糖皮质激素刺激的 M1 巨噬细胞产生的外泌体 miR-1a-3p 通过靶向 Cebpz 促进糖皮质激素相关性股骨头坏死中 BMSCs 的成脂分化。

IF 10.6 1区 生物学 Q1 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Journal of Nanobiotechnology Pub Date : 2024-10-22 DOI:10.1186/s12951-024-02923-5
Ping Duan, Yong-Le Yu, Yan-Nan Cheng, Meng-Han Nie, Qing Yang, Liang-Hui Xia, Yan-Xiao Ji, Zhen-Yu Pan
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引用次数: 0

摘要

背景:通过与骨髓间充质干细胞(BMSCs)相互作用并通过外泌体调节其功能,骨巨噬细胞在各种骨相关疾病中发挥着至关重要的作用。研究表明,在糖皮质激素相关性股骨头坏死(GA-ONFH)中,M1巨噬细胞的数量明显增加。然而,在糖皮质激素刺激的环境中,M1 巨噬细胞和 BMSCs 之间错综复杂的相互作用尚未完全阐明,GA-ONFH 发生的潜在调控机制仍不清楚:我们利用体内小鼠模型和 GA-ONFH 患者的临床样本研究了 M1 巨噬细胞和 BMSCs 之间的相互作用。免疫荧光染色用于评估 M1 巨噬细胞和 BMSCs 的共定位。流式细胞术和转录组分析评估了来自正常(n-M1)和糖皮质激素刺激的 M1 巨噬细胞(GC-M1)的外泌体对 BMSC 分化的影响。此外,还改变了miR-1a-3p在体外和体内的表达,以评估其在调节成脂分化中的作用:结果:在 GA-ONFH 患者和小鼠模型中,观察到 M1 巨噬细胞和 BMSCs 的共定位,并进一步证实了 M1 巨噬细胞数量的增加和骨修复能力的下降。研究发现,n-M1 和 GC-M1 在一定程度上通过外泌体分泌抑制了 BMSCs 的成骨分化。更重要的是,从 GC-M1 巨噬细胞中提取的外泌体显示出更强的调节 BMSCs 成脂肪分化的能力,而这是由 miR-1a-3p 介导的。在体内和体外,miR-1a-3p通过靶向Cebpz促进了BMSCs的成脂分化,并在GA-ONFH的发病和进展中发挥了重要作用:结论:我们证明,来自GC-M1巨噬细胞的外泌体破坏了BMSCs成骨和成脂分化之间的平衡,导致了GA-ONFH的发病机制。在体外和体内抑制miR-1a-3p的表达,能显著减轻BMSCs的优先成脂分化,从而减缓GA-ONFH的进展。这些发现为GA-ONFH的调控机制提供了新的见解,并突出了潜在的干预治疗靶点。
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Exosomal miR-1a-3p derived from glucocorticoid-stimulated M1 macrophages promotes the adipogenic differentiation of BMSCs in glucocorticoid-associated osteonecrosis of the femoral head by targeting Cebpz.

Background: By interacting with bone marrow mesenchymal stem cells (BMSCs) and regulating their function through exosomes, bone macrophages play crucial roles in various bone-related diseases. Research has highlighted a notable increase in the number of M1 macrophages in glucocorticoid-associated osteonecrosis of the femoral head (GA-ONFH). Nevertheless, the intricate crosstalk between M1 macrophages and BMSCs in the glucocorticoid-stimulated environment has not been fully elucidated, and the underlying regulatory mechanisms involved in the occurrence of GA-ONFH remain unclear.

Methods: We employed in vivo mouse models and clinical samples from GA-ONFH patients to investigate the interactions between M1 macrophages and BMSCs. Immunofluorescence staining was used to assess the colocalization of M1 macrophages and BMSCs. Flow cytometry and transcriptomic analysis were performed to evaluate the impact of exosomes derived from normal (n-M1) and glucocorticoid-stimulated M1 macrophages (GC-M1) on BMSC differentiation. Additionally, miR-1a-3p expression was altered in vitro and in vivo to assess its role in regulating adipogenic differentiation.

Results: In vivo, the colocalization of M1 macrophages and BMSCs was observed, and an increase in M1 macrophage numbers and a decrease in bone repair capabilities were further confirmed in both GA-ONFH patients and mouse models. Both n-M1 and GC-M1 were identified as contributors to the inhibition of osteogenic differentiation in BMSCs to a certain extent via exosome secretion. More importantly, exosomes derived from GC-M1 macrophages exhibited a heightened capacity to regulate the adipogenic differentiation of BMSCs, which was mediated by miR-1a-3p. In vivo and in vitro, miR-1a-3p promoted the adipogenic differentiation of BMSCs by targeting Cebpz and played an important role in the onset and progression of GA-ONFH.

Conclusion: We demonstrated that exosomes derived from GC-M1 macrophages disrupt the balance between osteogenic and adipogenic differentiation in BMSCs, contributing to the pathogenesis of GA-ONFH. Inhibiting miR-1a-3p expression, both in vitro and in vivo, significantly mitigates the preferential adipogenic differentiation of BMSCs, thus slowing the progression of GA-ONFH. These findings provide new insights into the regulatory mechanisms underlying GA-ONFH and highlight potential therapeutic targets for intervention.

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来源期刊
Journal of Nanobiotechnology
Journal of Nanobiotechnology BIOTECHNOLOGY & APPLIED MICROBIOLOGY-NANOSCIENCE & NANOTECHNOLOGY
CiteScore
13.90
自引率
4.90%
发文量
493
审稿时长
16 weeks
期刊介绍: Journal of Nanobiotechnology is an open access peer-reviewed journal communicating scientific and technological advances in the fields of medicine and biology, with an emphasis in their interface with nanoscale sciences. The journal provides biomedical scientists and the international biotechnology business community with the latest developments in the growing field of Nanobiotechnology.
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