解构局灶性缺血性血管性痴呆中的细胞间相互作用组以用于治疗应用。
Deconstructing the intercellular interactome in vascular dementia with focal ischemia for therapeutic applications.
作者信息
Tian Min, Kawaguchi Riki, Shen Yang, Machnicki Michal, Villegas Nikole G, Cooper Delaney R, Montgomery Natalia, Cai Ying, Haring Jacqueline, Lan Ruirui, Yuan Angelina H, Williams Christopher K, Magaki Shino, Vinters Harry V, Zhang Ye, De Biase Lindsay M, Silva Alcino J, Carmichael S Thomas
机构信息
Department of Neurology, the David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
Department of Psychiatry and Biobehavioral Sciences, the David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
出版信息
Cell. 2025 Jun 24. doi: 10.1016/j.cell.2025.06.002.
Vascular dementia (VaD), the second-leading cause of dementia, is primarily a white matter ischemic disease with no direct therapies. Cell-cell interactions within lesion sites dictate disease progression or repair. To elucidate key intercellular pathways, we employ a VaD mouse model with focal ischemia replicating many elements of the complex pathophysiology of human VaD combined with transcriptomic and functional analyses. By integrating cell-type-specific mouse VaD transcriptomes and human VaD single-nucleus RNA sequencing (snRNA-seq) data plus a custom ligand-receptor database (4,053 human and 2,032 mouse pairs), conserved dysregulated intercellular pathways in both species are identified. We demonstrate that two intercellular signaling systems, Serpine2-Lrp1 and CD39-A3AR, are disrupted in VaD. Reduced Serpine2 expression enhances oligodendrocyte progenitor cell (OPC) differentiation, promoting repair, while an A3AR-specific agonist-currently in clinical trials for psoriasis-restores tissue integrity and behavioral function in the VaD model. This study reveals intercellular signaling targets and provides a foundation for developing innovative therapies for VaD.
血管性痴呆（VaD）是痴呆的第二大常见病因，主要是一种白质缺血性疾病，目前尚无直接治疗方法。病变部位的细胞间相互作用决定了疾病的进展或修复。为了阐明关键的细胞间通路，我们采用了一种局灶性缺血的VaD小鼠模型，该模型复制了人类VaD复杂病理生理学的许多要素，并结合了转录组学和功能分析。通过整合细胞类型特异性的小鼠VaD转录组和人类VaD单核RNA测序（snRNA-seq）数据以及一个定制的配体-受体数据库（4053个人类和2032个小鼠配对），确定了两个物种中保守的失调细胞间通路。我们证明，在VaD中，两个细胞间信号系统Serpine2-Lrp1和CD39-A3AR受到破坏。Serpine2表达降低可增强少突胶质细胞祖细胞（OPC）的分化，促进修复，而一种A3AR特异性激动剂（目前正在进行银屑病的临床试验）可恢复VaD模型中的组织完整性和行为功能。这项研究揭示了细胞间信号转导靶点，为开发VaD的创新疗法提供了基础。
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