Dubner Allison M, Lu Sizhao, Jolly Austin J, Strand Keith A, Mutryn Marie F, Hinthorn Tyler, Noble Tysen, Nemenoff Raphael A, Moulton Karen S, Majesky Mark W, Weiser-Evans Mary Cm
Department of Medicine, Division of Renal Diseases and Hypertension, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
Integrated Physiology PhD Program, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO, USA.
bioRxiv. 2023 Jul 19:2023.07.18.549539. doi: 10.1101/2023.07.18.549539.
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 differentiate into fibroblasts, SMCs, or remain in a stem-like state. Klf4 knockout specifically in AdvSca1-SM cells induced transition to a more collagen-enriched myofibroblast phenotype compared to WT mice. Additionally, Klf4 depletion drastically modified the phenotypes of non-AdvSca1-SM-derived cells, resulting in more contractile SMCs and atheroprotective macrophages. Functionally, overall plaque burden was not altered with Klf4 depletion, but multiple indices of plaque vulnerability were reduced. Collectively, these data support that modulating the AdvSca1-SM population confers increased protection from the development of unstable atherosclerotic plaques.
我们先前已经确定，血管平滑肌来源的外膜祖细胞（AdvSca1-SM）在急性血管损伤时优先分化为肌成纤维细胞并促进纤维化。然而，这些祖细胞在慢性动脉粥样硬化中的作用尚未明确。利用AdvSca1-SM谱系追踪模型、单细胞RNA测序、流式细胞术和组织学方法，我们证实AdvSca1-SM细胞定位于整个血管壁和动脉粥样硬化斑块中，在那里它们主要分化为成纤维细胞、平滑肌细胞，或保持干细胞样状态。与野生型小鼠相比，AdvSca1-SM细胞中特异性敲除Klf4可诱导其转变为胶原含量更高的肌成纤维细胞表型。此外，Klf4缺失极大地改变了非AdvSca1-SM来源细胞的表型，产生更多收缩性平滑肌细胞和具有抗动脉粥样硬化作用的巨噬细胞。在功能上，Klf4缺失并未改变总体斑块负担，但斑块易损性的多个指标有所降低。总的来说，这些数据支持调节AdvSca1-SM群体可增强对不稳定动脉粥样硬化斑块形成的保护作用。
