Abstract
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-CreERT2;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.