Extracellular vesicles derived from bone marrow mesenchymal stem cells loaded on magnetic nanoparticles delay the progression of diabetic osteoporosis via delivery of miR-150-5p,Cell Biology and Toxicology

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Extracellular vesicles derived from bone marrow mesenchymal stem cells loaded on magnetic nanoparticles delay the progression of diabetic osteoporosis via delivery of miR-150-5p
Cell Biology and Toxicology ( IF 5.3 ) Pub Date : 2022-09-16 , DOI: 10.1007/s10565-022-09744-y
Chen Xu _{1,

2,

3} , Zhaodong Wang ₁ , Yajun Liu ₁ , Bangguo Wei ₁ , Xiangyu Liu ₁ , Keyou Duan ₁ , Pinghui Zhou _{1,

2} , Zhao Xie ₄ , Min Wu ₁ , Jianzhong Guan _{1,

2,

3}

Affiliation

Extracellular vesicles derived from bone marrow mesenchymal stem cells (BMSC-EVs) are emerged as carriers of therapeutic targets against bone disorders, yet its isolation and purification are limited with recent techniques. Magnetic nanoparticles (MNPs) can load EVs with a unique targeted drug delivery system. We constructed gold-coated magnetic nanoparticles (GMNPs) by decorating the surface of the Fe₃O₄@SiO₂ core and a silica shell with poly(ethylene glycol) (PEG)-aldehyde (CHO) and examined the role of BMSC-EVs loaded on GMNPs in diabetic osteoporosis (DO). The osteoporosis-related differentially expressed miR-150-5p was singled out by microarray analysis. DO models were then established in Sprague–Dawley rats by streptozotocin injection, where poor expression of miR-150-5p was validated in the bone tissues. Next, GMNP_E was prepared by combining GMNPs with anti-CD63, after which osteoblasts were co-cultured with the GMNP_E-BMSC-EVs. The re-expression of miR-150-5p facilitated osteogenesis in osteoblasts. GMNP_E could promote the enrichment of EVs in the bone tissues of DO rats. BMSC-EVs delivered miR-150-5p to osteoblasts, where miR-150-5p targeted MMP14 and consequently activated Wnt/β-catenin pathway. This effect contributed to the enhancement of osteoblast proliferation and maturation. Furthermore, GMNP_E enhanced the EV-based delivery of miR-150-5p to regulate the MMP14/Wnt/β-catenin axis, resulting in promotion of osteogenesis. Overall, our findings suggest the potential of GMNP-BMSC-EVs to strengthen osteoblast proliferation and maturation in DO, showing promise as an appealing drug delivery strategy against DO.

Graphical abstract

1. GMNPs-BMSCs-EVs-miR-150-5p promotes the osteogenesis of DO rats.

2. miR-150-5p induces osteoblast proliferation and maturation by targeting MMP14.

3. Inhibition of MMP14 activates Wnt/β-catenin and increases osteogenesis.

4. miR-150-5p activates the Wnt/β-catenin pathway by downregulating MMP14.

中文翻译：

负载磁性纳米粒子的骨髓间充质干细胞来源的细胞外囊泡通过传递 miR-150-5p 延缓糖尿病骨质疏松症的进展

源自骨髓间充质干细胞（BMSC-EV）的细胞外囊泡已成为骨疾病治疗靶点的载体，但其分离和纯化受到最新技术的限制。磁性纳米颗粒 (MNP) 可以通过独特的靶向药物输送系统装载 EV。_{我们通过用聚乙二醇（PEG）-醛（CHO）修饰 Fe 3} O ₄ @SiO ₂核和二氧化硅壳的表面构建了金包覆磁性纳米粒子（GMNP），并检查了 BMSC-EV 的作用加载 GMNP 治疗糖尿病骨质疏松症 (DO)。通过微阵列分析筛选出与骨质疏松症相关的差异表达的miR-150-5p。然后通过注射链脲佐菌素在 Sprague-Dawley 大鼠中建立 DO 模型，验证了骨组织中 miR-150-5p 的低表达。接下来，通过将GMNP与抗CD63组合来制备GMNP _E，之后将成骨细胞与GMNP _E -BMSC-EV共培养。miR-150-5p 的重新表达促进成骨细胞的成骨。GMNP _E可以促进DO大鼠骨组织中EV的富集。BMSC-EV 将 miR-150-5p 递送至成骨细胞，其中 miR-150-5p 靶向 MMP14，从而激活 Wnt/β-catenin 通路。这种作用有助于增强成骨细胞增殖和成熟。此外，GMNP _E增强了基于 EV 的 miR-150-5p 传递，以调节 MMP14/Wnt/β-连环蛋白轴，从而促进成骨。总体而言，我们的研究结果表明 GMNP-BMSC-EV 具有增强 DO 中成骨细胞增殖和成熟的潜力，显示出作为一种有吸引力的 DO 药物递送策略的前景。