Cells in concert Engineering the cardiac pacemaker and conduction system using hiPSCs

Cardiovascular disease remains the leading cause of death worldwide, claiming an estimated 18 million lives annually. At the heart of proper cardiac function lies the cardiac conduction system (CCS), a specialized network of cells responsible for generating and propagating electrical impulses. Dysfunction in the CCS has profound short- and long-term consequences for cardiac homeostasis. Advancing our understanding of the mechanisms governing this system is crucial for developing innovative treatments to improve patient outcomes. While animal models have provided significant insights into CCS physiology, species-specific differences—such as variations in heart rate and ion channel composition—limit their translatability to human systems. Recently, human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have emerged as a powerful platform for studying the CCS. These cells replicate key features of native human cardiomyocytes, making them invaluable for in vitro investigations of cardiac development and disease. This dissertation explores the use of hiPSC-CMs to model the cardiac conduction system in vitro, assess pharmacological interventions, and establish the foundations for biological pacemaking. Leveraging these cells alongside cutting-edge tissue engineering and single-cell analysis techniques offers immense potential to uncover the processes underlying early CCS development, elucidate the mechanisms of cardiac conduction, and inform novel therapeutic strategies for CCS-related diseases.