Multiple cell types contribute to the atherosclerotic lesion fibrous cap by PDGFRβ and bioenergetic mechanisms.
Multiple cell types contribute to the atherosclerotic lesion fibrous cap by PDGFRβ and bioenergetic mechanisms.
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多种细胞类型通过PDGFRβ和生物能量机制参与动脉粥样硬化病变纤维帽的形成。
DOI：
10.1038/s42255-020-00338-8
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发表时间：
2021-03
影响因子：
20.8
通讯作者：
Owens GK
中科院分区：
文献类型：
--
作者：
Newman AAC;Serbulea V;Baylis RA;Shankman LS;Bradley X;Alencar GF;Owsiany K;Deaton RA;Karnewar S;Shamsuzzaman S;Salamon A;Reddy MS;Guo L;Finn A;Virmani R;Cherepanova OA;Owens GK
稳定的动脉粥样硬化斑块的特征是厚的细胞外基质（ECM）丰富的纤维帽，由保护性的ACTA2+肌成纤维细胞（MF）样细胞填充，假设几乎完全来源于平滑肌细胞（SMC）。在此，我们表明，在小鼠和人类病变中，分别有20%至40%的ACTA2+纤维帽细胞来自非smc来源，包括内皮细胞（EC）或巨噬细胞，它们经历了内皮到间充质（EndoMT）或巨噬细胞到间充质（MMT）的转变。此外，我们发现，在喂食西方饮食（WD） 18周的Apoe - / -小鼠中，SMC特异性敲除血小板衍生生长因子受体β (PDGFRB)导致头臂动脉（BCA）病变几乎没有SMC，但病变大小、重塑或稳定性指标（包括ACTA2+纤维帽细胞的百分比）没有变化。然而，长时间WD喂养SMC-PDGFRB敲除小鼠导致稳定性指标降低，这表明EndoMT和mmt衍生的MFs不能无限期地补偿smc衍生的MFs的损失。通过对BCA区域和体外模型的单细胞和大量RNA-seq分析，我们提供了证据，证明SMC到MF的转变（SMC- mft）是由PDGF和TGFβ诱导的，依赖于有氧糖酵解，而EndoMT是由IL1β和TGFβ诱导的。总之，我们提供的证据表明，ACTA2+纤维帽起源于一系列细胞类型，这些细胞类型通过不同的信号通路过渡到MF状态，这些信号通路依赖于或与广泛的代谢重编程相关。
Stable atherosclerotic plaques are characterized by a thick extracellular matrix (ECM)-rich fibrous cap populated by protective ACTA2+ myofibroblast (MF)-like cells, assumed to be almost exclusively derived from smooth muscle cells (SMC). Herein, we show that in murine and human lesions, 20 to 40% of ACTA2+ fibrous caps cells, respectively, are derived from non-SMC sources, including endothelial cells (EC) or macrophages that have undergone Endothelial-to-Mesenchymal (EndoMT) or Macrophage-to-Mesenchymal (MMT) transitions. In addition, we show that SMC-specific knockout of the platelet derived growth factor receptor beta (PDGFRB) in Apoe−/− mice fed a Western diet (WD) for 18 weeks resulted in brachiocephalic artery (BCA) lesions nearly devoid of SMC but with no changes in lesion size, remodeling, or indices of stability including percent of ACTA2+ fibrous cap cells. However, prolonged WD feeding of SMC-PDGFRB knockout mice resulted in reduced indices of stability, indicating that EndoMT and MMT-derived MFs cannot compensate indefinitely for loss of SMC-derived MFs. Using single cell and bulk RNA-seq analyses of the BCA region and in vitro models, we provide evidence that SMC to MF transitions (SMC-MFT) are induced by PDGF and TFGβ and dependent on aerobic glycolysis, while EndoMT is induced by IL1β and TGFβ. Together, we provide evidence that the ACTA2+ fibrous cap originates from a tapestry of cell types, which transition to an MF state through distinct signaling pathways that are either dependent on or associated with extensive metabolic reprogramming.
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影响因子：
82.9
作者：
Gomez D;Baylis RA;Durgin BG;Newman AAC;Alencar GF;Mahan S;St Hilaire C;Müller W;Waisman A;Francis SE;Pinteaux E;Randolph GJ;Gram H;Owens GK
通讯作者：
Owens GK
DOI：
10.1161/atvbaha.117.310097
发表时间：
2017-11
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
--
作者：
Baylis RA;Gomez D;Mallat Z;Pasterkamp G;Owens GK
通讯作者：
Owens GK
内皮 TGF-β 信号传导驱动血管炎症和动脉粥样硬化
影响因子：
20.8
作者：
Chen, Pei-Yu;Qin, Lingfeng;Simons, Michael
通讯作者：
Simons, Michael
影响因子：
11.4
作者：
Giles, F. J.;le Coutre, P. D.;Kantarjian, H. M.
通讯作者：
Kantarjian, H. M.
影响因子：
37.8
作者：
Iwata, Hiroshi;Manabe, Ichiro;Nagai, Ryozo
通讯作者：
Nagai, Ryozo