The synovium, a thin layer of tissue that is adjacent to the joints and secretes synovial fluid, undergoes changes in aging that contribute to intense shoulder pain and other joint diseases. However, the mechanism underlying human synovial aging remains poorly characterized. Here, we generated a comprehensive transcriptomic profile of synovial cells present in the subacromial synovium from young and aged individuals. By delineating aging-related transcriptomic changes across different cell types and their associated regulatory networks, we identified two subsets of mesenchymal stromal cells (MSCs) in human synovium, which are lining and sublining MSCs, and found that angiogenesis and fibrosis-associated genes were upregulated whereas genes associated with cell adhesion and cartilage development were downregulated in aged MSCs. Moreover, the specific cell-cell communications in aged synovium mirrors that of aging-related inflammation and tissue remodeling, including vascular hyperplasia and tissue fibrosis. In particular, we identified forkhead box O1 (FOXO1) as one of the major regulons for aging differentially expressed genes (DEGs) in synovial MSCs, and validated its downregulation in both lining and sublining MSC populations of the aged synovium. In human FOXO1-depleted MSCs derived from human embryonic stem cells, we recapitulated the senescent phenotype observed in the subacromial synovium of aged donors. These data indicate an important role of FOXO1 in the regulation of human synovial aging. Overall, our study improves our understanding of synovial aging during joint degeneration, thereby informing the development of novel intervention strategies aimed at rejuvenating the aged joint.

中文翻译：

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通过单核转录组分析鉴定 FOXO1 作为人类滑膜中的衰老保护剂。


滑膜是邻近关节并分泌滑液的薄层组织，随着年龄的增长，滑膜会发生变化，导致剧烈的肩部疼痛和其他关节疾病。然而，人类滑膜衰老的机制仍然知之甚少。在这里，我们生成了年轻和老年人肩峰下滑膜中滑膜细胞的全面转录组学谱。通过描绘不同细胞类型及其相关调控网络中与衰老相关的转录组变化，我们鉴定了人类滑膜中的两个间充质基质细胞（MSC）子集，即衬层和亚衬层间充质干细胞，并发现血管生成和纤维化相关基因上调而与细胞粘附和软骨发育相关的基因在衰老的间充质干细胞中下调。此外，衰老滑膜中特定的细胞间通讯反映了与衰老相关的炎症和组织重塑，包括血管增生和组织纤维化。特别是，我们确定了叉头框 O1 (FOXO1) 是滑膜 MSC 中衰老差异表达基因 (DEG) 的主要调节子之一，并验证了其在衰老滑膜的内层和亚内层 MSC 群体中的下调。在源自人胚胎干细胞的人 FOXO1 耗尽的 MSC 中，我们重现了在老年供体肩峰下滑膜中观察到的衰老表型。这些数据表明FOXO1在调节人类滑膜衰老中发挥着重要作用。总体而言，我们的研究提高了我们对关节退化过程中滑膜老化的理解，从而为旨在使老化关节恢复活力的新型干预策略的开发提供信息。