Exosomes from adipose-derived stem cells regulate M1/M2 macrophage phenotypic polarization to promote bone healing via miR-451a/MIF.
Exosomes from adipose-derived stem cells regulate M1/M2 macrophage phenotypic polarization to promote bone healing via miR-451a/MIF.
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脂肪来源干细胞分泌的外泌体通过miR - 451a/巨噬细胞移动抑制因子（MIF）调节M1/M2巨噬细胞表型极化以促进骨愈合。
DOI：
10.1186/s13287-022-02823-1
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发表时间：
2022-04-08
影响因子：
7.5
通讯作者：
Ji P
中科院分区：
文献类型：
--
作者：
Li R;Li D;Wang H;Chen K;Wang S;Xu J;Ji P
疾病和创伤引起的骨缺损通常伴有炎症反应，而生物材料作为一种常见的修复方法也被发现会引起炎症反应，影响骨代谢和新骨形成。本研究探讨脂肪来源干细胞外切体(ADSC-Exos)在创伤性骨缺损中是否起到免疫调节作用，并阐明其潜在机制。以明胶纳米颗粒(GNPs)为载体负载ADSC-Exos，通过Zeta电位、表面形貌和流变学等方法分析其物化性能。我们采用大鼠颅骨缺损区模型进行体内研究，采用显微CT和组织学染色方法分析骨缺损区的组织学变化。RT-qPCR和Western blotting验证ADSC-Exos对M1/M2巨噬细胞极化的调节作用。通过microRNA(MiRNA)阵列分析确定ADSC-Exos的miRNA表达谱。用miR-451a模拟物、miR-451a抑制剂和ISO-1处理巨噬细胞后，用RT-qPCR和Western blotting检测基因和蛋白的相对表达。体内显微CT和组织学染色结果表明，GNP-Exos水凝胶具有良好的生物相容性和较强的机械适应性，主要通过调节巨噬细胞免疫和促进骨组织愈合而发挥免疫调节作用。免疫荧光进一步表明，ADSC-Exos降低了M1标记(INOS)的表达，增加了M2标记(CD206)的表达。此外，体外研究表明，ADSC-Exos抑制M1巨噬细胞标志的表达，上调M2巨噬细胞标志的表达。MIR-451a富含ADSC-Exos和靶向巨噬细胞移动抑制因子(MIF)。经miR-451a模拟物处理的巨噬细胞M1标志物表达降低。相反，miR-451a抑制剂处理上调M1标志物的表达，下调M2标志物的表达，而ISO-1(MIF抑制剂)处理上调miR-451a的表达，下调M1巨噬细胞标志物的表达。GNP-Exos可部分通过miR-451a的免疫调节作用，有效调节骨免疫代谢，进一步促进骨愈合，为骨修复提供治疗方向。网上版载有补充材料，可在10.1186/s13287-022-02823-1查阅。
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. 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. 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. 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. The online version contains supplementary material available at 10.1186/s13287-022-02823-1.
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影响因子：
16.1
作者：
Agarwal R;García AJ
通讯作者：
García AJ
影响因子：
7.5
作者：
Chen G;Jin Y;Shi X;Qiu Y;Zhang Y;Cheng M;Wang X;Chen C;Wu Y;Jiang F;Li L;Zhou H;Fu Q;Liu X
通讯作者：
Liu X
影响因子：
5.3
作者：
Lu Y;Wen H;Huang J;Liao P;Liao H;Tu J;Zeng Y
通讯作者：
Zeng Y
影响因子：
3.7
作者：
Babapoor S;Fleming E;Wu R;Dadras SS
通讯作者：
Dadras SS
大鼠脂肪衍生的间充质干细胞的外泌体对挤压损伤后神经突生长和坐骨神经再生的影响。
影响因子：
5.1
作者：
Bucan V;Vaslaitis D;Peck CT;Strauß S;Vogt PM;Radtke C
通讯作者：
Radtke C