Generation of Small RNA-Modulated Exosome Mimetics for Bone Regeneration.
Generation of Small RNA-Modulated Exosome Mimetics for Bone Regeneration.
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DOI：
10.1021/acsnano.0c05122
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发表时间：
2020-09-22
期刊：
影响因子：
17.1
通讯作者：
Lee M
中科院分区：
文献类型：
--
作者：
Fan J;Lee CS;Kim S;Chen C;Aghaloo T;Lee M
外泌体的施用被认为是骨骼修复和病理性疾病治疗的有吸引力的无细胞方法。然而，生产技术的低产量和外泌体的意想不到的治疗功效已经成为其在临床实践中广泛使用的障碍。在这里，我们报告了一种替代策略，以产生高产量和改善再生能力的外泌体相关囊泡。采用挤压方法从人间充质干细胞（hMSCs）中积累外泌体模拟物（EMs）。与MSC来源的外泌体相比，收集的EM中外泌体特异性CD-63标记物阳性的囊泡比例显着增加。EMs进一步从基因修饰的hMSCs中获得，其中noggin（一种天然骨形态发生蛋白拮抗剂）的表达被下调以增强EMs的成骨特性。此外，将hMSCEM与可注射壳聚糖水凝胶结合施用到小鼠非愈合性颅骨缺损中显示出稳健的骨再生。重要的是，机制研究表明，通过抑制头蛋白的EM增强的骨生成是通过抑制miR-29 a介导的。这些发现表明MSC介导的EM和小RNA信号转导的调节对于骨骼再生和无细胞治疗的巨大前景。
Administration of exosomes is considered an attractive cell-free approach to skeletal repair and pathological disease treatment. However, poor yield for the production technique and unexpected therapeutic efficacy of exosomes have been obstacles to their widespread use in clinical practices. Here, we report an alternative strategy to produce exosome-related vesicles with high yields and improved regenerative capability. An extrusion approach was employed to amass exosome mimetics (EMs) from human mesenchymal stem cells (hMSCs). The collected EMs had a significantly increased proportion of vesicles positive for the exosome specific CD-63 marker compared with MSC-derived exosomes. EMs were further obtained from genetically modified hMSCs in which expression of noggin, a natural bone morphogenetic protein antagonist, was downregulated to enhance osteogenic properties of EMs. Moreover, the administration of hMSCEMs in conjunction with an injectable chitosan hydrogel into mouse non-healing calvarial defects demonstrated robust bone regeneration. Importantly, mechanistic studies revealed that the enhanced osteogenesis by EMs in which noggin was suppressed was mediated via inhibition of miR-29a. These findings demonstrate the great promise of MSC-mediated EMs and modulation of small RNA signaling for skeletal regeneration and cell-free therapy.
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影响因子：
28.1
作者：
Mochizuki, Mayumi;Guc, Esra;Martino, Mikael M
通讯作者：
Martino, Mikael M
影响因子：
23.9
作者：
Caplan AI;Correa D
通讯作者：
Correa D
影响因子：
46.9
作者：
Alvarez-Erviti, Lydia;Seow, Yiqi;Wood, Matthew J. A.
通讯作者：
Wood, Matthew J. A.
DOI：
10.1016/j.jconrel.2015.07.030
发表时间：
2015-12-10
期刊：
Journal of controlled release : official journal of the Controlled Release Society
影响因子：
--
作者：
Batrakova EV;Kim MS
通讯作者：
Kim MS
影响因子：
41.2
作者：
Chaudhuri O;Gu L;Klumpers D;Darnell M;Bencherif SA;Weaver JC;Huebsch N;Lee HP;Lippens E;Duda GN;Mooney DJ
通讯作者：
Mooney DJ