Platelet-derived growth factor BB mediates the tropism of human mesenchymal stem cells for malignant gliomas.
Platelet-derived growth factor BB mediates the tropism of human mesenchymal stem cells for malignant gliomas.
复制标题
血小板衍生的生长因子BB介导人间充质干细胞的性质因子神经胶质瘤。
DOI：
10.1227/01.neu.0000363149.58885.2e
复制
发表时间：
2010-01
期刊：
影响因子：
4.8
通讯作者：
Lang FF
中科院分区：
文献类型：
--
作者：
Hata N;Shinojima N;Gumin J;Yong R;Marini F;Andreeff M;Lang FF
骨髓间充质干细胞（hMSCs）能够在全身递送后定位于胶质瘤，并可用于胶质瘤治疗。然而，hMSCs对胶质瘤的趋化性的机制仍不清楚。体外研究表明，血小板衍生生长因子（PDGF-BB）可能介导这种向性。然而，PDGF-BB的因果作用尚未在体内得到证实。因此，我们在体外和体内测试了PDGF-BB介导hMSCs对胶质瘤的吸引力的假设。体外侵袭实验表明，与低分泌胶质瘤相比，更多的hMSCs向胶质瘤细胞（U87或LN 229）迁移，这些胶质瘤细胞被设计为分泌高水平的PDGF-BB。抗PDGF-BB中和抗体消除了这种迁移增加。用抗PDGF受体-β的抑制性抗体预处理hMSC也减少hMSC迁移。为了证明PDGF-BB介导hMSC在体内的定位，将hMSCs-Ad-Luc注射到具有原位7天大的U87-PDGF-BB-高分泌或U87-PDGF-BB-低分泌异种移植物的小鼠的颈动脉中，并通过生物发光成像进行分析。与PDGF-BB-低异种移植物相比，在PDGF-BB-高异种移植物中观察到hMSC的统计学显著增加。为了控制PDGF-BB诱导的肿瘤大小和血管分布的差异，将gfp标记的hMSC注射到携带4天大PDGF-BB高分泌异种移植物或7天大PDGF-BB低分泌异种移植物的动物的颈动脉中。在这些时候，肿瘤具有相似的大小和血管密度。与PDGF-BB-低分泌异种移植物相比，统计学上显著更多的hMSC定位于PDGF-BB-高分泌异种移植物。用抗PDGFR-β抑制性抗体预处理hMSC降低了hMSC在该颅内模型中的定位。PDGF-BB在体外和体内增加了hMSCs对胶质瘤的吸引力，并且这种向性是通过hMSCs上的PDGF-β受体介导的。这些发现可以用于推进hMSC治疗。
Bone marrow-derived human mesenchymal stem cells (hMSCs) are capable of localizing to gliomas after systemic delivery and can be used in glioma therapy. However, the mechanism underlying the tropism of hMSCs for gliomas remains unclear. In vitro studies suggest that platelet derived growth factor (PDGF-BB) may mediate this tropism. However, a causal role of PDGF-BB has not been demonstrated in vivo. Therefore, we tested the hypothesis that PDGF-BB mediates the attraction of hMSCs to gliomas in vitro and in vivo. In vitro invasion assays showed that significantly more hMSCs migrated toward glioma cells (U87 or LN229) engineered to secrete high levels of PDGF-BB compared with low-secreting gliomas. Anti-PDGF-BB-neutralizing antibody abrogated this increase in migration. Pretreatment of hMSCs with inhibitory antibodies against PDGF receptor-β also reduced hMSC migration. To demonstrate that PDGF-BB mediates the localization of hMSCs in vivo, hMSCs-Ad-Luc were injected into the carotid artery of mice harboring orthotopic 7 day old U87-PDGF-BB-high secreting or U87-PDGF-BB-low secreting xenografts and analyzed by bioluminescence imaging. Statistically significant increases in hMSCs were seen within PDGF-BB-high xenografts compared with PDGF-BB-low xenografts. To control for PDGF-BB-induced differences in tumor size and vascularity, gfp-labeled hMSCs were injected into the carotid arteries of animals harboring 4-day old PDGF-BB-high secreting xenografts or 7-day old PDGF-BB-low secreting xenografts. At these times tumors had similar size and vessel density. Statistically significant more hMSCs localized to PDGF-BB-high secreting xenografts compared with PDGF-BB-low secreting xenografts. Pretreatment of hMSCs with anti-PDGFR-β-inhibitory antibodies decreased the localization of hMSCs in this intracranial model. PDGF-BB increases the attraction of hMSCs for gliomas in vitro and in vivo, and this tropism is mediated via PDGF-β receptors on hMSCs. These finding can be exploited for advancing hMSC treatment.