Albarrán-Juárez Julián, Kaur Harmandeep, Grimm Myriam, Offermanns Stefan, Wettschureck Nina
Department of Pharmacology, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.
Department of Pharmacology, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.
Atherosclerosis. 2016 Aug;251:445-453. doi: 10.1016/j.atherosclerosis.2016.06.012. Epub 2016 Jun 11.
Despite the clinical importance of atherosclerosis, the origin of cells within atherosclerotic plaques is not fully understood. Due to the lack of a definitive lineage-tracing strategy, previous studies have provided controversial results about the origin of cells expressing smooth muscle and macrophage markers in atherosclerosis. We here aim to identify the origin of vascular smooth muscle (SM) cells and macrophages within atherosclerosis lesions.
We combined a genetic fate mapping approach with single cell expression analysis in a murine model of atherosclerosis.
We found that 16% of CD68-positive plaque macrophage-like cells were derived from mature SM cells and not from myeloid sources, whereas 31% of αSMA-positive smooth muscle-like cells in plaques were not SM-derived. Further analysis at the single cell level showed that SM-derived CD68(+) cells expressed higher levels of inflammatory markers such as cyclooxygenase 2 (Ptgs2, p = 0.02), and vascular cell adhesion molecule (Vcam1, p = 0.05), as well as increased mRNA levels of genes related to matrix synthesis such as Col1a2 (p = 0.01) and Fn1 (p = 0.04), than non SM-derived CD68(+) cells.
These results demonstrate that smooth muscle cells within atherosclerotic lesions can switch to a macrophage-like phenotype characterized by higher expression of inflammatory and synthetic markers genes that may further contribute to plaque progression.
尽管动脉粥样硬化具有临床重要性，但其粥样硬化斑块内细胞的起源尚未完全明确。由于缺乏明确的谱系追踪策略，以往关于动脉粥样硬化中表达平滑肌和巨噬细胞标志物的细胞起源的研究结果存在争议。我们旨在确定动脉粥样硬化病变中血管平滑肌（SM）细胞和巨噬细胞的起源。
我们在动脉粥样硬化小鼠模型中，将遗传命运图谱方法与单细胞表达分析相结合。
我们发现，16%的CD68阳性斑块巨噬样细胞源自成熟SM细胞，而非髓系来源；而斑块中31%的αSMA阳性平滑肌样细胞并非源自SM。单细胞水平的进一步分析表明，与非SM来源的CD68(+)细胞相比，SM来源的CD68(+)细胞表达更高水平的炎症标志物，如环氧合酶2（Ptgs2，p = 0.02）和血管细胞黏附分子（Vcam1，p = 0.05），以及与基质合成相关基因如Col1a2（p = 0.01）和Fn1（p = 0.04）的mRNA水平升高。
这些结果表明，动脉粥样硬化病变中的平滑肌细胞可转变为巨噬样表型，其特征是炎症和合成标志物基因表达升高，这可能进一步促进斑块进展。
