PDF(Pubmed)
Abstract：
Tissue fibrosis following tendon injury is a major clinical problem due to the increased risk of re-injury and limited treatment options; however, its mechanism remains unclear. Evidence suggests that insufficient resolution of inflammation contributes to fibrotic healing by disrupting tenocyte activity, with the NF-κB pathway being identified as a potential mediator. Equine embryonic stem cell (ESC) derived tenocytes may offer a potential cell-based therapy to improve tendon regeneration, but how they respond to an inflammatory environment is largely unknown. Our findings reveal for the first time that, unlike adult tenocytes, ESC-tenocytes are unaffected by IFN-γ, TNFα, and IL-1β stimulation; producing minimal changes to tendon-associated gene expression and generating 3-D collagen gel constructs indistinguishable from unstimulated controls. Inflammatory pathway analysis found these inflammatory cytokines failed to activate NF-κB in the ESC-tenocytes. However, NF-κB could be activated to induce changes in gene expression following stimulation with NF-κB pharmaceutical activators. Transcriptomic analysis revealed differences between cytokine and NF-κB signalling components between adult and ESC-tenocytes, which may contribute to the mechanism by which ESC-tenocytes escape inflammatory stimuli. Further investigation of these molecular mechanisms will help guide novel therapies to reduce fibrosis and encourage superior tendon healing.
摘要：
肌腱损伤后的组织纤维化是一个主要的临床问题，因为再损伤的风险增加和治疗选择有限；然而，其机制尚不清楚。有证据表明，炎症的不充分解决有助于纤维化愈合通过破坏肌腱细胞的活性，NF-κB途径被鉴定为潜在的介质。马胚胎干细胞（ESC）衍生的肌腱细胞可能提供一种潜在的基于细胞的疗法来改善肌腱再生，但是他们对炎症环境的反应在很大程度上是未知的。我们的发现首次揭示,与成年肌腱细胞不同，ESC-肌腱细胞不受IFN-γ的影响，TNFα,和IL-1β刺激；对肌腱相关基因表达产生最小的变化，并产生与未刺激对照无法区分的3-D胶原凝胶构建体。炎症途径分析发现，这些炎症细胞因子未能激活ESC肌腱细胞中的NF-κB。然而,在用NF-κB药物激活剂刺激后，NF-κB可以被激活以诱导基因表达的变化。转录组学分析揭示了成人和ESC-tenocytes之间的细胞因子和NF-κB信号传导成分之间的差异，这可能有助于ESC肌腱细胞逃避炎症刺激的机制。对这些分子机制的进一步研究将有助于指导新疗法以减少纤维化并促进肌腱愈合。
