TGFα诱导EGFR信号调控CSPCs在OA治疗中的机制研究

Osteoarthritis (OA) is a degenerative joint disorder commonly encountered in clinical practice, and is the leading cause of disability in elderly people. Due to the poor self-healing capacity of articular cartilage and lack of specific diagnostic biomarkers, OA is a challenging disease with limited treatment options. Mesenchymal stem cells (MSCs) have been widely used in OA therapy for several years. Many reports recommended that MSCs have effect in inhibiting inflammation, OA pain and joints dysfunction, while there is no convincing evidence of cartilage repair effect by MSCs. Recently, some study revealed that tissue-specific stem cells have significant function in maintaining tissue homeostasis and improving tissue renewal and repair, while there is still no report about the application of cartilage-derived stem/progenitor cells (CSPCs) in OA therapy. The main difficulty hinder further study is the uncontrollability of the differentiation of MSCs in vivo, and the differentiation stage of CSPCs in vitro. Our previous study has proved for the first time that EGFR signaling maintains the morphology, physiological function and stem cell properties of superficial chondrocytes, which have been identified as CSPCs, through inducing proliferation, inhibiting apoptosis and differentiation. In addition, EGFR activated by TGFα dramatically stimulates the expression of Prg4 in superficial chondrocytes to enhance the lubrication function of joint. Therefore, the application of CSPCs regulated by TGFα induced EGFR signaling in OA therapy may provide innovative method and theoretical support for stem cells therapy in the future. On the other hand, our study will detect the adhesion, migration, proliferation, differentiation and three-dimensional spatial distribution of CSPCs in OA cartilage at several stages by GFP tracing under confocal microscope to reveal the mechanism of CSPCs in cartilage repair.

骨关节炎(OA)是临床最常见关节退行性病变，因关节软骨自我修复能力薄弱、特异性生物学诊断指标匮乏，其治疗手段极其有限。多篇报道证实MSCs治疗在抑制炎性反应、缓解疼痛症状及减轻关节功能障碍方面有显著疗效。然而MSCs治疗对退变关节软骨的修复作用并没有确切证据。近期研究表明多种组织源性干细胞对组织更新、修复及稳态维持有显著作用，但使用软骨源性干/祖细胞（CSPCs）治疗OA尚无文献报道。阻碍研究进展的关键在于MSCs体内分化以及CSPCs向软骨细胞分化阶段的不可控性。我们前期研究首次证实EGFR可通过促进增殖、减少凋亡、抑制分化等方面维持表层软骨细胞（被定性为CSPCs）形态、功能及其干细胞属性。此外，TGFα激活EGFR信号通路可刺激表层软骨细胞Prg4表达，从而促进关节软骨润滑功能。因此，使用TGFα诱导EGFR信号调控的CSPCs治疗OA将为软骨损伤的干细胞治疗提供全新的方法及思路。

骨关节炎(OA)是一种广泛存在的关节疾病且尚无完善的治疗方法。此前，我们发现软骨特异性表皮生长因子受体(epidermal growth factor receptor, EGFR) 活性缺失诱导并加剧小鼠膝关节骨性关节炎，为EGFR靶向治疗OA奠定了理论基础。然而，由于EGFR激活剂TGF分子量较低(5.6 kDa)，在循环中不稳定，直接注射入膝关节将被迅速清除无法发挥作用。为克服该困难，结合干细胞治疗OA相关研究，多篇报道证实MSCs治疗在抑制炎性反应、缓解疼痛症状及减轻关节功能障碍方面有显著疗效，本项目拟通过向OA造模小鼠关节腔注射EGFR信号激活的CSPCs，通过体内、外实验深入研究EGFR通路及CSPCs参与OA软骨退变修复的机制，以期发现OA防治的全新靶点及途径。