Exosomes from adipose-derived stem cells regulate M1/M2 macrophage phenotypic polarization to promote bone healing via miR-451a/MIF

作者全名："Li, Rui; Li, Dize; Wang, Huanan; Chen, Kaiwen; Wang, Si; Xu, Jie; Ji, Ping"

作者地址："[Li, Rui; Li, Dize; Wang, Si; Xu, Jie; Ji, Ping] Chongqing Med Univ, Coll Stomatol, Dept Pediat Dent, 426 North Songshi Rd, Chongqing 401147, Peoples R China; [Li, Rui; Li, Dize; Wang, Si; Xu, Jie; Ji, Ping] Chongqing Key Lab Oral Dis & Biomed Sci, Dept Oral & Maxillofacial Surg, Chongqing, Peoples R China; [Li, Rui; Li, Dize; Wang, Si; Xu, Jie; Ji, Ping] Chongqing Municipal Key Lab Oral Biomed Engn High, Chongqing, Peoples R China; [Wang, Huanan; Chen, Kaiwen] Dalian Univ Technol, Sch Bioengn, Key State Lab Fine Chem, Dalian 116023, Peoples R China"

通信作者："Wang, S; Xu, J; Ji, P (通讯作者)，Chongqing Med Univ, Coll Stomatol, Dept Pediat Dent, 426 North Songshi Rd, Chongqing 401147, Peoples R China.; Wang, S; Xu, J; Ji, P (通讯作者)，Chongqing Key Lab Oral Dis & Biomed Sci, Dept Oral & Maxillofacial Surg, Chongqing, Peoples R China.; Wang, S; Xu, J; Ji, P (通讯作者)，Chongqing Municipal Key Lab Oral Biomed Engn High, Chongqing, Peoples R China."

来源：STEM CELL RESEARCH & THERAPY

ESI学科分类：MOLECULAR BIOLOGY & GENETICS

WOS号：WOS:000781383300007

JCR分区：Q1

影响因子：7.5

年份：2022

卷号：13

期号：1

开始页：　

结束页：　

文献类型：Article

关键词：Exosomes; Adipose-derived stem cells; Macrophages; Bone healing; MiRNA

摘要："Objectives Bone defects caused by diseases and trauma are usually accompanied by inflammation, and the implantation of biomaterials as a common repair method has also been found to cause inflammatory reactions, which affect bone metabolism and new bone formation. This study investigated whether exosomes from adipose-derived stem cells (ADSC-Exos) plays an immunomodulatory role in traumatic bone defects and elucidated the underlying mechanisms. Methods ADSC-Exos were loaded by a biomaterial named gelatine nanoparticles (GNPs), physical and chemical properties were analysed by zeta potential, surface topography and rheology. A rat model of skull defect was used for our in vivo studies, and micro-CT and histological staining were used to analyse histological changes in the bone defect area. RT-qPCR and western blotting were performed to verify that ADSC-Exos could regulate M1/M2 macrophage polarization. MicroRNA (miRNA) array analysis was conducted to determine the miRNA expression profiles of ADSC-Exos. After macrophages were treated with a miR-451a mimic, miR-451a inhibitor and ISO-1, the relative expression of genes and proteins was measured by RT-qPCR and western blotting. Results In vivo, micro-CT and histological staining showed that exosome-loaded GNPs (GNP-Exos) hydrogel, with good biocompatibility and strong mechanical adaptability, exhibited immunomodulatory effect mainly by regulating macrophage immunity and promoting bone tissue healing. Immunofluorescence further indicated that ADSC-Exos reduced M1 marker (iNOS) expression and increased M2 marker (CD206) expression. Moreover, in vitro studies, western blotting and RT-qPCR showed that ADSC-Exos inhibited M1 macrophage marker expression and upregulated M2 macrophage marker expression. MiR-451a was enriched in ADSC-Exos and targeted macrophage migration inhibitory factor (MIF). Macrophages treated with the miR-451a mimic showed lower expression of M1 markers. In contrast, miR-451a inhibitor treatment upregulated the expression of M1 markers and downregulated the expression of M2 markers, while ISO-1 (a MIF inhibitor) treatment upregulated miR-451a expression and downregulated M1 macrophage marker expression. Conclusion GNP-Exos can effectively regulate bone immune metabolism and further promote bone healing partly through immune regulation of miR-451a, which may provide a therapeutic direction for bone repair."

基金机构："National Natural Science Foundation of China [81800999]; Natural Science Foundation of Chongqing, China [stc2019jcyjmsxmX0150]; Science and Technology Research Program of Chongqing Municipal Education Commission [KJQN201900415]; Program for Innovation Team Building at Institutions of Higher Education in Chongqing"

基金资助正文："This work was supported by the National Natural Science Foundation of China (Grant No.81800999), the Natural Science Foundation of Chongqing, China (Grant No. stc2019jcyjmsxmX0150), the Science and Technology Research Program of Chongqing Municipal Education Commission (Grant No. KJQN201900415), the Project Supported by Program for Innovation Team Building at Institutions of Higher Education in Chongqing in 2016."