Liu Xuanyu, Chen Wen, Zhu Guoyan, Yang Hang, Li Wenke, Luo Mingyao, Shu Chang, Zhou Zhou
State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Beijing Key Laboratory for Molecular Diagnostics of Cardiovascular Diseases, Center of Laboratory Medicine, Fuwai Hospital, Beijing, China.
Cell Discov. 2022 Feb 8;8(1):11. doi: 10.1038/s41421-021-00362-2.
Thoracic aortic aneurysm and dissection (TAAD) is a life-threatening condition characterized by medial layer degeneration of the thoracic aorta. A thorough understanding of the regulator changes during pathogenesis is essential for medical therapy development. To delineate the cellular and molecular changes during the development of TAAD, we performed single-cell RNA sequencing of thoracic aortic cells from β-aminopropionitrile-induced TAAD mouse models at three time points that spanned from the early to the advanced stages of the disease. Comparative analyses were performed to delineate the temporal dynamics of changes in cellular composition, lineage-specific regulation, and cell-cell communications. Excessive activation of stress-responsive and Toll-like receptor signaling pathways contributed to the smooth muscle cell senescence at the early stage. Three subpopulations of aortic macrophages were identified, i.e., Lyve1 resident-like, Cd74 antigen-presenting, and Il1rn/Trem1 pro-inflammatory macrophages. In both mice and humans, the pro-inflammatory macrophage subpopulation was found to represent the predominant source of most detrimental molecules. Suppression of macrophage accumulation in the aorta with Ki20227 could significantly decrease the incidence of TAAD and aortic rupture in mice. Targeting the Il1rn/Trem1 macrophage subpopulation via blockade of Trem1 using mLR12 could significantly decrease the aortic rupture rate in mice. We present the first comprehensive analysis of the cellular and molecular changes during the development of TAAD at single-cell resolution. Our results highlight the importance of anti-inflammation therapy in TAAD, and pinpoint the macrophage subpopulation as the predominant source of detrimental molecules for TAAD. Targeting the IL1RN/TREM1 macrophage subpopulation via blockade of TREM1 may represent a promising medical treatment.
胸主动脉瘤和夹层（TAAD）是一种危及生命的疾病，其特征是胸主动脉中层退变。深入了解发病机制过程中的调节因子变化对于开发医学治疗方法至关重要。为了描绘TAAD发展过程中的细胞和分子变化，我们对β-氨基丙腈诱导的TAAD小鼠模型在疾病早期到晚期的三个时间点的胸主动脉细胞进行了单细胞RNA测序。进行了比较分析，以描绘细胞组成、谱系特异性调节和细胞间通讯变化的时间动态。应激反应和Toll样受体信号通路的过度激活在疾病早期导致平滑肌细胞衰老。鉴定出了主动脉巨噬细胞的三个亚群，即Lyve1驻留样巨噬细胞、Cd74抗原呈递巨噬细胞和Il1rn/Trem1促炎巨噬细胞。在小鼠和人类中，均发现促炎巨噬细胞亚群是大多数有害分子的主要来源。用Ki20227抑制主动脉中巨噬细胞的积聚可显著降低小鼠TAAD和主动脉破裂的发生率。使用mLR12通过阻断Trem1靶向Il1rn/Trem1巨噬细胞亚群可显著降低小鼠的主动脉破裂率。我们首次在单细胞分辨率下对TAAD发展过程中的细胞和分子变化进行了全面分析。我们的结果强调了抗炎治疗在TAAD中的重要性，并指出巨噬细胞亚群是TAAD有害分子的主要来源。通过阻断TREM1靶向IL1RN/TREM1巨噬细胞亚群可能是一种有前景的医学治疗方法。
