Smooth Muscle Cell Reprogramming in Aortic Aneurysms
Smooth Muscle Cell Reprogramming in Aortic Aneurysms
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DOI：
10.1016/j.stem.2020.02.013
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发表时间：
2020-04-02
期刊：
影响因子：
23.9
通讯作者：
Simons, Michael
中科院分区：
文献类型：
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作者：
Chen, Pei-Yu;Qin, Lingfeng;Simons, Michael
主动脉瘤的病因目前知之甚少，但它与动脉粥样硬化、高胆固醇血症和平滑肌转化生长因子-β信号的异常有关。在这里，我们研究了这些不同因素之间在主动脉瘤发展过程中的相互作用，并确定了平滑肌细胞(SMC)重新编程为间充质干细胞(MSC)样状态的关键作用。在高胆固醇饮食的APOE(-/-)小鼠中，SMC特异性地阻断转化生长因子-β信号导致了主动脉瘤的发展，显示出人类疾病的所有特征，这与收缩的SMC子集转分化为MSC样的中间状态有关，从而产生成骨细胞、软骨细胞、脂肪细胞和巨噬细胞。这种中层SMC丢失和非SMC主动脉细胞团块显著增加的组合导致了主动脉的旺盛生长和扩张，主动脉壁的钙化和骨化，以及炎症，导致动脉瘤的发展。
The etiology of aortic aneurysms is poorly understood, but it is associated with atherosclerosis, hypercholesterolemia, and abnormal transforming growth factor beta (TGF-beta) signaling in smooth muscle. Here, we investigated the interactions between these different factors in aortic aneurysmdevelopment and identified a key role for smooth muscle cell (SMC) reprogramming into a mesenchymal stem cell (MSC)like state. SMC-specific ablation of TGF-beta signaling in Apoe(-/-) mice on a hypercholesterolemic diet led to development of aortic aneurysms exhibiting all the features of human disease, which was associated with transdifferentiation of a subset of contractile SMCs into an MSC-like intermediate state that generated osteoblasts, chondrocytes, adipocytes, and macrophages. This combination of medial SMC loss with marked increases in non-SMC aortic cell mass induced exuberant growth and dilation of the aorta, calcification and ossification of the aortic wall, and inflammation, resulting in aneurysm development.