Zhou Yi-Kun, Han Chun-Shan, Zhu Zi-Lu, Chen Peng, Wang Yi-Ming, Lin Shuai, Chen Liu-Jing, Zhuang Zi-Meng, Zhou Yan-Heng, Yang Rui-Li
Department of Orthodontics, Peking University School and Hospital of Stomatology, Haidian District, Beijing, China.
National Clinical Research Center for Oral Diseases & National Engineering Laboratory for Digital and Material Technology of Stomatology, Haidian District, Beijing, China.
Bioact Mater. 2023 Aug 12;31:192-205. doi: 10.1016/j.bioactmat.2023.08.006. eCollection 2024 Jan.
Bone defects caused by trauma or tumor led to high medical costs and poor life quality for patients. The exosomes, micro vesicles of 30-150 nm in diameter, derived from macrophages manipulated bone regeneration. However, the role of hydrogen sulfide (HS) in the biogenesis and function of exosomes and its effects on bone regeneration remains elusive. In this study, we used HS slow releasing donor GYY4137 to stimulate macrophages and found that HS promoted the polarization of M2 macrophages to increase bone regeneration of MSCs and . Moreover, we developed the HS pre-treated M2 macrophage exosomes and found these exosomes displayed significantly higher capacity to promote bone regeneration in calvarial bone defects by re-establishing the local immune microenvironment. Mechanically, HS treatment altered the protein profile of exosomes derived from M2 macrophages. One of the significantly enriched exosomal proteins stimulated by HS, moesin protein, facilitated the exosomes endocytosis into MSCs, leading to activated the β-catenin signaling pathway to promote osteogenic differentiation of MSCs. In summary, HS pretreated M2 exosomes promoted the bone regeneration of MSCs facilitating exosomes uptake by MSCs and activate β-catenin signaling pathway. This study not only provides new strategies for promoting bone regeneration, but also provides new insights for the effect and mechanism of exosomes internalization.
创伤或肿瘤导致的骨缺损给患者带来了高昂的医疗费用和较差的生活质量。源自经调控的巨噬细胞的外泌体（直径为30 - 150纳米的微囊泡）可调控骨再生。然而，硫化氢（HS）在外泌体生物发生和功能中的作用及其对骨再生的影响仍不清楚。在本研究中，我们使用HS缓释供体GYY4137刺激巨噬细胞，发现HS促进M2巨噬细胞极化，以增加间充质干细胞（MSCs）的骨再生。此外，我们制备了经HS预处理的M2巨噬细胞外泌体，发现这些外泌体通过重建局部免疫微环境，在颅骨缺损中显示出显著更高的促进骨再生的能力。从机制上讲，HS处理改变了源自M2巨噬细胞的外泌体的蛋白质谱。HS刺激显著富集的一种外泌体蛋白——埃兹蛋白，促进外泌体内吞进入MSCs，从而激活β-连环蛋白信号通路，促进MSCs的成骨分化。总之，经HS预处理的M2外泌体促进了MSCs的骨再生，促进了MSCs对外泌体的摄取并激活了β-连环蛋白信号通路。本研究不仅为促进骨再生提供了新策略，也为外泌体内化的作用和机制提供了新见解。
