PDF(Pubmed)
Abstract：
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.
摘要：
滑膜,与关节相邻并分泌滑液的薄层组织，经历衰老的变化，导致强烈的肩部疼痛和其他关节疾病。然而,人类滑膜老化的潜在机制仍未得到充分表征。这里,我们从年轻和老年个体的肩峰下滑膜中获得了滑膜细胞类型的全面概况。通过描绘细胞类型及其相关调节网络之间的衰老相关转录组变化，我们确定了人滑膜中间充质基质细胞（MSC）的两个亚群，它们是MSC的衬里和衬里，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过程中下调。此外，老年滑膜中特定的细胞间通讯反映了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,我们确定了叉头盒O1（FOXO1）是滑膜MSCs老化DEG的主要调节子之一，并验证了其在老年滑膜的衬里和衬里MSC群体中的下调。在源自人类胚胎干细胞的人FOXO1耗尽的MSCs中，我们概述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在调节人滑膜老化中的重要作用。总的来说,我们的研究提高了我们对关节变性过程中滑膜老化的理解，从而为开发旨在使老年关节恢复活力的新疗法提供信息。
