Characterizing Infiltrating Macrophages in Intracranial Aneurysm with IA Animal Models and Spatial Transcriptomics

Translational Stroke Research (2026) 17:48 https://doi.org/10.1007/s12975-026-01437-6 REVIEW Characterizing Infiltrating Macrophages in Intracranial Aneurysm with IA Animal Models and Spatial Transcriptomics Hosu Kim1 · Tomohiro Aoki2 · Masahiko Itani2,3 · Isao Ono4 · Yong-Hee Kim5 · Chung-Gyu Park1,5,6,7,8,9,10 Received: 27 January 2026 / Revised: 6 April 2026 / Accepted: 13 April 2026 © The Author(s) 2026 Abstract Intracranial aneurysm (IA) prevalence in the general population can be as high as 3%. Most IAs are asymptomatic and diagnosed incidentally. However, IAs can cause subarachnoid hemorrhage (SAH), which is responsible for high mortality and morbidity. No effective medical therapy is currently available to control the IA and reduce the SAH risk. Understanding IA pathophysiology to identify potential targets is, therefore, an essential clinical objective. IAs typically form at arterial bifurcations and are characterized by macrophage infiltration. Macrophages are innate immune cells that present antigens to adaptive immune cells and promote inflammation. The potential role of macrophages in IA was demonstrated when inhibiting the macrophage recruitment contained aneurysm formation or growth. Recent advances in spatial transcriptomics enable the study of infiltrating macrophages within the aneurysmal lesion and the identification of pathogenic changes that were previously challenging to probe. While sample availability may limit the use of spatial transcriptomics, judicious use of IA animal models will enable translational research to address unmet clinical needs. With spatial insights and refined animal models, researchers can identify key characteristics of infiltrating macrophages, including their ontogeny, transcriptomic profiles, and interactions with other cell subsets. This review article summarizes the current understanding of infiltrating macrophages in IAs and introduces available animal models of IA and spatial transcriptomics approaches for studying macrophage infiltration. Keywords Intracranial aneurysm · Macrophages · Animal models · Spatial transcriptomics Hosu Kim and Tomohiro Aoki contributed equally to this work. Responsible Editor: Samuel Shin Chung-Gyu Park 5 Transplantation Research Institute, Medical Research Center, Seoul National University College of Medicine, Seoul, Republic of Korea 6 Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea 7 Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, Republic of Korea 1 Translational Medicine Major, Department of Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea 2 Department of Pharmacology, the Jikei University School of Medicine, Tokyo, Japan 3 Department of Neurosurgery, Kyoto University Graduate School of Medicine, Kyoto, Japan 8 4 Department of Neurosurgery, Hikone Municipal Hospital, Shiga, Japan Institute of Endemic Diseases, Seoul National University College of Medicine, Seoul, Republic of Korea 9 Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea 10 BK21 Plus Biomedical Science Project, Seoul National University College of Medicine, Seoul, Republic of Korea 13 48 Page 2 of 16 Introduction Intracranial aneurysms (IAs) are common in the general population, with a reported prevalence of up to 3% [1, 2]. Ruptured IAs lead to subarachnoid hemorrhages (SAH), associated with high mortality and morbidity [3–5]. Currently, no approved medical therapy exists to prevent the development or progression of IA [6]. Surgical or endovascular procedures carry a non-negligible risk, and there is a definite unmet clinical need for effective medical therapy [7, 8]. Understanding the immunological contributions to disease pathogenesis can accelerate the development of medical therapies. For example, improved understanding of the PD-1/PD-L1/CTLA-4 axes has led to the development of effective anticancer immunotherapies [9–12]. The initial trigger and the factors that promote growth and rupture require further investigation. However, non-physiological hemodynamic forces, low wall shear stress, and disrupted laminar flow are thought to contribute to the pathophysiology of IA [2, 13, 14]. The later stage involves a weakened arterial wall, enlarged by hemodynamic forces, with immune cell infiltration. The role of immune cell infiltration remains poorly defined, and understanding the mechanisms underlying these cells could provide valuable insights for the development of medical therapies [2]. Macrophages account for the bulk of immune cell infiltration [15–18]. Inhibiting macrophage infiltration also reduced IA growth and rupture in animal studies [19–21]. However, the causal relationship between macrophage infiltration and IA remains unclear and warrants further investigation. The immune system comprises heterogeneous cell populations, and probing a specific cell subset for its contribution to pathology can therefore be challenging. Although there is no single perfect toolkit, spatial transcriptomics projects RNA expression patterns onto tissue architectures, enabling the discovery of previously unrecognized structures and an in-depth understanding of immune cell spatial distribution and activity profiles [22, 23]. For instance, Lai et al. used Stereo-seq, in addition to single-cell transcriptomics, to identify previously unrecognized tertiary lymphoid organs in carotid plaques. They demonstrated robust B-cell activity in these structures in patients undergoing carotid endarterectomy [24]. In IAs, infiltrating macrophage transcriptomics can be analyzed spatially, revealing their presence in the tunica intima, media, and adventitia, as well as adjacent brain or extracranial lymphoid structures. Unlike single-cell transcriptomics, spatial transcriptomics can determine whether infiltrating macrophages in the tunica intima and adventitia share similar transcriptomic profiles, providing insights difficult to obtain with single-cell transcriptomics alone [23, 25–27]. A key obstacle to studying infiltrating macrophages 13 Translational Stroke Research (2026) 17:48 in IAs using spatial transcriptomics is the limited availability of high-quality human samples. Collaboration will be required to collect enough samples. Established animal models will mitigate some of the difficulties. As with other diseases, the individual IA clinical courses will depend on aneurysm size, location, morphology, risk factors, and other demographic information such as age or sex [28, 29]. Accounting for disease heterogeneity will be important when studying infiltrating macrophages using spatial transcriptomics. For example, IAs at arterial bifurcations are exposed to distinct hemodynamic stresses, which are likely to alter transcriptomic patterns via mechanotransduction [30]. Finally, female sex is a risk factor, and aneurysms freque (...truncated)