The human heart and the great vessels comprise various cell types that collectively support the heart’s homeostasis. Single-cell genomics has expanded our knowledge of the heart’s cellular heterogeneity. By gaining a deeper understanding of its cellular makeup, we can uncover how these cells converge to define cardiac identity and function and how perturbation to cellular identities can lead to diseases.

This dissertation focuses on generating a high-resolution atlas of the first and second-trimester human heart and great vessels using single-cell genomics. The atlas contains 63 cell types with distinct identity, function, or location-specific signatures, such as the cardiomyocytes of different chambers and the vessel components specific to coronary or great vessels. Alongside molecular profiling, cellular communication mechanisms and gene regulatory networks are investigated, collectively aiming to advance in vitro models of cardiac cells.

Chapter 1 introduces the topics covered throughout the thesis. After describing the materials and methods utilised in Chapter 2, an overview of the atlas is provided in Chapter 3. This is followed by a description of the individual cell types in subsequent chapters based on the macro anatomical structures they are associated with. Chapter 4 focuses on cardiomyocytes, which constitute the majority of the myocardium. In Chapter 5, the focus shifts to the vessels, encompassing the coronary and the great vessels. Chapter 6 explores the pericardium and endocardium as the two layers enveloping the myocardium. Ultimately, through the profiling obtained from the atlas, Chapter 7 proposes a framework to generate enhanced stem cell models to mimic the corresponding cells in vivo.