Age-related epithelial defects limit thymic function and regeneration [visium]

The thymus is essential for establishing adaptive immunity yet undergoes age-related involution that leads to compromised immune responsiveness. The thymus is also extremely sensitive to acute insult and although capable of regeneration, this capacity declines with age for unknown reasons. We applied single-cell and spatial transcriptomics, lineage-tracing and advanced imaging to define age-related changes in non-hematopoietic stromal cells and discovered the emergence of two atypical thymic epithelial cell (TEC) states. These age-associated (aa)TECs formed high-density peri-medullary epithelial clusters that were devoid of thymocytes; an accretion of non-productive thymic tissue that worsened with age, exhibited features of epithelial-to-mesenchymal transition (EMT), and was associated with downregulation of FOXN1. Interaction analysis revealed that the emergence of aaTEC drew tonic signals from other functional TEC populations at baseline acting as a sink for TEC growth factors. Following acute injury, aaTEC expanded substantially, further perturbing trophic regeneration pathways and correlating with defective repair of the involuted thymus. These findings therefore define a unique feature of thymic involution linked to immune aging and could have implications for developing immune boosting therapies in older individuals. Spatial transcriptomic profiles of thymus from 2-month-old and 18-month-old mice at steady state (day 0; d0).胸腺对于适应性免疫的建立至关重要，却会发生年龄相关性萎缩，进而导致免疫应答受损。胸腺对急性损伤也极为敏感，尽管具备再生能力，但该能力随年龄增长而下降，具体机制尚不明确。本研究采用单细胞及空间转录组学、谱系追踪与先进成像技术，对非造血基质细胞的年龄相关变化进行系统解析，发现了两种非典型胸腺上皮细胞（thymic epithelial cell, TEC）状态的出现。这类年龄相关胸腺上皮细胞（age-associated TEC, aaTEC）会形成高密度髓周上皮簇，该簇内缺乏胸腺细胞；这种非功能性胸腺组织的堆积随年龄增长而加剧，且呈现上皮间质转化（epithelial-to-mesenchymal transition, EMT）特征，同时伴随FOXN1的表达下调。相互作用分析显示，aaTEC在基础稳态下会从其他功能性TEC群体获取紧张性信号，并充当TEC生长因子的吸收池。急性损伤后，aaTEC会大幅扩增，进一步干扰营养再生通路，并与萎缩胸腺的修复缺陷密切相关。综上，本研究明确了与免疫衰老相关的胸腺萎缩的独特特征，其结果或可为老年人群的免疫增强治疗开发提供参考。本数据集涵盖稳态条件下（第0天，d0）2月龄与18月龄小鼠的胸腺空间转录组图谱。