Wu Hong, Yang Xiaoping, Chen Ting, Yu Baoqi, Chen Mengjia, Wang Ting, Jiang Liujun, Zhang Bohuan, Zhou Xuhao, Cheng Junning, Chen Kai, Zhang Tao, Hu Yanhua, Xu Simon, Lian Jiangfang, Zhang Hongkun, Xiao Qingzhong, Ye Honghua, Xu Qingbo
Department of Cardiology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.
Department of Cardiology, Ningbo Institute of Innovation for Combined Medicine and Engineering, Lihuili Hospital Affiliated to Ningbo University, Ningbo University, Ningbo, Zhejiang, 315000, China.
Adv Sci (Weinh). 2025 Feb;12(7):e2408996. doi: 10.1002/advs.202408996. Epub 2024 Dec 27.
Aortic aneurysm is a life-threatening disease caused by progressive dilation of the aorta and weakened aortic walls. Its pathogenesis involves an imbalance between connective tissue repair and degradation. CD34 cells comprise a heterogeneous population that exhibits stem cell and progenitor cell properties. However, the role of CD34 cells in abdominal aortic aneurysm (AAA) remains unclear. In this study, downregulated CD34 expression is observed in aneurysmal aortas from both patients and mouse models compared to that in non-dilated aortas. Furthermore, by combining Cd34-CreER;Rosa26-tdTomato;(Apoe) lineage tracing, bone marrow transplantation, and single-cell sequencing, it is found that during AAA development, non-bone marrow CD34 cells are activated to transdifferentiate into Periostin myofibroblasts, thereby contributing to the formation of fibrotic collars. Dual recombinase-based lineage tracing confirms the presence and involvement of CD34/Periostin myofibroblasts in fibrotic collar formation during AAA development. Functionally, selective depletion of systemic or non-bone marrow CD34 cells, as well as CD34/Periostin myofibroblasts, by diphtheria toxin significantly exacerbates AAA progression and increases disease mortality. Mechanistically, it is identified that the PDGF-PDGFRb-PI3K axis is indispensable for Periostin myofibroblast generation from non-bone marrow CD34 cells in AAA, offering a new therapeutic target for patients with AAA at a high risk of rupture.
主动脉瘤是一种由主动脉进行性扩张和主动脉壁薄弱引起的危及生命的疾病。其发病机制涉及结缔组织修复与降解之间的失衡。CD34细胞是一个具有干细胞和祖细胞特性的异质性群体。然而，CD34细胞在腹主动脉瘤（AAA）中的作用仍不清楚。在本研究中，与未扩张的主动脉相比，在患者和小鼠模型的动脉瘤主动脉中均观察到CD34表达下调。此外，通过结合Cd34-CreER;Rosa26-tdTomato;(Apoe)谱系追踪、骨髓移植和单细胞测序，发现在AAA发展过程中，非骨髓CD34细胞被激活并转分化为骨膜蛋白成肌纤维细胞，从而促进纤维化环的形成。基于双重组酶的谱系追踪证实了CD34/骨膜蛋白成肌纤维细胞在AAA发展过程中纤维化环形成中的存在和参与。在功能上，通过白喉毒素选择性消耗全身或非骨髓CD34细胞以及CD34/骨膜蛋白成肌纤维细胞，会显著加剧AAA进展并增加疾病死亡率。在机制上，已确定PDGF-PDGFRb-PI3K轴对于AAA中非骨髓CD34细胞生成骨膜蛋白成肌纤维细胞是不可或缺的，这为具有高破裂风险的AAA患者提供了一个新的治疗靶点。
