缺氧预处理自体骨髓干细胞来源的细胞外基质支架抑制软骨样细胞肥大化的作用机制研究

Bone mesenchymal stem cells (BMSC) therapy play an important role in the clinical application of cartilage defect therapy. BMSC derived cartilage-like cells easily switch toward a hypertrophic phenotype especially suffered from oxidative stress and inflammation, which could seriously influence the therapeutic effect of cartilage regeneration. Runx2 plays an important role in the hypertrophic differentiation of cartilage-like cells. Recent data indicated that the hypoxic-preconditioned (HP) BMSC could help to reduce the hypertrophic differentiation of coculture with cartilage-like cells by inhibiting Runx2 up-regulation. Current studies suggest that the therapeutic effects of coculture with BMSC are mainly mediated by extracellular matrix which contained many BMSC secreted proteins. The HP-BMSC derived extracellular matrix (HP-ECM) was collected and fabricated into porous scaffold in our preliminary experiment. The HP-ECM scaffold could continuously down-regulate Runx2, and inhibit the hypertrophic differentiation of cartilage-like cells in vitro. Therefore, we suppose that the HP-ECM scaffold could inhibit Runx2 up-regulation of cartilage-like cells, reduce the hypertrophic differentiation, and improve the therapeutic effect of cartilage regeneration. We aim to comprehensively clarify whether the HP-ECM scaffold could regulate the expression of Runx2 and reduce the hypertrophic differentiation of cartilage-like cells. Finally, the results may provide a theoretical basis for HP-ECM scaffold treatment in cartilage regeneration.

骨髓干细胞（BMSC）移植是治疗软骨损伤的重要方法，但BMSC分化的软骨样细胞容易肥大化，特别是在氧化应激和炎症环境中，严重影响软骨修复疗效。Runx2是软骨样细胞肥大化的重要调控靶点。研究发现BMSC经缺氧预处理（HP）可下调共培养体系中软骨样细胞Runx2表达，提高抗氧化应激和炎症反应能力，抑制肥大化。目前研究认为共培养体系下的BMSC主要是通过富含旁分泌因子的细胞外基质发挥生物学功能。我们前期体外预实验发现：BMSC经缺氧预处理后其来源的细胞外基质（HP-ECM）支架可持续下调软骨样细胞Runx2表达、抑制肥大化。由此提出科学假说：应用HP-ECM支架可持续下调软骨样细胞Runx2表达，提高抗氧化应激和炎症反应能力，抑制肥大化。本项目拟从模型动物、细胞及分子水平探讨HP-ECM支架调控Runx2表达、抑制软骨样细胞肥大化的作用及分子机制，为临床应用该支架治疗软骨损伤提供理论依据。

骨髓干细胞（BMSC）移植是治疗软骨损伤的重要方法，但BMSC分化的软骨样细胞容易肥大化，特别是在氧化应激和炎症环境中，严重影响软骨修复疗效。研究发现BMSC经缺氧预处理（HP）可下调共培养体系中软骨样细胞Runx2表达，提高抗氧化应激和炎症反应能力，抑制肥大化。研究发现：BMSC经缺氧预处理后其来源的细胞外基质（HP-ECM）支架可持续下调软骨样细胞Runx2表达、抑制肥大化。应用HP-ECM支架可持续下调软骨样细胞Runx2表达，提高抗氧化应激和炎症反应能力，抑制肥大化。本项目从模型动物、细胞及分子水平表明HP-ECM支架调控Runx2表达、抑制软骨样细胞肥大化的作用及分子机制，为临床应用该支架治疗软骨损伤提供理论依据。