Smooth Muscle Cell Reprogramming in Aortic Aneurysms

• Published in: Cell stem cell Vol. 26; no. 4; pp. 542 - 557.e11
• Main Authors: Chen, Pei-Yu, Qin, Lingfeng, Li, Guangxin, Malagon-Lopez, Jose, Wang, Zheng, Bergaya, Sonia, Gujja, Sharvari, Caulk, Alexander W, Murtada, Sae-Il, Zhang, Xinbo, Zhuang, Zhen W, Rao, Deepak A, Wang, Guilin, Tobiasova, Zuzana, Jiang, Bo, Montgomery, Ruth R, Sun, Lele, Sun, Hongye, Fisher, Edward A, Gulcher, Jeffrey R, Fernandez-Hernando, Carlos, Humphrey, Jay D, Tellides, George, Chittenden, Thomas W, Simons, Michael
• Format: Journal Article
• Language: English
• Published: United States 02.04.2020
• Subjects: Animals; Aorta; Aortic Aneurysm; Cellular Reprogramming; Mice; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Transforming Growth Factor beta; atherosclerosis; smooth muscle cells; aneurysm; cell reprogramming; mesenchymal stem cell; TGF-beta; scRNA-seq; cell fate; aorta; artificial intelligence
• ISSN: 1934-5909; 1875-9777; 1875-9777
• DOI: 10.1016/j.stem.2020.02.013

The etiology of aortic aneurysms is poorly understood, but it is associated with atherosclerosis, hypercholesterolemia, and abnormal transforming growth factor β (TGF-β) signaling in smooth muscle. Here, we investigated the interactions between these different factors in aortic aneurysm development and identified a key role for smooth muscle cell (SMC) reprogramming into a mesenchymal stem cell (MSC)-like state. SMC-specific ablation of TGF-β 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.