The ontogenetic programming of the atherosclerotic macrophage phenotype

Prica, Filip (2025): The ontogenetic programming of the atherosclerotic macrophage phenotype. Dissertation, LMU München: Faculty of Medicine

Abstract

Tissue-resident macrophages originate from embryonic erythromyeloid progenitors (EMPs) or hematopoietic stem cells (HSCs). The ontogeny of tissue macrophages plays a critical role in maintaining homeostasis in a wide array of tissue they populate. However, their role and fate in the progression of pathological conditions, such as atherosclerosis, remains unknown. In this thesis, we interrogated the contribution of EMP-derived macrophages to the macrophage pool in atherosclerotic lesions, particularly their dynamics and phenotype in disease progression and regression. Using RankCre Rosa26eYFP mouse models, we traced the lineage of EMP-derived macrophages within atherosclerotic plaques induced by reversible LDLR downregulation and dietary-induced hypercholesterolemia. High-resolution immunofluorescence imaging and flow cytometry were employed to characterise macrophage heterogeneity in atherosclerotic tissue, revealing a significant increase in phenotypically distinct eYFP+ macrophages in advanced plaques. These macrophages maintained distinct localisation, greater proliferative capacity, higher lipid uptake, and a larger fraction of TUNEL+ cells in association with disease progression. Notably, the heterogeneity persisted even after plaque regression, indicating a long-term phenotypic variation. Our findings suggest that this population of eYFP+ macrophages exhibit unique roles in atherosclerotic progression and regression.

• Item Type: Theses (Dissertation, LMU Munich)
• Keywords: Macrophages, Ontogeny, Atherosclerosis, Fate-Mapping
• Subjects: 600 Technology, Medicine; 600 Technology, Medicine > 610 Medical sciences and medicine
• Faculties: Faculty of Medicine
• Language: English
• Date of oral examination: 30. April 2025
• 1. Referee: Schulz, Christian
• Signature of the printed copy: 0700/UMD 22769