Abstract Tu0002: Newly Differentiated Smooth Muscle Cells from Sca1 Progenitors Generate De Novo Elastic Fibers in the False Lumen Wall Following Aortic Dissection

Background: Aortic dissection (AD) often leads to a false lumen aneurysm as a life-threatening complication during its late phase. Previous preclinical studies of AD have predominantly focused on the mechanism of disease initiation and the acute phase. Therefore, the pathophysiology underlying false lumen aneurysm formation and stability remains poorly understood. Methods and Results: To determine pathological features of false lumen aneurysm, a time course study was performed using AD induced in mice by administration of β-aminopropionitrile (BAPN, 0.5% wt/vol, drinking water). After 4 weeks of BAPN administration, mice developed a false lumen formation in the descending aorta with minimal dilatation, primarily filled with fresh thrombus. However, after 12 weeks of BAPN administration, the false lumen exhibited significant vascular wall thickening and severe aneurysm formation, accompanied by organized thrombus. Interestingly, the thickened vascular wall of the false lumen contained substantial amounts of disorganized elastic fibers. qPCR revealed a significantly increased abundance of elastin mRNA and other elastic fiber-related genes, such as Fbn1 , Fbln5, and Lox , in AD after 12 weeks of BAPN administration compared to mice with normal aortas. These findings indicate that elastic fibers are newly synthesized in response to AD progression. Importantly, mice that succumbed to false lumen rupture during the study did not exhibit evidence of de novo elastic fiber formation, suggesting that these newly synthesized fibers contribute to stabilization of the false lumen wall. Immunostaining revealed that cells of the false lumen wall were composed predominantly of cells expressing smooth muscle cell (SMC) markers, such as MYH11 and αSMA. However, the lineage-tracing study showed that these cells did not originate from resident SMCs in the native aortic wall. Of note, these cells expressed stem cell antigen 1 (Sca1), a marker for progenitor cells. In situ hybridization showed that Sca1 progenitor cells were coincident with newly synthesized elastin mRNA. Conclusion: Following aortic dissection, Sca1 progenitor cells differentiated into SMCs and synthesized de novo elastic fibers in the false lumen wall, which protected against false lumen rupture.