Department of Orthopedics/Sports Medicine Center, State Key Laboratory of Trauma, Burn and Combined Injury, Southwest Hospital, Third Military Medical University, Chongqing, China.
Department of Gastroenterology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Front Immunol. 2023 May 8;14:1092778. doi: 10.3389/fimmu.2023.1092778. eCollection 2023.
Tendinopathy, the most common form of chronic tendon disorder, leads to persistent tendon pain and loss of function. Profiling the heterogeneous cellular composition in the tendon microenvironment helps to elucidate rational molecular mechanisms of tendinopathy.
In this study, through a multi-modal analysis, a single-cell RNA- and ATAC-seq integrated tendinopathy landscape was generated for the first time. We found that a specific cell subpopulation with low expression exhibited a higher level of inflammation, lower proliferation and migration ability, which not only promoted tendon injury but also led to microenvironment deterioration. Mechanistically, a motif enrichment analysis of chromatin accessibility showed that was an upstream regulator of PRDX2 transcription, and we confirmed that functional blockade of activity induced silencing. The TNF signaling pathway was significantly activated in the -low group, and TNF inhibition effectively restored diseased cell degradation.
We revealed an essential role of diseased cells in tendinopathy and proposed the FOXO1-PRDX2-TNF axis is a potential regulatory mechanism for the treatment of tendinopathy.
肌腱病是最常见的慢性肌腱疾病，会导致持续的肌腱疼痛和功能丧失。分析肌腱微环境中的异质细胞组成有助于阐明肌腱病的合理分子机制。
在这项研究中，通过多模式分析，首次生成了单细胞 RNA 和 ATAC-seq 整合的肌腱病图谱。我们发现，具有低表达的特定细胞亚群表现出更高水平的炎症、更低的增殖和迁移能力，这不仅促进了肌腱损伤，而且导致了微环境恶化。从染色质可及性的基序富集分析来看，FOXO1 是 PRDX2 转录的上游调节剂，我们证实了 活性的功能阻断诱导了 的沉默。TNF 信号通路在 -low 组中显著激活，TNF 抑制可有效恢复病变细胞降解。
我们揭示了病变细胞在肌腱病中的重要作用，并提出 FOXO1-PRDX2-TNF 轴是治疗肌腱病的潜在调控机制。
