Exploring Origin-Dependent Susceptibility of Smooth Muscle Cells to Aortic Diseases Through Intersectional Genetics

作者：Ximeng Han, Yi Li, Yi Li, Enci Wang, Huan Zhu, Xiuzhen Huang, Wenjuan Pu, Mingjun Zhang, Kuo Liu, Huan Zhao, Zixin Liu, Yufei Zhao, Linghong Shen, Yán Li, Yán Li, Xiao Yang, Qing‐Dong Wang, Xin Ma, Ruling Shen, Kathy O. Lui, Lixin Wang, Ben He, Bin Zhou · 发表于：Circulation · 年份：2025 · DOI：10.1161/circulationaha.124.070782 · 被引用次数：15 · 研究领域：Congenital heart defects research、Williams Syndrome Research、Single-cell and spatial transcriptomics

BACKGROUND: The developmental diversity among smooth muscle cells (SMCs) plays a crucial role in segment-specific aortic diseases. However, traditional genetic approaches are inadequate for enabling in vivo analysis of disease susceptibility associated with cellular origin. There is an urgent need to build genetic technologies that target different developmental origins to investigate the mechanisms of aortopathies, thereby facilitating the development of effective therapeutics. METHODS: To address this challenge, we developed an advanced dual recombinase-mediated intersectional genetic system, specifically designed to precisely target SMCs from various developmental origins in mice. Specifically, we used Isl1-Dre , Wnt1-Dre , Meox1-DreER , and Upk3b-Dre to target SMC progenitors from the second heart field, cardiac neural crest, somites, and mesothelium, respectively. This system was combined with single-cell RNA sequencing to investigate the impact of TGF-β (transforming growth factor-β) signaling in different segments of the aorta by selectively knocking out Tgfbr2 in the ascending aorta and Smad4 in the aortic arch, respectively. RESULTS: Through intersectional genetic approaches, we use the Myh11-Cre(ER ) driver along with origin-specific Dre drivers to trace cells of diverse developmental origins within the SMC population. We found that a deficiency of Tgfbr2 in SMCs of the ascending aorta leads to aneurysm formation in this specific region. We also demonstrate the crit...