Date of Award
8-1-2024
Degree Name
Doctor of Philosophy (PhD)
Degree Type
Dissertation
Abstract
Myocardial infarction (MI) occurs following cessation of blood flow to an area of the heart and leads to ischemia, cardiomyocyte death, and inflammation. Chronically, MI initiates a compensatory process referred to as left ventricular remodeling, which is characterized by cardiomyocyte hypertrophy, fibrosis, and a decline in heart function. Left ventricular remodeling is central to the pathogenesis of heart failure. During myocardial infarction, Ly6chigh CCR2+ monocytes enter the heart and differentiate into a variety of macrophage populations including inflammatory CCR2+ macrophages. Resident cardiac macrophages are also present within the heart at homeostasis. Previous research from several groups has shown that once monocytes enter the heart during myocardial infarction, they differentiate into various subpopulations of macrophages with unique morphologies, tissue distributions, and unknown functions. Furthermore, the identity of macrophages present within the heart at the time of myocardial infarction has profound effects on the severity of cardiac remodeling. This indicates that manipulation of macrophage populations provides a therapeutic potential for myocardial infarction. However, the mechanisms and dynamics of monocyte differentiation into various macrophage subpopulations within this context are unknown. Hypoxia, or low oxygen conditions, is an important variable in the pathology of myocardial infarction because there is a loss of blood perfusion. This work hypothesized that hypoxia sensing in macrophages regulates monocyte and macrophage differentiation following reperfused myocardial infarction. This was investigated through (1) assessing the effects of hypoxia sensing in monocytes and macrophages on left ventricular remodeling and macrophage specification during myocardial infarction (2) characterizing a monocyte-derived macrophage subpopulation that is overrepresented when macrophage hypoxia sensing is disrupted and (3) fate tracing of monocyte derived macrophages during the progression of myocardial infarction in the context of hypoxia sensing. In this thesis, I show that deletion of Hif1α, a transcriptional regulator of the cell’s response to hypoxia, in resident cardiac macrophages leads to aberrant left ventricular remodeling after myocardial infarction. Furthermore, Hif1α deletion in resident cardiac macrophages caused an overrepresentation of a macrophage subpopulation characterized by Arg1 expression (Arg1+ macrophages) after myocardial infarction. I further characterized Arg1+ macrophages and found that they display an inflammatory gene signature, are monocyte derived, are specified prior to extravasation into the heart, and represent an intermediate of monocyte to macrophage differentiation in the context of ischemic heart injury. Next, lineage tracing of Arg1+ macrophages during ischemic injury indicated that they differentiate into multiple downstream macrophage subsets that were unique from other monocyte to macrophage differentiation trajectories. Finally, Hif1α deletion in resident cardiac macrophages caused a halt or delay in the progression of this differentiation trajectory and an accumulation of Arg1+ macrophages. Depletion of the Arg1 differentiation trajectory resulted in reduced cardiac function after ischemic injury. Taken together, this work identifies hypoxia as an environmental factor that influences monocyte to macrophage differentiation and left ventricular remodeling following myocardial infarction and identifies a unique differentiation trajectory of monocytes to macrophages which progresses through Arg1+ macrophages.
Language
English (en)
Chair and Committee
Kory Lavine
Committee Members
Benjamin Humphreys; David Ornitz; Gwendalyn Randolph; Joel Schilling
Recommended Citation
Kadyrov, Farid Faridovich, "Effects of Hypoxia on Monocyte Differentiation and Macrophage Specification during Ischemic Heart Injury" (2024). Arts & Sciences Electronic Theses and Dissertations. 3302.
https://openscholarship.wustl.edu/art_sci_etds/3302