2024 Theses Doctoral

Engineering patient-specific iPSC-derived models for studying immune-cardiac interactions

Lock, Roberta Imogen

The immune system plays critical roles in the human heart in health, injury, and disease. Of the major immune cell types that reside in the cellular landscape of the myocardium, macrophages are particularly prevalent. Macrophages are responsible for a wide range of biological processes, including immunosurveillance, maintaining cardiomyocyte homeostasis, and regulating electrical conduction of cardiomyocytes. Within certain pathophysiological contexts such as Myocardial Infarction, they also facilitate the initiation and resolution of inflammation, and regulate cardiac repair and remodeling, significantly affecting injury trajectory and outcome.

In addition to these already intricate interactions, both the immune system and the cardiovascular system are known to display sex-specific disparities, particularly under pathophysiological conditions, which may have important ramifications for patient health. The complex interplay within the human cardiac immune system has become increasingly evident, and therefore, understanding the interactions along the immune-cardiac axis and how they may vary among patient populations is of great interest to the clinical and research communities. An opportunity to study these interactions is presented by leveraging recent advances in induced pluripotent stem cell technology to engineer iPSC-derived models, which enable patient-specific studies of immune-cardiac interactions in a highly controllable environment. In this dissertation, we engineer patient-specific iPSC-derived models for studying immune-cardiac interactions.

In Chapters 1 and 2, we introduce the importance of engineered models for studying the functions of the human heart, review the current state of the field, and identify key ways in which these models can be advanced. In Chapter 3, we create an iPSC-derived engineered cardiac tissue model with a resident macrophage population and investigate its impact on the function of the model under healthy conditions. In Chapter 4, we illustrate the capacity of iPSC-derived models to be patient-specific by showing how iPSC-derived macrophages demonstrate sex-specific dimorphism that emerges in response to an inflammatory stimulus. Finally, in Chapter 5, we present the optimization of an engineered model of myocardial ischemia reperfusion injury, which can be applied in future studies to study immune-cardiac interactions in the context of injury. Collectively, this dissertation provides a set of engineered tools that can be leveraged for improved understanding of the relationship between the heart and the immune system.