Ren Pengwei, Jiang Bo, Hassab Abdulrahman H M, Li Guangxin, Li Wei, Assi Roland, Tellides George
Department of Surgery (Cardiac) (P.R., B.J., A.H., G.L., W.L., R.A., G.T.), Yale School of Medicine, New Haven, CT.
Now with Department of Vascular Surgery, The First Hospital of China Medical University, Shenyang, Liaoning Province (B.J.).
Arterioscler Thromb Vasc Biol. 2025 Feb;45(2):260-276. doi: 10.1161/ATVBAHA.124.321706. Epub 2024 Dec 19.
Smooth muscle cells (SMCs) of cardiac and neural crest origin contribute to the developing proximal aorta and are linked to disease propensity in adults.
We analyzed single-cell transcriptomes of aortic SMCs from adult mice to determine basal states and changes after disrupting TGFβ (transforming growth factor-β) signaling necessary for aortic homeostasis.
A minority of Myh11 lineage-marked SMCs differentially expressed genes suggestive of embryological origin. Additional analyses in Nkx2-5 and Wnt1 lineage-marked SMCs derived from cardiac and neural crest progenitors, respectively, showed both lineages contributed to a major common cluster and each lineage to a minor distinct cluster. Common cluster SMCs extended from root to arch, cardiac subset cluster SMCs from root to ascending, and neural crest subset cluster SMCs were restricted to the arch. The neural crest subset cluster had greater expression of a subgroup of TGFβ-dependent genes. Nonetheless, conditional deletion of TGFβ receptors resulted in similar transcriptional changes among all SMC clusters. Several disease-associated transcriptional responses were comparable among SMC clusters in a mouse model of Marfan syndrome aortopathy, while many embryological markers of murine aortic SMCs were not detected in adult human aortas.
There are multiple subtypes of cardiac-derived and neural crest-derived SMCs with shared or distinctive transcriptional profiles; neural crest subset cluster SMCs with increased expression of certain TGFβ-inducible genes are not spatially linked to the aortic root predisposed to aneurysms from aberrant TGFβ signaling; and loss of TGFβ responses after receptor deletion is uniform among SMC clusters.
心脏和神经嵴来源的平滑肌细胞（SMC）有助于近端主动脉的发育，并与成人的疾病易感性相关。
我们分析了成年小鼠主动脉SMC的单细胞转录组，以确定基础状态以及破坏主动脉稳态所需的TGFβ（转化生长因子-β）信号后发生的变化。
少数由Myh11谱系标记的SMC差异表达提示胚胎起源的基因。分别对源自心脏和神经嵴祖细胞的Nkx2-5和Wnt1谱系标记的SMC进行的额外分析表明，这两个谱系都对一个主要的共同簇有贡献，且每个谱系都对一个较小的独特簇有贡献。共同簇的SMC从根部延伸至弓部，心脏亚群簇的SMC从根部延伸至升主动脉，而神经嵴亚群簇的SMC局限于弓部。神经嵴亚群簇中一组TGFβ依赖性基因的表达更高。尽管如此，TGFβ受体的条件性缺失在所有SMC簇中导致了相似的转录变化。在马凡综合征主动脉病变小鼠模型中，SMC簇之间的几种疾病相关转录反应具有可比性，而在成人主动脉中未检测到许多小鼠主动脉SMC的胚胎学标记物。
存在多种心脏来源和神经嵴来源的SMC亚型，它们具有共同或独特的转录谱；某些TGFβ诱导基因表达增加的神经嵴亚群簇SMC在空间上与因异常TGFβ信号而易发动脉瘤的主动脉根部没有关联；受体缺失后TGFβ反应的丧失在SMC簇中是一致的。
