Bone mesenchymal stem cells stimulation by magnetic nanoparticles and a static magnetic field: release of exosomal miR-1260a improves osteogenesis and angiogenesis.
Bone mesenchymal stem cells stimulation by magnetic nanoparticles and a static magnetic field: release of exosomal miR-1260a improves osteogenesis and angiogenesis.
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磁性纳米粒子和静磁场刺激骨间充质干细胞：外泌体 miR-1260a 的释放可改善成骨和血管生成
DOI：
10.1186/s12951-021-00958-6
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发表时间：
2021-07-13
影响因子：
10.2
通讯作者：
Wu Z
中科院分区：
文献类型：
--
作者：
Wu D;Chang X;Tian J;Kang L;Wu Y;Liu J;Wu X;Huang Y;Gao B;Wang H;Qiu G;Wu Z
背景干细胞来源的外泌体的治疗潜力最近引起了越来越多的兴趣，因为它们可以发挥干细胞类似的旁分泌功能并克服干细胞移植的局限性。源自骨间充质干细胞（BMSC-Exos）的外泌体已被证实可促进成骨和血管生成。磁性纳米颗粒（例如 Fe3O4、γ-Fe2O3）与静磁场 (SMF) 相结合，通常用于促进伤口愈合和骨再生。因此，本研究旨在评估用低剂量 Fe3O4 纳米颗粒预处理（有或没有 SMF）的 BMSC 衍生的外泌体是否在骨再生中发挥优异的促成骨和促血管生成活性及其相关机制。 磁性纳米粒子和/或SMF。然后，通过超速离心分离新的外泌体并进行表征。随后，我们进行了体外实验，测量了成骨分化、细胞增殖、细胞迁移和管形成，然后建立了体内临界尺寸颅骨缺损大鼠模型。比较外泌体之间的 miRNA 表达谱，以检测改善成骨和血管生成的潜在机制。最后，通过一系列体外功能获得和功能丧失实验证实了外泌体 miRNA 在骨再生过程中的功能。结果选择 50 µg/mL Fe3O4 纳米颗粒和 100 mT SMF 作为最佳磁性条件来制备两种新型外泌体，命名为 BMSC-Fe3O4-Exos 和 BMSC-Fe3O4-SMF-Exos。与 BMSC-Exos 相比，它们均被证实在体外和体内增强成骨和血管生成，其中 BMSC-Fe3O4-SMF-Exos 的效果最显着。研究发现这种促进作用与BMSC-Fe3O4-SMF-Exos中高度丰富的miR-1260a有关。此外，miR-1260a 被证实可分别通过抑制 HDAC7 和 COL4A2 来增强成骨和血管生成。结论这些结果表明，低剂量的 Fe3O4 纳米颗粒与 SMF 结合触发外泌体增强成骨和血管生成，并且外泌体 miR-1260a 靶向 HDAC7 和 COL4A2 在此过程中发挥着至关重要的作用。这项工作可以为未来促进组织工程骨再生提供新的方案。图解摘要
BackgroundThe therapeutic potential of exosomes derived from stem cells has attracted increasing interest recently, because they can exert similar paracrine functions of stem cells and overcome the limitations of stem cells transplantation. Exosomes derived from bone mesenchymal stem cells (BMSC-Exos) have been confirmed to promote osteogenesis and angiogenesis. The magnetic nanoparticles (eg. Fe3O4, γ-Fe2O3) combined with a static magnetic field (SMF) has been commonly used to increase wound healing and bone regeneration. Hence, this study aims to evaluate whether exosomes derived from BMSCs preconditioned with a low dose of Fe3O4nanoparticles with or without the SMF, exert superior pro-osteogenic and pro-angiogenic activities in bone regeneration and the underlying mechanisms involved.MethodsTwo novel types of exosomes derived from preconditioned BMSCs that fabricated by regulating the contents with the stimulation of magnetic nanoparticles and/or a SMF. Then, the new exosomes were isolated by ultracentrifugation and characterized. Afterwards, we conducted in vitro experiments in which we measured osteogenic differentiation, cell proliferation, cell migration, and tube formation, then established an in vivo critical-sized calvarial defect rat model. The miRNA expression profiles were compared among the exosomes to detect the potential mechanism of improving osteogenesis and angiogenesis. At last, the function of exosomal miRNA during bone regeneration was confirmed by utilizing a series of gain- and loss-of-function experiments in vitro.Results50 µg/mL Fe3O4nanoparticles and a 100 mT SMF were chosen as the optimum magnetic conditions to fabricate two new exosomes, named BMSC-Fe3O4-Exos and BMSC-Fe3O4-SMF-Exos. They were both confirmed to enhance osteogenesis and angiogenesis in vitro and in vivo compared with BMSC-Exos, and BMSC-Fe3O4-SMF-Exos had the most marked effect. The promotion effect was found to be related to the highly riched miR-1260a in BMSC-Fe3O4-SMF-Exos. Furthermore, miR-1260a was verified to enhance osteogenesis and angiogenesis through inhibition of HDAC7 and COL4A2, respectively.ConclusionThese results suggest that low doses of Fe3O4nanoparticles combined with a SMF trigger exosomes to exert enhanced osteogenesis and angiogenesis and that targeting of HDAC7 and COL4A2 by exosomal miR-1260a plays a crucial role in this process. This work could provide a new protocol to promote bone regeneration for tissue engineering in the future.Graphical abstract
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影响因子：
4.8
作者：
He, Yu;Yu, Lingjia;Qiu, Guixing
通讯作者：
Qiu, Guixing
DOI：
10.1126/science.aau6977
发表时间：
2020-02-07
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Kalluri R;LeBleu VS
通讯作者：
LeBleu VS
影响因子：
16
作者：
Imai T;Takahashi Y;Nishikawa M;Kato K;Morishita M;Yamashita T;Matsumoto A;Charoenviriyakul C;Takakura Y
通讯作者：
Takakura Y
影响因子：
2.1
作者：
Kazemi, Mansure;Azami, Mahmoud;Farajollahi, Mohammad
通讯作者：
Farajollahi, Mohammad
影响因子：
13.6
作者：
Lee, Ju-Ro;Park, Bong-Woo;Kim, Byung-Soo
通讯作者：
Kim, Byung-Soo