IntroductionWerner Syndrome (WS) is a rare autosomal recessive genetic disorder in which aging accelerates after puberty and causes the early onset of aging-associated symptoms such as cataracts, graying, loss of hair, diabetes, atherosclerosis, and cancers. The responsible gene is WRN, which is a member of the RecQ helicase family and plays an important role in DNA replication, repair, and telomere maintenance. While WS is rare globally, its incidence in Japan is significantly higher, with an estimated 2000 patients 1). After cancer, atherosclerosis is the leading cause of death in WS patients. A study reported that 17 out of 43 WS patients (39.5%) were diagnosed with atherosclerosis 2). Atherosclerosis involves complex interactions between macrophages (Mφ), vascular endothelial cells (VECs), and vascular smooth muscle cells (VSMCs). Although animal models like ApoE-/- mice provide in vivo insights, they fail to recapitulate WS-specific pathology, as a mouse model of WS does not recapitulate atherosclerosis 3). Moreover, a recent study reports that WRN-deficient embryonic stem cells differentiated into endothelial cells do not show features of premature aging 4). Therefore, the pathogenesis of atherosclerosis in WS remains unclear. As an alternative approach to investigate this, in vitro differentiation of atherosclerosis-associated cells from WS patient-specific pluripotent stem cells offers a promising platform for studying the mechanism of atherosclerosis in WS. Recently, we developed an innovative two-dimensional (2D) in vitro model of atherosclerosis using Mφ and vascular cells derived from WS patient-specific induced pluripotent stem cells (iPSCs) with a uniform genetic background. We uncovered type I interferon (IFN) signaling triggered by the reactivation of retrotransposable elements (RTE) in WS patient iPSC-derived Mφ, adversely affecting vascular health in co-culture with iPS-derived vascular cells 5). However, the low yield of the current system hinders its suitability for multi-omics analysis targeting epigenetic abnormalities and restricts its potential for therapeutic applications and scalability in high-throughput drug screening, which demands a substantial number of cells. To address this, we have developed a novel doxycycline-inducible cell immortalization technique through genetic manipulation to create immortalized Mφ, VEC, and VSMC from human iPSC, with robust expansion potential (Paul et al, unpublished) (Japanese patent application: 2021-109513). Using these immortalized cells, we established a scalable two-dimensional (2D) Sudip Kumar Paul2022. 5 ～ 2024. 4Naoya Takayama, Associate ProfessorDepartment of Regenerative Medicine, Chiba University Graduate School of Medicine― 244 ―Establishment of in vitro atherosclerosis model using immortalized cells derived from human iPSCs
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