Diverse cellular architecture of atherosclerotic plaque derives from clonal expansion of a few medial SMCs
Diverse cellular architecture of atherosclerotic plaque derives from clonal expansion of a few medial SMCs
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DOI：
10.1172/jci.insight.95890
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发表时间：
2017-10-05
期刊：
影响因子：
8
通讯作者：
Bentzon, Jacob Fog
中科院分区：
文献类型：
--
作者：
Jacobsen, Kevin;Lund, Marie Bek;Bentzon, Jacob Fog
纤维帽平滑肌细胞（SMC）保护动脉粥样硬化病变免于破裂和引起血栓形成，而其他斑块SMC可能在斑块发展中起有害作用。为了深入了解不同斑块SMC的募集，我们在eGFP（+）Apoe（-/-）和Apoe（-/-）小鼠胚胎的聚集嵌合体中以及在中膜SMC中具有荧光蛋白镶嵌表达的小鼠中绘制了它们的克隆结构，所述中膜SMC由PCSK 9诱导的高胆固醇血症导致动脉粥样硬化。发现聚集嵌合体中的纤维帽由eGFP（+）或非荧光SMC的大的内皮对齐层构建，表明少数细胞的大量克隆扩增。同样，SMC限制性Confetti表达的小鼠斑块显示寡克隆SMC群体，不同中膜SMC的后代之间几乎没有混合。表型包括帽中的ACTA 2（+）SMC和斑块内部的异质ACTA 2（-）SMC，包括软骨细胞样细胞和具有细胞内脂质和结晶物质的细胞。纤维帽SMC总是排列在内皮对齐的克隆片，证实了聚集嵌合体的结果。克隆结构的分析表明，少量的局部中膜SMC参与动脉粥样硬化，单个中膜SMC可以在斑块中产生几种不同的SMC表型。综合结果表明，在小鼠动脉粥样硬化中，很少有中膜SMC增殖形成整个表型异质性斑块SMC群体。
Fibrous cap smooth muscle cells (SMCs) protect atherosclerotic lesions from rupturing and causing thrombosis, while other plaque SMCs may have detrimental roles in plaque development. To gain insight into recruitment of different plaque SMCs, we mapped their clonal architecture in aggregation chimeras of eGFP(+) Apoe(-/-) and Apoe(-/-) mouse embryos and in mice with a mosaic expression of fluorescent proteins in medial SMCs that were rendered atherosclerotic by PCSK9-induced hypercholesterolemia. Fibrous caps in aggregation chimeras were found constructed from large, endothelial-aligned layers of either eGFP(+) or nonfluorescent SMCs, indicating substantial clonal expansion of a few cells. Similarly, plaques in mice with SMC-restricted Confetti expression showed oligoclonal SMC populations with little intermixing between the progeny of different medial SMCs. Phenotypes comprised both ACTA2(+) SMCs in the cap and heterogeneous ACTA2(-) SMCs in the plaque interior, including chondrocyte-like cells and cells with intracellular lipid and crystalline material. Fibrous cap SMCs were invariably arranged in endothelium-aligned clonal sheets, confirming results in the aggregation chimeras. Analysis of the clonal structure showed that a low number of local medial SMCs partake in atherosclerosis and that single medial SMCs can produce several different SMC phenotypes in plaque. The combined results show that few medial SMCs proliferate to form the entire phenotypically heterogeneous plaque SMC population in murine atherosclerosis.