Molecular symphony Charting the transcriptional dynamics of human cardiac pacemaker cells

The human heart develops through tightly regulated molecular and cellular processes, ensuring the formation of specialized cardiomyocyte subtypes that govern contraction and electrical conduction. Disruptions in these processes contribute to congenital and acquired cardiac diseases. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) provide a unique platform to study cardiac development, function, and disease in vitro. However, key challenges remain in understanding the differentiation and specialization of distinct cardiomyocyte subtypes.
This thesis explores the mechanisms driving the differentiation of sinoatrial nodal (SANCMs) and atrioventricular canal cardiomyocytes (AVCMs) and their functional properties in engineered cardiac tissues. Single-cell RNA sequencing and trajectory inference reveal transcriptional regulators and signaling pathways guiding SANCM subtype specification, providing insights into pacemaker cell development. Three-dimensional cardiac models demonstrate that SANCMs functionally integrate into pacemaker-atrial interfaces, replicating physiological pacemaker activity. Additionally, the development of an in vitro model of the atrioventricular conduction system shows that AVCMs enable unidirectional conduction and recapitulate physiological AV delay.
By integrating developmental biology, stem cell differentiation, and tissue engineering, this work advances the understanding of cardiomyocyte subtype specification and function. The findings contribute to the development of physiologically relevant cardiac models for studying disease mechanisms and exploring new therapeutic strategies.