Smooth Muscle Cell Reprogramming in Aortic Aneurysms

• DOI: 10.1016/j.stem.2020.02.013
• Publication Date: 2020-04-02T14:51:44Z
• Authors: Pei-Yu Chen; Lingfeng Qin; Guangxin Li; Jose Malagon-Lopez; Zheng Wang; Sonia Bergaya; Sharvari Gujja; Alexander W. Caulk; Sae-Il Murtada; Xinbo Zhang; Zhen W. Zhuang; Deepak A. Rao; Guilin Wang; Zuzana Tobiasova; Bo Jiang; Ruth R. Montgomery; Lele Sun; Hongye Sun; Edward A. Fisher; Jeffrey R. Gulcher; Carlos Fernandez-...; Jay D. Humphrey; George Tellides; Thomas W. Chittenden; Michael Simons
• Keywords: Transdifferentiation

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.