Characterizing Immune Cell Sexual Dimorphism in Intracranial Aneurysm via Rat IA Model and Spatial Transcriptomics 2306413

Abstract

Abstract Introduction Intracranial aneurysm (IA) prevalence in the general population can be as high as 3%. Most IAs are diagnosed incidentally. However, IAs can cause subarachnoid hemorrhage and are responsible for high mortality and morbidity. No effective medical therapy is available for IA. Female sex is a known risk factor for IA formation and rupture. In addition, the rupture risk escalates in postmenopausal women, suggesting that low estrogen level promotes ruptures. This study investigates whether immune cell sexual dimorphism in IA exists and whether it promotes IA formation, growth, and rupture. Subsequently, the study will evaluate how low estrogen exacerbates aneurysms by defining the responsible pathways. Methods We will perform spatial transcriptomics (GeoMx DSP) on formalin-fixed, paraffin-embedded aneurysm tissues from established rat IA models that can reproduce human pathology. The study comprises six groups, each containing three rats: the control male and female groups, the male and female aneurysm-induction groups, the induction after ovariectomy group, and the induction after ovariectomy and hormone replacement group. The GeoMx morphology markers are CD68, α-smooth muscle actin, and androgen receptor. The findings will be validated in human IA tissues from both sexes using single-cell spatial transcriptomics. Results The preliminary data demonstrate CD68+ macrophages infiltrating a male aneurysm on GeoMx immunofluorescent images. Two male control arteries showed no infiltration. The study aims to identify sexual dimorphism in macrophages by analyzing ontogeny, transcriptomic profiles, and interactions with lymphocytes, such as Th17 CD4+ T cells. The study also examines the relationships among other innate and adaptive immune cells in the context of IA, across sex and hormonal status. Conclusion Understanding the immune cell sexual dimorphism and its contribution to IA will aid the development of therapeutics tailored to women and postmenopausal women, who experience the greatest disease burden. Funding Source Joint support from Seoul National University College of Medicine Physician Scientist Training Program and the MD-PhD/Medical Scientist Training Program through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea. Topic Categories Translational and Interventional Immunology (TI)