Extracellular Vesicles of Stem Cells to Prevent BRONJ
Extracellular Vesicles of Stem Cells to Prevent BRONJ
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DOI：
10.1177/0022034520906793
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发表时间：
2020-03-02
影响因子：
7.6
通讯作者：
Hibi, H.
中科院分区：
文献类型：
--
作者：
Watanabe, J.;Sakai, K.;Hibi, H.
细胞外囊泡（EV）大小为数十至数百纳米，是细胞分泌的用于细胞间通讯的囊泡。间充质干细胞（MSC-EV）释放的 EV 具有治疗多种疾病的潜力。本研究旨在确定 MSC-EV 对双磷酸盐相关颌骨坏死 (BRONJ) 的影响，该病的发病机制和治疗方法尚未确定。为此，在体外对骨髓细胞和成纤维细胞施用唑来膦酸（ZOL）。在体内，通过给大鼠注射 ZOL 并拔牙来制作 BRONJ 模型。对每个 MSC-EV 治疗组和未治疗组进行组织学和分子学比较。在体外，未治疗组的 β-半乳糖苷酶阳性细胞数量增加，衰老相关基因 p21、pRB 和衰老相关炎症细胞因子的表达增加。相反，MSC-EV 给药减少了衰老细胞的数量以及 p21、pRB 和炎症细胞因子的表达水平。在体内，在未治疗组中，牙槽部分被口腔上皮覆盖，留下暴露的骨头。相反，在 MSC-EV 治疗组中，牙槽窝愈合了。此外，在未治疗组中，牙槽窝中存在β-半乳糖苷酶阳性细胞，并与CD90和骨膜素阳性细胞共定位。然而，MSC-EV治疗组中β-半乳糖苷酶阳性细胞很少。此外，与未治疗组相比，MSC-EV治疗组中干细胞标志物Bmi1和Hmga2以及血管内皮标志物VEGF的基因表达显着增加。这些结果表明，MSC-EV 可防止 ZOL 诱导的干细胞、成骨细胞和成纤维细胞衰老，并减少炎症细胞因子。此外，MSC-EV 的施用可以防止参与伤口愈合的细胞衰老以及衰老细胞周围慢性炎症的扩散，从而促进血管生成和骨再生并预防 BRONJ。
Extracellular vesicles (EVs), several tens to hundreds of nanometers in size, are vesicles secreted by cells for intercellular communication. EVs released from mesenchymal stem cells (MSC-EVs) have the potential to treat multiple diseases. This study aimed to determine the effects of MSC-EVs on bisphosphonate-related osteonecrosis of the jaw (BRONJ), whose pathogenesis and treatment are not yet established. To this end, zoledronic acid (ZOL) was administered to bone marrow cells and fibroblasts in vitro. In vivo, a BRONJ model was produced by administering ZOL to rats and extracting teeth. Each MSC-EV-treated and nontreated group was compared histologically and molecularly. In vitro, the nontreated group showed an increased number of beta-galactosidase-positive cells and expression of senescence-associated genes p21, pRB and senescence-related inflammatory cytokines. Conversely, MSC-EV administration decreased the number of senescent cells and expression levels of p21, pRB and inflammatory cytokines. In vivo, in the nontreated group, the socket was partially uncovered by the oral epithelium, leaving an exposed bone. Conversely, in the MSC-EV-treated group, the socket was healed. Besides, in the nontreated group, beta-galactosidase-positive cells existed in the socket and colocalized with the CD90 and periostin-positive cells. However, there were few beta-galactosidase-positive cells in the MSC-EV-treated group. Furthermore, gene expression of stem cell markers Bmi1 and Hmga2 and the vascular endothelial marker VEGF was significantly increased in the MSC-EV-treated group, compared with that in the nontreated group. These results indicate that MSC-EVs prevent ZOL-induced senescence in stem cells, osteoblasts, and fibroblasts and reduce inflammatory cytokines. Furthermore, administration of MSC-EVs prevented senescence of cells involved in wound healing and the spread of chronic inflammation around senescent cells, thereby promoting angiogenesis and bone regeneration and preventing BRONJ.