Exploring Origin-Dependent Susceptibility of Smooth Muscle Cells to Aortic Diseases Through Intersectional Genetics
文献类型：期刊论文
| 作者 | Han, Ximeng2,3; Li, Yi2; Wang, Enci4; Zhu, Huan3; Huang, Xiuzhen3; Pu, Wenjuan3; Zhang, Mingjun3; Liu, Kuo5; Zhao, Huan3; Liu, Zixin3 |
| 刊名 | CIRCULATION
 |
| 出版日期 | 2025-04-29 |
| 卷号 | 151期号:17页码:1248-1267 |
| 关键词 | aortic diseases developmental origin lineage tracing smooth muscle cell TGF-beta |
| ISSN号 | 0009-7322 |
| DOI | 10.1161/CIRCULATIONAHA.124.070782 |
| 英文摘要 | 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-beta (transforming growth factor-beta) 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 critical role of Smad4 in preserving aortic wall integrity and homeostasis in SMCs of the aortic arch.CONCLUSIONS:Our approach to genetically targeting SMC subtypes provides a novel platform for exploring origin-dependent or location-specific aortic vascular diseases. This genetic system enables comprehensive analysis of contributions from different cell lineages to SMC behavior and pathology, thereby paving the way for targeted research and therapeutic interventions in the future. |
| WOS关键词 | NEURAL CREST CELLS ; JUVENILE POLYPOSIS SYNDROME ; ANGIOTENSIN-II ; CARDIOVASCULAR DEVELOPMENT ; ANEURYSM PROGRESSION ; EXPRESSION DOMAIN ; DRE RECOMBINASE ; SMAD4 ; DIFFERENTIATION ; AORTOPATHY |
| 资助项目 | National Key Research & Development Program of China[2024YFA1803302] ; National Key Research & Development Program of China[2023YFA1800700] ; National Key Research & Development Program of China[2022YFA1104200] ; National Key Research & Development Program of China[2022YFA1104201] ; National Science Foundation of China[82088101] ; National Science Foundation of China[82130012] ; National Science Foundation of China[82300552] ; National Science Foundation of China[32370783] ; National Science Foundation of China[32170848] ; National Science Foundation of China[32370897] ; National Science Foundation of China[32370802] ; National Science Foundation of China[82200448] ; Chinese Academy of Sciences (CAS) Project for Young Scientists in Basic Research[YSBR-012] ; CAS-Croucher Funding Scheme for Joint Laboratories, Youth Innovation Promotion Association CAS, Shanghai Pilot Program for Basic Research-CAS, Shanghai Branch[JCYJ-SHFY-2021-0] ; CAS Strategic Priority Research Program[XDB0990101] ; Innovative Research Team of High-Level Local Universities in Shanghai, Postdoctoral Fellowship Program of CPSF[318733] ; Fellowship of China National Postdoctoral Program for Innovative Talents[BX20220209] ; CAS-Croucher Funding Scheme for Joint Laboratories ; New Cornerstone Science Foundation through the New Cornerstone Investigator Program ; XPLORER PRIZE |
| WOS研究方向 | Cardiovascular System & Cardiology |
| 语种 | 英语 |
| WOS记录号 | WOS:001476909200006 |
| 出版者 | LIPPINCOTT WILLIAMS & WILKINS |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/317539]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Wang, Lixin; He, Ben; Zhou, Bin |
| 作者单位 | 1.Bohai Rim Adv Res Inst Drug Discovery, Shandong Lab Yantai Drug Discovery, Yantai, Peoples R China 2.Shanghai Jiao Tong Univ, Shanghai Chest Hosp, Dept Cardiol, Sch Med, Shanghai, Peoples R China 3.Univ Chinese Acad Sci, Chinese Acad Sci, Shanghai Inst Biochem & Cell Biol, Ctr Excellence Mol Cell Sci,CAS CEMCS CUHK Joint L, Shanghai, Peoples R China 4.Fudan Univ, Zhongshan Hosp, Dept Vasc Surg, Shanghai 200032, Peoples R China 5.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Life Sci, Key Lab Syst Hlth Sci Zhejiang Prov, Hangzhou, Peoples R China 6.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai, Peoples R China 7.Beijing Inst Life, Beijing Proteome Res Ctr, Natl Ctr Prot Sci, State Key Lab Med Prote, Beijing, Peoples R China 8.AstraZeneca, BioPharmaceut R&D, Biosci Cardiovasc Res & Early Dev, Cardiovasc Renal & Metab, Gothenburg, Sweden 9.Jiangnan Univ, Wuxi Sch Med, Dept Pharmacol, Wuxi, Peoples R China 10.Shanghai Lab Anim Res Ctr, Shanghai, Peoples R China |
| 推荐引用方式 GB/T 7714 | Han, Ximeng,Li, Yi,Wang, Enci,et al. Exploring Origin-Dependent Susceptibility of Smooth Muscle Cells to Aortic Diseases Through Intersectional Genetics[J]. CIRCULATION,2025,151(17):1248-1267. |
| APA | Han, Ximeng.,Li, Yi.,Wang, Enci.,Zhu, Huan.,Huang, Xiuzhen.,...&Zhou, Bin.(2025).Exploring Origin-Dependent Susceptibility of Smooth Muscle Cells to Aortic Diseases Through Intersectional Genetics.CIRCULATION,151(17),1248-1267. |
| MLA | Han, Ximeng,et al."Exploring Origin-Dependent Susceptibility of Smooth Muscle Cells to Aortic Diseases Through Intersectional Genetics".CIRCULATION 151.17(2025):1248-1267. |
入库方式： OAI收割
来源：上海药物研究所
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