Extracellular vesicles from adipose tissue-derived stem cells alleviate osteoporosis through osteoprotegerin and miR-21-5p.
Extracellular vesicles from adipose tissue-derived stem cells alleviate osteoporosis through osteoprotegerin and miR-21-5p.
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DOI：
10.1002/jev2.12152
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发表时间：
2021-10
影响因子：
16
通讯作者：
Jo DG
中科院分区：
文献类型：
--
作者：
Lee KS;Lee J;Kim HK;Yeom SH;Woo CH;Jung YJ;Yun YE;Park SY;Han J;Kim E;Sul JH;Jung JM;Park JH;Choi JS;Cho YW;Jo DG
骨质疏松症是最常见的骨骼疾病之一，由骨形成和吸收之间的失衡引起，导致骨组织的定量损失。由于干细胞衍生的细胞外囊泡（EV）作为具有优于亲本干细胞的新型无细胞治疗剂越来越受到关注，因此研究了来自脂肪组织衍生的干细胞（ASC-EV）的EV对骨质疏松症发病机制的治疗作用。通过基于切向流过滤（TFF）系统的多重过滤系统分离ASC-EV，并使用透射电子显微镜、动态光散射、zeta电位、流式细胞术、细胞因子阵列和酶联免疫吸附试验进行表征。EV富含与骨代谢和间充质干细胞（MSC）迁移相关的生长因子和细胞因子。特别是，骨保护素（OPG），一种核因子-κB配体受体激活剂（RANKL）的天然抑制剂，在ASC-EV中高度富集。我们发现，静脉注射ASC-EV可减轻骨质疏松症小鼠的骨丢失。此外，ASC-EV显著抑制巨噬细胞的破骨细胞分化，并促进骨髓源性MSC（BM-MSC）的迁移。然而，OPG耗尽的ASC-EV未显示出抗破骨细胞生成作用，表明OPG对于ASC-EV的治疗作用至关重要。此外，分析小RNA测序数据以鉴定与抗骨质疏松作用相关的miRNA候选物。ASC-EV中的miR-21 - 5 p通过Acvr 2a下调抑制破骨细胞分化。此外，ASC-EV中的let-7 b-5 p显著降低了破骨细胞生成相关基因的表达。最后，ASC-EV在静脉注射后到达骨组织，并且保持更长时间。ASC-EV中的OPG、miR-21 - 5 p和let-7 b-5 p抑制破骨细胞分化并减少与骨吸收相关的基因表达，表明ASC-EV作为骨质疏松症治疗的无细胞治疗剂非常有前途。
Osteoporosis is one of the most common skeletal disorders caused by the imbalance between bone formation and resorption, resulting in quantitative loss of bone tissue. Since stem cell‐derived extracellular vesicles (EVs) are growing attention as novel cell‐free therapeutics that have advantages over parental stem cells, the therapeutic effects of EVs from adipose tissue‐derived stem cells (ASC‐EVs) on osteoporosis pathogenesis were investigated. ASC‐EVs were isolated by a multi‐filtration system based on the tangential flow filtration (TFF) system and characterized using transmission electron microscopy, dynamic light scattering, zeta potential, flow cytometry, cytokine arrays, and enzyme‐linked immunosorbent assay. EVs are rich in growth factors and cytokines related to bone metabolism and mesenchymal stem cell (MSC) migration. In particular, osteoprotegerin (OPG), a natural inhibitor of receptor activator of nuclear factor‐κB ligand (RANKL), was highly enriched in ASC‐EVs. We found that the intravenous administration of ASC‐EVs attenuated bone loss in osteoporosis mice. Also, ASC‐EVs significantly inhibited osteoclast differentiation of macrophages and promoted the migration of bone marrow‐derived MSCs (BM‐MSCs). However, OPG‐depleted ASC‐EVs did not show anti‐osteoclastogenesis effects, demonstrating that OPG is critical for the therapeutic effects of ASC‐EVs. Additionally, small RNA sequencing data were analysed to identify miRNA candidates related to anti‐osteoporosis effects. miR‐21‐5p in ASC‐EVs inhibited osteoclast differentiation through Acvr2a down‐regulation. Also, let‐7b‐5p in ASC‐EVs significantly reduced the expression of genes related to osteoclastogenesis. Finally, ASC‐EVs reached the bone tissue after they were injected intravenously, and they remained longer. OPG, miR‐21‐5p, and let‐7b‐5p in ASC‐EVs inhibit osteoclast differentiation and reduce gene expression related to bone resorption, suggesting that ASC‐EVs are highly promising as cell‐free therapeutic agents for osteoporosis treatment.
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