Liu Shuchen, Wang Zhuoran, Li Yuhuan, Pan Ziyi, Huang Lei, Cui Jing, Zhang Xue, Yang Mingxi, Zhang Yuan, Li Daowei, Sun Hongchen
Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, School and Hospital of Stomatology, Jilin University, 1500 Qinghua Road, Changchun, 130021, China.
Department of Surgery, Experimental Surgery, CCM, CVK, Charité - Berlin University Medicine, Free University of Berlin and Humboldt University of Berlin, 10117, Berlin, Germany.
Adv Sci (Weinh). 2025 Jun;12(23):e2500554. doi: 10.1002/advs.202500554. Epub 2025 Apr 28.
Loss of periodontal tissue due to persistent inflammation in periodontitis is a major cause of tooth loss in adults. Overcoming osteogenic inhibition in the inflammatory periodontal environment and restoring the regenerative capacity of endogenous bone marrow mesenchymal stem cells (BMSCs) remain critical challenges in current treatment approaches. Macrophage-derived extracellular vesicles (EVs) are key regulators of osteogenesis in recipient cells, yet the role of erythropoietin (EPO) in modifying macrophages and the function of their EVs in bone regeneration remain unclear. In this study, EVs from EPO-stimulated macrophages (EPO-EVs) are isolated, and they are encapsulated in a chitosan/β-sodium glycerophosphate/gelatin (CS/β-GP/gelatin) hydrogel to create a controlled-release EVs delivery system for localized periodontal environment. EPO-EVs restore the osteogenic function of mouse BMSCs (mBMSCs) and mitigate inflammatory bone loss in a periodontitis mouse model. Mechanistically, miR-5107-5p, significantly enriched in EPO-EVs, is delivered to mBMSCs, where it suppresses epidermal growth factor receptor (EGFR) expression and alleviates EGFR's inhibitory effect on RhoA. This process counteracts osteogenic inhibition in inflammatory settings through the EGFR/RhoA axis. Overall, EVs from EPO pretreated macrophages restore the osteogenic capacity of mBMSCs under inflammation by inhibiting EGFR expression, providing new insight into therapeutic mechanisms and offering a promising approach for future periodontitis treatment.
牙周炎中持续炎症导致的牙周组织丧失是成年人牙齿缺失的主要原因。克服炎症性牙周环境中的成骨抑制并恢复内源性骨髓间充质干细胞（BMSCs）的再生能力仍然是当前治疗方法中的关键挑战。巨噬细胞衍生的细胞外囊泡（EVs）是受体细胞中成骨作用的关键调节因子，但促红细胞生成素（EPO）在修饰巨噬细胞中的作用及其EVs在骨再生中的功能仍不清楚。在本研究中，分离了来自EPO刺激的巨噬细胞的EVs（EPO-EVs），并将它们封装在壳聚糖/β-甘油磷酸钠/明胶（CS/β-GP/明胶）水凝胶中，以创建用于局部牙周环境的可控释放EVs递送系统。EPO-EVs恢复了小鼠BMSCs（mBMSCs）的成骨功能，并减轻了牙周炎小鼠模型中的炎症性骨质流失。从机制上讲，在EPO-EVs中显著富集的miR-5107-5p被递送至mBMSCs，在那里它抑制表皮生长因子受体（EGFR）的表达并减轻EGFR对RhoA的抑制作用。这一过程通过EGFR/RhoA轴抵消了炎症环境中的成骨抑制。总体而言，来自EPO预处理巨噬细胞的EVs通过抑制EGFR表达恢复了炎症状态下mBMSCs的成骨能力，为治疗机制提供了新的见解，并为未来的牙周炎治疗提供了一种有前景的方法。
