Title: Tissues with Issues: Mechanistic Insights from Engineered Heart Tissues Models of HCM
Abstract: Three-dimensional engineered heart tissues (EHTs) derived from iPSCs are better aligned, more mature, and respond better to physiological stimuli than monolayer iPSC-derived cardiomyocytes. Moreover, the three-dimensional nature of EHTs enables direct measurement of force production. Over the last three decades, EHTs have taken on many shapes and sizes and have been made using chicken, rat, mouse, human ES and human iPSC cardiomyocytes. During this time the Ralphe Lab contributed to the development and optimization of rat, mouse and human iPSC EHTs and has used these EHT cultures to study hypertrophic cardiomyopathy (HCM).
HCM is an inherited cardiac disease, caused primarily by mutations in sarcomeric protein encoding genes. Clinically, HCM is characterized by left ventricular hypertrophy that may cause outflow tract obstruction, sudden cardiac arrest and diastolic, and in some cases systolic, heart failure. The Ralphe Lab has used a variety of mouse and isogenic gene edited human iPSC-derived EHT models to gain mechanistic insights into how sarcomeric mutations cause HCM.
Our data show that EHT carrying HCM mutations can cause diverse contractile phenotypes at an early stage, ranging from hypercontractile with fast relaxation to hypocontractile. Over time-in-culture, however, the phenotypic presentation converges and by 6 weeks all genotypes studied present with impaired relaxation and a tendency towards hypocontractility. These data suggest that the contractile defect caused by the mutation likely triggers convergent downstream pathways that lead to the HCM phenotype. Additionally, we are using our human iPSC-derived EHT models to test whether cardiac myosin inhibitor (CMI) treatment, approved for treating obstructive HCM, can be used to arrest or prevent contractile dysfunction in EHTs. Our data show that while CMI treatment ameliorated the contractile dysfunction in EHTs carrying some mutations, it failed to do so in others.
Together these data demonstrate how human iPSC EHTs can be used as models to study cardiac pathology, and that iPSC EHTs can be used as platforms to study the effects of pharmacologic agents and small molecules on contractility.
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