Lin Chien-Jung, Keating Campbell, Roth Robyn, Caliskan Yasar, Nazzal Mustafa, Exil Vernat, DiPaolo Richard, Verma Divya Ratan, Harjai Kishore, Zayed Mohamed, Lin Chieh-Yu, Mecham Robert P, Jain Ajay K
Division of Cardiology, Department of Internal Medicine, SSM-Saint Louis University Hospital, St. Louis, MO 63110, USA.
Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
J Cardiovasc Dev Dis. 2024 Nov 1;11(11):349. doi: 10.3390/jcdd11110349.
Thoracic and abdominal aortic aneurysms (TAAs and AAAs, respectively) share morphological features but have distinct clinical and hereditary characteristics. Studies using bulk RNA comparisons revealed distinct patterns of gene expression in human TAA and AAA tissues. However, given the summative nature of bulk RNA studies, these findings represent the totality of gene expression without regards to the differences in cellular composition. Single-cell RNA sequencing provides an opportunity to interrogate cell-type-specific transcriptomes. Single cell RNA sequencing datasets from mouse TAA (GSE153534) and AAA (GSE164678 and GSE152583) with respective controls were obtained from the Gene Expression Omnibus. Bioinformatic analysis was performed with the Seurat 4, clusterProfiler, and Connectome software packages (V1.0.1). Immunostaining was performed with standard protocols. Within normal and aneurysmal aortae, three unique populations of cells that express smooth muscle cell (SMC) markers were identified (SMC1, SMC2, and SMCmod). A greater proportion of TAA SMCs clustered as a unique population, SMCmod, relative to the AAA SMCs (38% vs. 10-12%). These cells exhibited transcriptional features distinct from other SMCs, which were characterized by and expression. Genes upregulated in TAA SMCs were enriched for the Reactome terms "extracellular matrix organization" and "insulin-like growth factor (IGF) transport and uptake by IGF binding proteins (IGFBPs)", indicating a role for in TAA pathogenesis. Regulon analysis revealed transcription factors enriched in TAAs and AAAs. Validating these mouse bioinformatic findings, immunostaining demonstrated that both IGFBP2 and TNFRSF11B proteins increased in human TAAs compared to AAAs. These results highlight the unique cellular composition and transcriptional signature of SMCs in TAAs and AAAs. Future studies are needed to reveal the pathogenetic pathways of and .
胸主动脉瘤和腹主动脉瘤（分别为TAA和AAA）具有共同的形态学特征，但临床和遗传特征不同。使用批量RNA比较的研究揭示了人类TAA和AAA组织中不同的基因表达模式。然而，鉴于批量RNA研究的汇总性质，这些发现代表了基因表达的总体情况，而未考虑细胞组成的差异。单细胞RNA测序为研究细胞类型特异性转录组提供了机会。从小鼠TAA（GSE153534）和AAA（GSE164678和GSE152583）以及各自的对照中获得的单细胞RNA测序数据集来自基因表达综合数据库。使用Seurat 4、clusterProfiler和Connectome软件包（V1.0.1）进行生物信息学分析。采用标准方案进行免疫染色。在正常和动脉瘤性主动脉中，鉴定出了三个表达平滑肌细胞（SMC）标志物的独特细胞群（SMC1、SMC2和SMCmod）。相对于AAA SMC，TAA SMC中更大比例聚集成一个独特的群体SMCmod（38%对10 - 12%）。这些细胞表现出与其他SMC不同的转录特征，其特征为[此处原文缺失相关内容]和[此处原文缺失相关内容]表达。在TAA SMC中上调的基因在Reactome术语“细胞外基质组织”和“胰岛素样生长因子（IGF）通过IGF结合蛋白（IGFBP）的转运和摄取”中富集，表明[此处原文缺失相关内容]在TAA发病机制中的作用。调控子分析揭示了在TAA和AAA中富集的转录因子。通过免疫染色验证这些小鼠生物信息学发现，结果表明与AAA相比，人类TAA中IGFBP2和TNFRSF11B蛋白均增加。这些结果突出了TAA和AAA中SMC独特的细胞组成和转录特征。未来需要开展研究以揭示[此处原文缺失相关内容]和[此处原文缺失相关内容]的致病途径。
