Contribution of smooth muscle-derived resident vascular progenitor cells to atherosclerotic plaque progression
Year: 2023
Type: dissertation
Abstract: Atherosclerosis is a complex inflammatory condition and the major driver of cardiovascular disease (CVD), a spectrum of diseases resulting in major morbidity and mortality worldwide. Current pharmacological management of atherosclerosis involves goal directed lipid-lowering, but statins fail to fully resolve CVD risk and many patients have residual inflammatory risks. Additionally, although inflammation is a major driver of atherosclerosis, anti-inflammatory treatment approaches result in an increased risk of infection and sepsis, and as such are not in widespread clinical use. Thus, additional therapeutic approaches are needed to directly target the vascular wall cells in atherosclerotic lesions and more comprehensively manage atherosclerosis.While previous atherosclerosis research has focused primarily on the vascular intima and media, more recent studies have provided compelling evidence for the adventitia as a driver of plaque initiation and progression. Contrary to its traditional reputation as a purely structural region of the blood vessel, the adventitia is home to a diverse assortment of cells including fibroblasts, leukocytes, and resident vascular progenitor cells. Our group discovered a subpopulation of these adventitial progenitor cells (AdvSca1-SM cells) derived from mature, contractile smooth muscle cells (SMC) that undergo KLF4-dependent reprogramming. We previously established that vascular smooth muscle-derived adventitial progenitor cells (AdvSca1-SM) preferentially differentiate into myofibroblasts and contribute to fibrosis in response to acute vascular injury. However, the role of these progenitor cells in chronic atherosclerosis has not been defined. Using an AdvSca1-SM lineage tracing model, scRNA-Seq, flow cytometry, and histological approaches, we confirmed that AdvSca1-SM cells localize throughout the vessel wall and atherosclerotic plaques, where they primarily differentiated into fibroblasts, smooth muscle cells (SMC), or remained in a stem-like state. Krüppel-like factor 4 (Klf4) knockout specifically in AdvSca1-SM cells induced transition to a more collagen-enriched fibroblast phenotype compared to WT mice. Additionally, Klf4 deletion significantly modified the phenotypes of non-AdvSca1-SM-derived cells, resulting in more contractile SMC and atheroprotective macrophages. Functionally, overall plaque burden was not altered with Klf4 deletion, but multiple indices of plaque composition complexity, including necrotic core area, macrophage accumulation, and fibrous cap thickness, were reduced. Collectively, these data support that modulation of AdvSca1-SM cells through KLF4 depletion confers increased protection from the development of potential unstable atherosclerotic plaques.
DOI: 10.25677/n1fy-vt82
Author: Dubner, Allison Milfred
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7134909143