Department of Cardiovascular Surgery, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, China.
State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Centre for Cardiovascular Diseases, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China.
BMC Med. 2023 Oct 20;21(1):396. doi: 10.1186/s12916-023-03077-1.
Thoracic aortic dissection (TAD) is a life-threatening disease caused by an intimal tear in the aorta. The histological characteristics differ significantly between the tear area (TA) and the distant area. Previous studies have emphasized that certain specific genes tend to cluster at the TA. Obtaining a thorough understanding of the precise molecular signatures near the TA will assist in discovering therapeutic strategies for TAD.
We performed a paired comparison of the pathological patterns in the TA with that in the remote area (RA). We used Tomo-seq, genome-wide transcriptional profiling with spatial resolution, to obtain gene expression signatures spanning from the TA to the RA. Samples from multiple sporadic TAD patients and animal models were used to validate our findings.
Pathological examination revealed that the TA of TAD exhibited more pronounced intimal hyperplasia, media degeneration, and inflammatory infiltration compared to the RA. The TA also had more apoptotic cells and CD31α-SMA cells. Tomo-seq revealed four distinct gene expression patterns from the TA to the RA, which were inflammation, collagen catabolism, extracellular matrix remodeling, and cell stress, respectively. The spatial distribution of genes allowed us to identify genes that were potentially relevant with TAD. NINJ1 encoded the protein-mediated cytoplasmic membrane rupture, regulated tissue remodeling, showed high expression levels in the tear area, and co-expressed within the inflammatory pattern. The use of short hairpin RNA to reduce NINJ1 expression in the beta-aminopropionitrile-induced TAD model led to a significant decrease in TAD formation. Additionally, it resulted in reduced infiltration of inflammatory cells and a decrease in the number of CD31α-SMA cells. The NINJ1-neutralizing antibody also demonstrated comparable therapeutic effects and can effectively impede the formation of TAD.
Our study showed that Tomo-seq had the advantage of obtaining spatial expression information of TAD across the TA and the RA. We pointed out that NINJ1 may be involved in inflammation and tissue remodeling, which played an important role in the formation of TAD. NINJ1 may serve as a potential therapeutic target for TAD.
胸主动脉夹层（TAD）是一种由主动脉内膜撕裂引起的危及生命的疾病。撕裂区域（TA）和远处区域（RA）的组织学特征有显著差异。既往研究强调，某些特定基因往往在 TA 处聚集。深入了解 TA 附近的精确分子特征将有助于发现 TAD 的治疗策略。
我们对 TA 与 RA 的病理模式进行配对比较。我们使用 Tomo-seq，即具有空间分辨率的全基因组转录谱分析，获取从 TA 到 RA 的基因表达特征。使用来自多个散发性 TAD 患者和动物模型的样本验证我们的发现。
病理检查显示，TAD 的 TA 比 RA 有更明显的内膜增生、中膜退变和炎症浸润。TA 也有更多的凋亡细胞和 CD31α-SMA 细胞。Tomo-seq 揭示了从 TA 到 RA 的四个不同的基因表达模式，分别为炎症、胶原分解代谢、细胞外基质重塑和细胞应激。基因的空间分布使我们能够识别与 TAD 相关的潜在基因。NINJ1 编码的蛋白介导细胞质膜破裂，调节组织重塑，在撕裂区域表达水平较高，与炎症模式共同表达。在β-氨基丙腈诱导的 TAD 模型中使用短发夹 RNA 降低 NINJ1 表达导致 TAD 形成显著减少。此外，还减少了炎症细胞的浸润和 CD31α-SMA 细胞的数量。NINJ1 中和抗体也表现出相当的治疗效果，可有效阻止 TAD 的形成。
我们的研究表明，Tomo-seq 具有获取 TAD 跨越 TA 和 RA 的空间表达信息的优势。我们指出，NINJ1 可能参与炎症和组织重塑，在 TAD 的形成中发挥重要作用。NINJ1 可能成为 TAD 的潜在治疗靶点。
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