Science and Technology Center for Engineering Mechanobiology, Washington University in Saint Louis, Saint Louis, MO 63130, USA; Center for Cardiovascular Research, Center for Regenerative Medicine, Center for Investigation of Membrane Excitability Diseases, Washington University in Saint Louis, Saint Louis, MO 63130, USA; Corresponding author
Summary: Hypertension is a major cause of morbidity and mortality in patients with hypertrophic cardiomyopathy (HCM), suggesting a potential role for mechanics in HCM pathogenesis. Here, we developed an in vitro physiological model to investigate how mechanics acts together with HCM-linked myosin binding protein C (MYBPC3) mutations to trigger disease. Micro-heart muscles (μHM) were engineered from induced pluripotent stem cell (iPSC)-derived cardiomyocytes bearing MYBPC3+/− mutations and challenged to contract against substrates of different elasticity. μHMs that worked against substrates with stiffness at or exceeding the stiffness of healthy adult heart muscle exhibited several hallmarks of HCM, including cellular hypertrophy, impaired contractile energetics, and maladaptive calcium handling. Remarkably, we discovered changes in troponin C and T localization in MYBPC3+/− μHM that were entirely absent in 2D culture. Pharmacologic studies suggested that excessive Ca2+ intake through membrane-embedded channels underlie the observed electrophysiological abnormalities. These results illustrate the power of physiologically relevant engineered tissue models to study inherited disease with iPSC technology.
