Delivery of miR-15b-5p via magnetic nanoparticle-enhanced bone marrow mesenchymal stem cell-derived extracellular vesicles mitigates diabetic osteoporosis by targeting GFAP.

IF 5.3 2区医学 Q2 CELL BIOLOGY Cell Biology and Toxicology Pub Date : 2024-07-05 DOI:10.1007/s10565-024-09877-2

Chen Xu, Zhaodong Wang, Yajun Liu, Keyou Duan, Jianzhong Guan

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Abstract

Diabetic osteoporosis (DO) presents significant clinical challenges. This study aimed to investigate the potential of magnetic nanoparticle-enhanced extracellular vesicles (GMNP_E-EVs) derived from bone marrow mesenchymal stem cells (BMSCs) to deliver miR-15b-5p, thereby targeting and downregulating glial fibrillary acidic protein (GFAP) expression in rat DO models. Data was sourced from DO-related RNA-seq datasets combined with GEO and GeneCards databases. Rat primary BMSCs, bone marrow-derived macrophages (BMMs), and osteoclasts were isolated and cultured. EVs were separated, and GMNP_E targeting EVs were synthesized. Bioinformatic analysis revealed a high GFAP expression in DO-related RNA-seq and GSE26168 datasets for disease models. Experimental results confirmed elevated GFAP in rat DO bone tissues, promoting osteoclast differentiation. miR-15b-5p was identified as a GFAP inhibitor, but was significantly downregulated in DO and enriched in BMSC-derived EVs. In vitro experiments showed that GMNP_E-EVs could transfer miR-15b-5p to osteoclasts, downregulating GFAP and inhibiting osteoclast differentiation. In vivo tests confirmed the therapeutic potential of this approach in alleviating rat DO. Collectively, GMNP_E-EVs can effectively deliver miR-15b-5p to osteoclasts, downregulating GFAP expression, and hence, offering a therapeutic strategy for rat DO.

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通过磁性纳米粒子增强骨髓间充质干细胞衍生的细胞外囊泡输送 miR-15b-5p 可通过靶向 GFAP 缓解糖尿病骨质疏松症。

糖尿病骨质疏松症（DO）给临床带来了巨大挑战。本研究旨在探讨由骨髓间充质干细胞（BMSCs）衍生的磁性纳米颗粒增强细胞外囊泡（GMNPE-EVs）传递miR-15b-5p的潜力，从而靶向下调大鼠DO模型中神经胶质纤维酸性蛋白（GFAP）的表达。数据来源于DO相关的RNA-seq数据集以及GEO和GeneCards数据库。分离并培养大鼠原代BMSCs、骨髓衍生巨噬细胞（BMMs）和破骨细胞。分离了EVs，并合成了靶向EVs的GMNPE。生物信息分析表明，在与 DO 相关的 RNA-seq 和 GSE26168 数据集中，疾病模型的 GFAP 高表达。实验结果证实，大鼠 DO 骨组织中 GFAP 升高，促进破骨细胞分化。miR-15b-5p 被鉴定为 GFAP 抑制剂，但在 DO 中显著下调，并在 BMSC 衍生的 EV 中富集。体外实验表明，GMNPE-EVs 可将 miR-15b-5p 转移到破骨细胞，从而下调 GFAP 并抑制破骨细胞分化。体内试验证实了这种方法在缓解大鼠 DO 方面的治疗潜力。总之，GMNPE-EVs 能有效地将 miR-15b-5p 传递到破骨细胞，下调 GFAP 的表达，从而为大鼠 DO 提供了一种治疗策略。

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来源期刊

Cell Biology and Toxicology 生物-毒理学

CiteScore

9.90

自引率

4.90%

发文量

101

审稿时长

>12 weeks

期刊介绍： Cell Biology and Toxicology (CBT) is an international journal focused on clinical and translational research with an emphasis on molecular and cell biology, genetic and epigenetic heterogeneity, drug discovery and development, and molecular pharmacology and toxicology. CBT has a disease-specific scope prioritizing publications on gene and protein-based regulation, intracellular signaling pathway dysfunction, cell type-specific function, and systems in biomedicine in drug discovery and development. CBT publishes original articles with outstanding, innovative and significant findings, important reviews on recent research advances and issues of high current interest, opinion articles of leading edge science, and rapid communication or reports, on molecular mechanisms and therapies in diseases.