PhD Dissertation Defense: Danielle Klinger

Title: Non-Destructive Contractility Measurements on Developing Cardioids

Abstract: The force generated by the heart depends in part on how much the cardiac muscle is stretched, and diseases that disrupt this mechanical function, are a major cause of heart failure. Cardioids are 3D engineered heart tissues, derived from human stem cells, that beat spontaneously and reproduce features of the developing heart, making them promising models for studying disease and testing drugs. However, measuring their mechanical function without disrupting the tissue remains challenging. In this work, I developed a non-destructive compression assay to measure contractile force and passive stiffness in intact cardioids. First, I applied it to track individual cardioids throughout maturation and showed that they become smaller, generate more force, and perform more mechanical work with each beat as they mature, similar to the developing human heart. Second, I demonstrated that cardioids exhibit a Frank-Starling response, the increase in contractile force with stretch, that helps the heart adapt to changing demands, and that this response strengthened with maturation. Third, I showed that the cardiac myosin inhibitor mavacamten suppresses this response in a dose-dependent manner. Finally, I applied the assay to a patient-derived model of restrictive cardiomyopathy and found greater contractile force and sensitivity to stretch compared with genetically corrected controls. Together, this work establishes a method for repeatedly measuring the mechanical function of intact human cardiac organoids, enabling studies of cardiac development, drug responses, and disease.

Please contact Anouk Priebe-Garcia for the Zoom link.