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SMART-seq profiling of the ascending aorta and aortic arch from male and female Wnt1-Cre;Rosa26-mTmG mice

ABSTRACT: Vascular smooth muscle cells (VSMCs) in the ascending aorta and aortic arch arise from two distinct embryonic origins: the second heart field (SHF) and the cardiac neural crest (CNC). Whether these populations exhibit sex-dependent differences remains unknown. Here, we used Wnt1-Cre;Rosa26-mTmG mice to genetically label CNC-derived VSMCs with GFP, while non-CNC-derived cells expressed tdTomato. The ascending aorta and aortic arch were dissected from male and female mice, and single-cell suspensions were generated by enzymatic digestion. Cells were then sorted by fluorescence-activated cell sorting (FACS) based on GFP or tdTomato expression. RNA-expression profiles for each group were obtained using the Smart-seq platform. Thi study revealed the differential expression of VSMCs from different embryonic origin in both sexes.

ORGANISM(S): Mus musculus

PROVIDER: GSE329247 | GEO | 2026/05/03

REPOSITORIES: GEO

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Project description:Background: Acute thoracic aortic dissection (ATAD) is a fatal condition characterized by tear of intima and formation of false lumen whereby leading to the rupture of aorta. To better understand the potential mechanism of ATAD, we analyzed characterization of different cell types between ATAD and control group and predicted interactions among different cell types which might promote the progression of ATAD. Methods: Single-cell RNA sequencing (scRNA-seq) was performed including 5 patients with ATAD and 4 healthy controls. Cells were digested from ascending aortic tissues and subpopulations of most cell types were identified on the basis of scRNA-seq data. The gene expression profiles of each cell type and related changes between ATAD and control group were analyzed via bioinformatic analysis. We also predicted potential interaction among different cell types and verified the results by immunohistochemistry (IHC) and immunofluorescence (IF). Results: We got 8 cell types from human ascending aorta and 50 subpopulations were identified after re-clustering including vascular smooth muscle cells (VSMCs), endothelial cells, fibroblasts, neutrophils, monocytes and macrophages. Higher proportion of synthetic VSMCs, dysfunctional neutrophils and monocytes were seen in ATAD group compared with control group. Next, we predicted cell differentiation trajectory of VSMCs, fibroblasts and neutrophils via CytoTRACE, then identified subpopulations with higher differentiation potential. Moreover, the hub genes of VSMCs, fibroblasts and neutrophils were examined by weighted gene co-expression network analysis. Further analysis revealed that six transmembrane epithelial antigen of prostate 4 metalloreductase (STEAP4) might be a new marker for isolation of synthetic VSMCs by verification with IHC and IF. We also found synthetic VSMCs-derived C-X-C motif chemokine ligand 12 (CXCL12) might interact with neutrophils and fibroblasts via combination with C-X-C motif chemokine receptor 4 (CXCR4) and atypical chemokine receptor 3 (ACKR3), respectively, which might recruit neutrophils and induce transdifferentitation of FBs into synthetic VSMCs. Conclusion: In this study, we demonstrated integrative composition of different cell types in normal and dissected human ascending aorta and identified a new marker favorable to isolation of synthetic VSMCs. Furthermore, we also proposed a potential mechanism that synthetic VSMCs could interact with neutrophils and fibroblasts via CXCL12-CXCR4/ACKR3 axis whereby deteriorating the progression of ATAD. In total, these findings in our study might provide new insights to better understand the development and progression of ATAD.

Project description:Pathologies of large vessels, such as atherosclerosis and aneurysms tend to develop at specific sites in the vascular tree. The consistency with which these events emerge suggests that a combination of unique local stressors, particularly physical forces and disturbances in gene expression profiles underlies disease etiology. We sought to investigate whether transcriptional diversity in specific segments of the aorta could be used to identify emergence of site-restricted vascular disease. Transcriptional profiling was performed using single cell RNA-seq in the carotids, aortic arch, thoracic and abdominal aorta across both sexes. Analyses of the data identified sex-invariant region-specific differences that were further validated by immunocytochemistry. Analysis of vascular smooth muscle cell transcriptomics from distinct regions of the aorta and carotids showed a high degree of similarity, but also uncovered skewed expression of a small percentage of transcripts (7.2%) towards particular vascular segments (carotid, aortic arch, thoracic and abdominal aorta). In silico cross-reference of genes known to be associated with vascular disease with the unique transcriptional signatures validated our proposed hypothesis. Specifically, we found correlations between localized-diseased causing GWAS candidate genes and region-enriched signatures. Pair-wise comparison between anatomic regions across sexes identified regional sex-specific gene signatures highlighting prominent regional-sex dependent differences were observed in vSMCs of the thoracic and abdominal aorta, consistent with sex-specific burden of aneurysm in these regions. Of these regional sex-enriched candidates’, Mcam/CD146, showed ventral thoraco-abdominal distribution, enriched expression in females and it was significantly reduced in the AngII / hypercholesterolemic model of aortic aneurysm. Furthermore, induction of aneurysms in mice lacking Mcam/CD146 resulted in larger lesions and accelerated death due to dissection.

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SMART-seq profiling of the ascending aorta and aortic arch from male and female Wnt1-Cre;Rosa26-mTmG mice

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