Exosomes Secreted by Human-Induced Pluripotent Stem Cell-Derived Mesenchymal Stem Cells Repair Critical-Sized Bone Defects through Enhanced Angiogenesis and Osteogenesis in Osteoporotic Rats.
Exosomes Secreted by Human-Induced Pluripotent Stem Cell-Derived Mesenchymal Stem Cells Repair Critical-Sized Bone Defects through Enhanced Angiogenesis and Osteogenesis in Osteoporotic Rats.
复制标题
人诱导多能干细胞衍生的间充质干细胞分泌的外泌体通过增强骨质疏松大鼠的血管生成和骨生成来修复严重大小的骨缺损
DOI：
10.7150/ijbs.14809
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发表时间：
2016
影响因子：
9.2
通讯作者：
Li X
中科院分区：
文献类型：
--
作者：
Qi X;Zhang J;Yuan H;Xu Z;Li Q;Niu X;Hu B;Wang Y;Li X
创伤、严重感染、肿瘤切除及骨骼畸形等引起的骨缺损是骨科常见的疾病，也是骨科手术面临的主要挑战，目前尚无有效的解决方法。因此，需要新的治疗方法来开发没有副作用的再生程序。由源自人诱导多能干细胞（hiPSC，hiPSC-MSC-Exos）的间充质干细胞（MSC）分泌的外泌体结合了MSC和iPSC两者的优点，没有免疫原性。然而，目前还没有关于hiPSC-MSC-Exos在骨质疏松条件下增强血管生成和成骨的应用的报道。在使用前分离并鉴定HiPSC-MSC-Exos。观察hiPSC-MSC-Exos对去卵巢大鼠骨髓间充质干细胞（rBMSCs-OVX）体外增殖和成骨分化的影响。在体内，将hiPSC-MSC-Exos植入去卵巢大鼠的临界大小骨缺损中，通过显微CT、荧光标记分析、显微灌注、组织学和免疫组织化学分析检测骨再生和血管生成。体外实验结果表明，hiPSC-MSC-Exos可促进rBMSCs-OVX细胞增殖，提高碱性磷酸酶（ALP）活性，上调成骨相关基因的mRNA和蛋白表达。体内实验显示，hiPSC-MSC-Exos显著刺激了卵巢切除大鼠中临界尺寸颅骨缺损中的骨再生和血管生成。hiPSC-MSC-Exos的作用随着浓度的增加而增加。在这项研究中，我们表明hiPSC-MSC-Exos有效地刺激rBMSCs-OVX的增殖和成骨分化，其效果随着外泌体浓度的增加而增加。进一步的分析表明，hiPSC-MSC-Exos+β-TCP支架的应用通过增强卵巢切除大鼠模型中的血管生成和成骨来促进临界尺寸颅骨缺损中的骨再生。
Bone defects caused by trauma, severe infection, tumor resection and skeletal abnormalities are common osteoporotic conditions and major challenges in orthopedic surgery, and there is still no effective solution to this problem. Consequently, new treatments are needed to develop regeneration procedures without side effects. Exosomes secreted by mesenchymal stem cells (MSCs) derived from human induced pluripotent stem cells (hiPSCs, hiPSC-MSC-Exos) incorporate the advantages of both MSCs and iPSCs with no immunogenicity. However, there are no reports on the application of hiPSC-MSC-Exos to enhance angiogenesis and osteogenesis under osteoporotic conditions. HiPSC-MSC-Exos were isolated and identified before use. The effect of hiPSC-MSC-Exos on the proliferation and osteogenic differentiation of bone marrow MSCs derived from ovariectomized (OVX) rats (rBMSCs-OVX) in vitro were investigated. In vivo, hiPSC-MSC-Exos were implanted into critical size bone defects in ovariectomized rats, and bone regeneration and angiogenesis were examined by microcomputed tomography (micro-CT), sequential fluorescent labeling analysis, microfil perfusion and histological and immunohistochemical analysis. The results in vitro showed that hiPSC-MSC-Exos enhanced cell proliferation and alkaline phosphatase (ALP) activity, and up-regulated mRNA and protein expression of osteoblast-related genes in rBMSCs-OVX. In vivo experiments revealed that hiPSC-MSC-Exos dramatically stimulated bone regeneration and angiogenesis in critical-sized calvarial defects in ovariectomized rats. The effect of hiPSC-MSC-Exos increased with increasing concentration. In this study, we showed that hiPSC-MSC-Exos effectively stimulate the proliferation and osteogenic differentiation of rBMSCs-OVX, with the effect increasing with increasing exosome concentration. Further analysis demonstrated that the application of hiPSC-MSC-Exos+β-TCP scaffolds promoted bone regeneration in critical-sized calvarial defects by enhancing angiogenesis and osteogenesis in an ovariectomized rat model.