Single-Cell Transcriptomic Profiling of Vascular Smooth Muscle Cell Phenotype Modulation in Marfan Syndrome Aortic Aneurysm
Single-Cell Transcriptomic Profiling of Vascular Smooth Muscle Cell Phenotype Modulation in Marfan Syndrome Aortic Aneurysm
复制标题
马凡综合征主动脉瘤血管平滑肌细胞表型调控的单细胞转录组学研究
DOI：
10.1161/atvbaha.120.314670
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发表时间：
2020-09-01
影响因子：
8.7
通讯作者：
Fischbein, Michael P.
中科院分区：
文献类型：
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作者：
Pedroza, Albert J.;Tashima, Yasushi;Fischbein, Michael P.
目的：探讨马凡综合征(MFS)患者主动脉瘤发生发展过程中血管平滑肌细胞(SMC)转录水平的时空动态变化。方法和结果：我们对Fbn1(C1041G/+)(MFS)小鼠和健康对照组的主动脉根部/升主动脉瘤组织进行了单细胞RNA测序，鉴定了所有的主动脉细胞类型。仅在成年Fbn1(C1041G/+)小鼠主动脉瘤组织中发现了转录调控的SMC(ModSMCs)簇。与动脉粥样硬化(ApoE(-/-)小鼠)相比，SMC的调节模式相似，但发现了MFS特异的基因特征，包括纤溶酶原激活物抑制物-1(SERPINE1)和Kruppel样因子4(KLF4)。我们鉴定了481个modSMC和SMC亚群之间的差异表达基因；功能注释强调了细胞外基质调节、胶原合成、黏附和增殖。Fbn1(C1041G/+)SMC/modSMC转录本的假时间轨迹分析发现，在表型调节过程中，差异激活的基因是不同的。尽管年轻的Fbn1(C1041G/+)小鼠的主动脉瘤较小，但未检测到modSMCs，但早期的多个modSMCs标记基因表达丰富，提示表型调控激活。未扩张的成人Fbn1(C1041G/+)降主动脉未见modSMCs。来自人类MFS主动脉根部动脉瘤组织的单细胞RNA测序证实了临床疾病中类似的SMC调节。在小鼠和人类数据集中，转化生长因子β(转化生长因子β)反应基因的表达增强与SMC调节相关。结论：动态SMC表型调节促进了MFS中细胞外基质的调节和主动脉瘤的进展。我们描述了modSMCs的疾病特异性特征，并为目前对转化生长因子-β在MFS大动脉病变中所起作用的理解提供了时间和转录背景。总的来说，单细胞RNA测序暗示转化生长因子-β信号和KLF4过度表达是SMC调节的潜在上游驱动因素。
Objective: To delineate temporal and spatial dynamics of vascular smooth muscle cell (SMC) transcriptomic changes during aortic aneurysm development in Marfan syndrome (MFS). Approach and Results: We performed single-cell RNA sequencing to study aortic root/ascending aneurysm tissue fromFbn1(C1041G/+)(MFS) mice and healthy controls, identifying all aortic cell types. A distinct cluster of transcriptomically modulated SMCs (modSMCs) was identified in adultFbn1(C1041G/+)mouse aortic aneurysm tissue only. Comparison with atherosclerotic aortic data (ApoE(-/-)mice) revealed similar patterns of SMC modulation but identified an MFS-specific gene signature, including plasminogen activator inhibitor-1 (Serpine1) and Kruppel-like factor 4 (Klf4). We identified 481 differentially expressed genes between modSMC and SMC subsets; functional annotation highlighted extracellular matrix modulation, collagen synthesis, adhesion, and proliferation. Pseudotime trajectory analysis ofFbn1(C1041G/+)SMC/modSMC transcriptomes identified genes activated differentially throughout the course of phenotype modulation. While modSMCs were not present in youngFbn1(C1041G/+)mouse aortas despite small aortic aneurysm, multiple early modSMCs marker genes were enriched, suggesting activation of phenotype modulation. modSMCs were not found in nondilated adultFbn1(C1041G/+)descending thoracic aortas. Single-cell RNA sequencing from human MFS aortic root aneurysm tissue confirmed analogous SMC modulation in clinical disease. Enhanced expression of TGF-beta (transforming growth factor beta)-responsive genes correlated with SMC modulation in mouse and human data sets. Conclusions: Dynamic SMC phenotype modulation promotes extracellular matrix substrate modulation and aortic aneurysm progression in MFS. We characterize the disease-specific signature of modSMCs and provide temporal, transcriptomic context to the current understanding of the role TGF-beta plays in MFS aortopathy. Collectively, single-cell RNA sequencing implicates TGF-beta signaling andKlf4overexpression as potential upstream drivers of SMC modulation.