From Fibrocyte Migration To Resident Cardiac Macrophage Phenotypes: The Evolution In Understanding of Macrophages In Non-Ischemic Myocardial Injury and Fibrosis

Abstract

Heart failure is a growing societal and healthcare issue for which the only long-term therapy is transplantation. Heart failure therapies have been limited by our understanding of a key process involved in healing termed myocardial fibrosis. Myocardial fibrosis is a primarily a reparative response for replacing and reinforcing injured/stressed tissue with extracellular matrix (ECM) proteins. Unfortunately, the ECM proteins which comprise fibrosis are non-contractile. In turn, as fibrosis accumulates, the heart loses its normal contraction and heart failure can ensue.

This thesis focuses on characterizing the evolution of thought on an ambiguous, elusive cell type in myocardial fibrosis. Work in the AngII model of myocardial fibrosis initially suggested a process driven by a single cell type, termed fibrocyte, that accumulates in the heart prior to the deposition of ECM proteins. Fibrocytes express hematopoietic and mesenchymal markers – a unique, hybrid phenotype that suggested they may be a novel source of ECM-producing fibroblasts. As such, my initial aim was to characterize fibrocyte migration to the heart in order to identify therapeutic opportunities to reduce myocardial fibrosis. As contrary evidence accumulated, my aim shifted toward targeting a more “monocyte-like” fibrocyte in circulation with cytotoxic liposomes. Through happenstance, I arrived at the realization that fibrocytes were likely a blip on an infinite scale of macrophage (MΦ) phenotypes. The focus of this thesis shifted once again: I was characterizing MΦ phenotypes in early AngII-mediated myocardial injury. Finally, as a culmination of misdirections and realizations, I found myself characterizing a truly novel cell type: cardiac resident MΦ (rCMΦ).

Specifically, the work I present in this thesis demonstrates that fibrocytes do not behave/migrate like progenitor cells. Rather, using the AngII model in tandem with chemokine receptor antagonists, receptor knockouts, and cytotoxic liposomes, I provide evidence that fibrocytes are more like an atypical monocyte/MΦ. Lastly, my work in CX3CR1-/- and CCR2-/- supported growing evidence for the importance of “anti-inflammatory” rCMΦ phenotypes in myocardial injury. Together, this body of work has helped erode the fibrocyte misdirection and drawn attention to the importance of circulation-derived and rCMΦ in non-ischemic myocardial injury, such as that which occurs in the AngII model.