Abstract 207: In Vitro Modeling of Variable Heart Diseases Due to Lamin A/C Mutation via Patient induced Pluripotent Stem Cell Derived Cardiomyocytes

Abstract

According to numerous fundamental studies, a mutated Lamin A/C gene ( LMNA ) can cause dilated cardiomyopathy, arrhythmia, and heart failure, yet the practical diagnosis and treatment for them is scarce. The LMNA encodes Lamin A/C proteins that make mesh like nuclear lamina under the nuclear envelope, and they interact to impact the nuclear shape, stability, protein transduction, and DNA replication. Although, almost all nucleated cells in the human body have Lamin A/C in the nuclear lamina, we study patients who have LMNA mutation with the main pathologies in the heart. Therefore, our goal is to understand the mechanisms of how an LMNA mutation can cause exclusively heart diseases. We hypothesize that an in vitro model using induced Pluripotent Stem Cell (iPSC)-derived cardiomyocytes can differentiate between a population of patients whose major phenotype presentation is heart disease due to an LMNA mutation from the control population in structural and functional mechanisms. We have used in vitro tissue engineering techniques to interrogate the iPSC-derived cardiomyocytes tissue structures and function. PATIENT’s and CONTROL’s skin fibroblasts were reprogrammed to iPSCs and differentiated to cardiomyocytes. The PATIENT and CONTROL iPSC-derived cardiomyocytes were immunostained, imaged and quantified. Moreover, for the functional assay, iPSC- derived cardiomyocytes were evaluated by the “Heart-on-a-Chip” device based on the muscular thin film technology. The dynamics of the PATIENTs and CONTROLs tissue constructs were recorded and analyzed for frequency and stress as a function of time. Our results demonstrate that it is possible to construct an iPSC-derived cardiomyocyte in vitro model that differentiates between our CONTROL and PATIENT population and shows significant differences between iPSC-derived cardiomyocytes of PATIENTs and CONTROLs in frequency and active stress. By further investigating the structural and functional differences between PATIENTs and CONTROLs iPSC-derived cardiomyocytes, we can find the downstream mechanisms of LMNA mutation consequences in heart and find the proper treatments through drug screening and the other techniques by monitoring the function and structure of the iPSC-derived cardiomyocytes.