Methodology for culturing organotypic cardiac slices from atria and ventricles from explanted human donor hearts rejected from transplantation
Mentor: Stacey Rentschler, M.D., Ph.D., Associate Professor, Department of Medicine, Cardiovascular Division
Research in the Rentschler lab is centered around three broad themes: defining the developmental and molecular mechanisms underlying congenital and acquired arrhythmias, defining the transcriptional and epigenetic mechanisms that regulate the programming and reprogramming of cellular electrophysiological phenotypes, and harnessing the power of developmental signaling cascades to treat conduction disorders. Specifically, we focus on the transcriptional and epigenetic pathways activated in response to Notch and Wnt signaling during development and in response to cardiac injury, which mediate changes in ion channel gene expression and cellular electrophysiology. Our group previously demonstrated that reactivation of developmental signaling pathways including Notch and Wnt could electrically remodel cardiomyocytes or “reprogram” them to adopt a new electrical phenotype in animal models. In heart failure, reactivation of the Notch signaling pathway may contribute to transcriptional changes influencing ion channel gene expression that may predispose to the development of lethal arrhythmias. In contrast, reactivation of distinct signaling networks within the adult myocardium may provide new avenues for regenerative medicine approaches for the treatment of arrhythmias, such as in the development of a biological pacemaker.
Projects: Current projects in the Rentschler lab include the development of a methodology for culturing organotypic cardiac slices from atria and ventricles from explanted human donor hearts rejected from transplantation. Functional readouts include optical mapping with voltage-sensitive dyes to visualize and quantify electrophysiological properties, as well as microelectrode recordings to assess changes in cellular physiology. In addition, we are performing genome-wide gene expression and epigenetic studies on mouse and human cardiac tissue to decipher the complex regulatory mechanisms that govern the expression of important regulators of electrophysiology within regions of the heart in both health and disease states. This methodology will allow us to test the response of human cardiac tissue to selected therapeutics, with the goal of expediting the prolonged process involved in getting new therapeutics validated for use in humans. More recently, Dr. Rentschler has built a team-science approach and led a multidisciplinary group of pathologists, cancer biologists, radiation oncologists, and cardiac electrophysiologists at Washington University to understanding mechanisms of cardiac irradiation to treat ventricular tachycardia first observed in the ENCORE-VT clinical trial.