Exosomes/tricalcium phosphate combination scaffolds can enhance bone regeneration by activating the PI3K/Akt signaling pathway.
Exosomes/tricalcium phosphate combination scaffolds can enhance bone regeneration by activating the PI3K/Akt signaling pathway.
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外泌体/磷酸三钙组合支架可通过激活 PI3K/Akt 信号通路增强骨再生
DOI：
10.1186/s13287-016-0391-3
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发表时间：
2016-09-20
影响因子：
7.5
通讯作者：
Wang Y
中科院分区：
文献类型：
--
作者：
Zhang J;Liu X;Li H;Chen C;Hu B;Niu X;Li Q;Zhao B;Xie Z;Wang Y
最近，越来越多的证据表明，外泌体作为细胞自然分泌的纳米载体，在没有亲本细胞的情况下，能够在多种疾病模型中发挥治疗作用。然而，外泌体在骨缺损修复和再生中的应用鲜有报道，其潜在机制也鲜为人知。
将人诱导多能干细胞衍生的间充质干细胞外泌体（hiPS - MSC - Exos）与磷酸三钙（β - TCP）结合用于修复临界尺寸的颅骨骨缺损，并通过组织学检查评估其疗效。我们分别通过细胞计数、划痕实验和实时定量逆转录聚合酶链反应（qRT - PCR）评估了hiPS - MSC - Exos在体外对人骨髓间充质干细胞（hBMSCs）增殖、迁移和成骨分化的影响。还利用基因表达谱分析和生物信息学分析来确定修复过程中的潜在机制。
我们发现，与纯β - TCP支架相比，外泌体/β - TCP复合支架能够增强成骨作用。体外实验表明，外泌体能够从β - TCP中释放出来，并能被hBMSCs内化。此外，外泌体被hBMSCs内化能够显著增强hBMSCs的增殖、迁移和成骨分化。进一步地，基因表达谱分析和生物信息学分析表明，外泌体/β - TCP复合支架显著改变了参与磷脂酰肌醇 - 3 - 激酶/蛋白激酶B（PI3K/Akt）信号通路的一系列基因的表达。功能研究进一步证实，PI3K/Akt信号通路是外泌体诱导hBMSCs成骨反应过程中的关键介导因子。
我们提出，外泌体能够通过激活hBMSCs的PI3K/Akt信号通路增强β - TCP的骨诱导性，这意味着外泌体/β - TCP复合支架比纯β - TCP支架具有更好的成骨活性。这些结果表明，自然分泌的纳米载体——外泌体可作为一种生物活性材料来提高生物材料的生物活性，并且hiPS - MSC - Exos与β - TCP支架结合可潜在地用于修复骨缺损。
本文的网络版（doi:10.1186/s13287 - 016 - 0391 - 3）包含补充材料，授权用户可获取。
BackgroundRecently, accumulating evidence has shown that exosomes, the naturally secreted nanocarriers of cells, can exert therapeutic effects in various disease models in the absence of parent cells. However, application of exosomes in bone defect repair and regeneration has been rarely reported, and little is known regarding their underlying mechanisms.MethodsExosomes derived from human-induced pluripotent stem cell-derived mesenchymal stem cells (hiPS-MSC-Exos) were combined with tricalcium phosphate (β-TCP) to repair critical-sized calvarial bone defects, and the efficacy was assessed by histological examination. We evaluated the in vitro effects of hiPSC-MSC-Exos on the proliferation, migration, and osteogenic differentiation of human bone marrow-derived mesenchymal stem cells (hBMSCs) by cell-counting, scratch assays, and qRT-PCR, respectively. Gene expression profiling and bioinformatics analyses were also used to identify the underlying mechanisms in the repair.ResultsWe found that the exosome/β-TCP combination scaffolds could enhance osteogenesis as compared to pure β-TCP scaffolds. In vitro assays showed that the exosomes could release from β-TCP and could be internalized by hBMSCs. In addition, the internalization of exosomes into hBMSCs could profoundly enhance the proliferation, migration, and osteogenic differentiation of hBMSCs. Furthermore, gene expression profiling and bioinformatics analyses demonstrated that exosome/β-TCP combination scaffolds significantly altered the expression of a network of genes involved in the PI3K/Akt signaling pathway. Functional studies further confirmed that the PI3K/Akt signaling pathway was the critical mediator during the exosome-induced osteogenic responses of hBMSCs.ConclusionsWe propose that the exosomes can enhance the osteoinductivity of β-TCP through activating the PI3K/Akt signaling pathway of hBMSCs, which means that the exosome/β-TCP combination scaffolds possess better osteogenesis activity than pure β-TCP scaffolds. These results indicate that naturally secreted nanocarriers-exosomes can be used as a bioactive material to improve the bioactivity of the biomaterials, and that hiPS-MSC-Exos combined with β-TCP scaffolds can be potentially used for repairing bone defects.
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影响因子：
7.7
作者：
Rahman MJ;Regn D;Bashratyan R;Dai YD
通讯作者：
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