Exosomes secreted from mutant-HIF-1-modified bone-marrow-derived mesenchymal stem cells attenuate early steroid-induced avascular necrosis of femoral head in rabbit
Exosomes secreted from mutant-HIF-1-modified bone-marrow-derived mesenchymal stem cells attenuate early steroid-induced avascular necrosis of femoral head in rabbit
复制标题
突变型 HIF-1α 修饰的骨髓间充质干细胞分泌的外泌体可减轻早期类固醇诱导的兔股骨头缺血性坏死
DOI：
10.1002/cbin.10869
复制
发表时间：
2017-12-01
影响因子：
3.9
通讯作者：
Huang, Jianhua
中科院分区：
文献类型：
--
作者：
Li, Haile;Liu, Danping;Huang, Jianhua
间充质干细胞（MSC）衍生的外泌体对受损或患病组织表现出保护作用。缺氧诱导因子1（HIF-1）在骨发育中起关键作用。然而，HIF-1在常氧条件下易于生物降解。用携带HIF-1编码序列（CDS）中的三重点突变（氨基酸402、564和803）的腺病毒转染骨髓来源的间充质干细胞（BMSC）。突变体HIF-1能在常氧条件下高效表达功能蛋白。迄今为止，尚无研究报道突变HIF-1修饰的BMSCs分泌的exosomes在早期激素诱导的股骨头缺血性坏死（SANFH）恢复中的作用。在本研究中，我们首先分析了突变型（BMSC-Exos（MU））或野生型HIF-1（BMSC-Exos（WT））修饰的BMSCs来源的exosomes。体外实验观察BMSC-Exos（MU）和BMSC-Exos（WT）修饰的BMSCs的成骨分化能力，以及BMSC-Exos（MU）和BMSC-Exos（WT）对人脐静脉内皮细胞（HUVECs）血管生成的影响。此外，还对股骨头的愈合进行了体内评估。我们发现BMSC-Exos（MU）处理的BMSCs在体外的成骨分化潜能高于野生型组。此外，BMSC-Exos（MU）以剂量依赖性方式刺激HUVECs的增殖、迁移和管形成。与BMSC-Exos（WT）或PBS对照组相比，BMSC-Exos（MU）注射组的骨小梁重建和微血管密度增加，骨再生和血管生成明显加快。综上所述，我们的数据表明，BMSC-Exos（MU）通过增强骨生成和血管生成促进SANFH的修复。
Mesenchymal stem cells (MSCs)-derived exosomes exhibit protective effects on damaged or diseased tissues. Hypoxia-inducible factor 1 (HIF-1) plays a critical role in bone development. However, HIF-1 is easily biodegradable under normoxic conditions. The bone-marrow-derived mesenchymal stem cells (BMSCs) were transfected with adenovirus carrying triple point-mutations (amino acids 402, 564, and 803) in the HIF-1 coding sequence (CDS). The mutant HIF-1 can efficiently express functional proteins under normoxic conditions. To date, no study has reported the role of exosomes secreted by mutant HIF-1 modified BMSCs in the recovery of the early steroid-induced avascular necrosis of femoral head (SANFH). In this study, we firstly analyzed exosomes derived from BMSCs modified by mutant (BMSC-Exos(MU)) or wild-type HIF-1 (BMSC-Exos(WT)). In vitro, we investigated the osteogenic differentiation capacity of BMSCs modified by BMSC-Exos(MU) or BMSC-Exos(WT), and the angiogenesis effects of BMSC-Exos(MU) and BMSC-Exos(WT) on human umbilical vein endothelial cells (HUVECs). Besides, the healing of the femoral head was also assessed in vivo. We found that the potential of osteogenic differentiation of BMSCs treated with BMSC-Exos(MU) was higher than the wild-type group in vitro. In addition, BMSC-Exos(MU) stimulated the proliferation, migration, and tube formation of HUVECs in a dose-dependent manner. Compared with the BMSC-Exos(WT) or PBS control group, the injection of BMSC-Exos(MU) into the necrosis region markedly accelerated the bone regeneration and angiogenesis, which were indicated by the increased trabecular reconstruction and microvascular density. Taken together, our data suggest that BMSC-Exos(MU) facilitates the repair of SANFH by enhancing osteogenesis and angiogenesis.