Tuesday, April 1, 2025
4/1/2025
Regulation of cardiac pacemaker cell cytoarchitecture - ABSTRACT: Cardiac pacemaker cells (CPCs) rhythmically initiate the electrical impulses that stimulate heart contraction. CPC dysfunction co-segregates with a broad variety of both cardiac and non-cardiac disease conditions and represents the leading cause for the surgical implantation of artificial pacemakers. Moreover, CPC dysfunction is a leading cause of sudden death among heart failure patients. Despite clinical burden of CPC dysfunction, very little is currently known regarding the cellular pathologies that disrupt normal pacemaking. Indeed, we lack even a basic understanding of the cellular and environmental conditions required for CPC homeostasis. Over the previous funding period, work conducted within this R01 has uncovered a novel paradigm demonstrating that CPCs require low cellular strain to maintain the cytoarchitectural features necessary for their function. Thus, the focus of this renewal application is to define the molecular pathways that produce a microenvironmental niche around CPCs that functionally minimizes cellular strain. Importantly, our preliminary data now demonstrate that CPCs express unique classes of paracrine factors which specifically activate their local interstitial support cells. This activation drives the formation of a biomechanically compliant extracellular matrix that surrounds and encapsulates CPCs (protecting them from contractile and hemodynamic forces present throughout the rest of the heart). We have also identified that ectopically increasing cellular strain results in breakdown of CPC activity and the loss of paracrine activation of their local interstitial cells. Collectively, these data have led to the hypothesis that a mechano-paracrine positive feedback loop co-regulates the behavior of CPCs and their support cells patterning the local tissue mechanics required for CPC activity. We will test this by defining the specific molecular pathways that integrate mechanical feedback within CPC (Aim1), identifying the paracrine factors that maintain CPC-interstitial cell crosstalk (Aim2), and determining how CPC-interstitial interactions changes under conditions of aging or pathological cardiac remodeling (Aim3). Thus, successful execution of this proposal will create a novel and holistic model of CPC homeostasis that accounts for the cooperative activity of multiple cell types within the sinoatrial node. We project these studies will establish fundamental principles that define CPC developmental optimization, inform our overall understanding of CPC- related disease progression, and instruct tissue engineering approaches designed to generate biological pacing systems for therapeutic purposes.
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