Human bone marrow-derived mesenchymal stem cells in the treatment of gliomas
Human bone marrow-derived mesenchymal stem cells in the treatment of gliomas
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DOI：
10.1158/0008-5472.can-04-1874
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发表时间：
2005-04-15
期刊：
影响因子：
11.2
通讯作者：
Lang, FF
中科院分区：
文献类型：
--
作者：
Nakamizo, A;Marini, F;Lang, FF
患有人类恶性神经胶质瘤的患者的较差存活率部分地与不能将治疗剂递送至肿瘤有关。因为它已被建议，循环骨髓来源的干细胞可以招募到实体器官组织应力的反应，我们假设，人骨髓来源的间充质干细胞（hMSC）可能有一个向性的脑肿瘤，从而可以被用作运载工具胶质瘤治疗。为了测试这一点，我们从正常志愿者的骨髓中分离hMSC，荧光标记细胞，并将其注射到携带人类胶质瘤颅内异种移植物（U87，U251和LN 229）的小鼠的颈动脉中。hMSC仅见于脑肿瘤内，无论细胞是否被注射到同侧或对侧颈动脉中。相比之下，颈动脉内注射成纤维细胞或U87胶质瘤细胞导致递送细胞的广泛分布，而没有肿瘤特异性。为了评估hMSCs追踪人脑胶质瘤的潜力，我们将hMSCs直接注射到与已建立的人脑胶质瘤相对的大脑半球中，并显示hMSCs能够在体内迁移到异种移植物中。同样，体外Matrigel侵袭试验表明，来自胶质瘤而不是来自成纤维细胞或星形胶质细胞的条件培养基支持hMSC的迁移，并且血小板衍生生长因子、表皮生长因子或基质细胞衍生因子-1 α而不是碱性成纤维细胞生长因子或血管内皮生长因子增强hMSC迁移。为了测试hMSC递送治疗剂的潜力，将hMSC工程化以释放IFN-β（hMSC-IFN-β）。体外共培养和Transwell实验显示hMSC-IFN-β对人胶质瘤的有效性。体内实验显示，与对照组相比，hMSC-IFN-β治疗人U87颅内胶质瘤异种移植物显著增加动物存活率（P < 0.05）。我们的结论是，人骨髓间充质干细胞可以整合到人胶质瘤血管内或局部交付后，这种植入可能是由生长因子介导的，这种嗜性的人骨髓间充质干细胞的人胶质瘤可以利用治疗优势。
The poor survival of patients with human malignant gliomas relates partly to the inability to deliver therapeutic agents to the tumor. Because it has been suggested that circulating bone marrow-derived stem cells can be recruited into solid organs in response to tissue stresses, we hypothesized that human bone marrow-derived mesenchymal stem cells (hMSC) may have a tropism for brain tumors and thus could be used as delivery vehicles for glioma therapy. To test this, we isolated hMSCs from bone marrow of normal volunteers, fluorescently labeled the cells, and injected them into the carotid artery of mice bearing human glioma intracranial xenografts (U87, U251, and LN229). hMSCs were seen exclusively within the brain tumors regardless of whether the cells were injected into the ipsilateral or contralateral carotid artery. In contrast, intracarotid injections of fibroblasts or U87 glioma cells resulted in widespread distribution of delivered cells without tumor specificity. To assess the potential of hMSCs to track human gliomas, we injected hMSCs directly into the cerebral hemisphere opposite an established human glioma and showed that the hMSCs were capable of migrating into the xenograft in vivo. Likewise, in vitro Matrigel invasion assays showed that conditioned medium from gliomas, but not from fibroblasts or astrocytes, supported the migration of hMSCs and that platelet-derived growth factor, epidermal growth factor, or stromal cell-derived factor-1 alpha, but not basic fibroblast growth factor or vascular endothelial growth factor, enhanced hMSC migration. To test the potential of hMSCs to deliver a therapeutic agent, hMSCs were engineered to release IFN-beta (hMSC-IFN-beta). In vitro coculture and Transwell experiments showed the efficacy of hMSC-IFN-beta against human gliomas. In vivo experiments showed that treatment of human U87 intracranial glioma xenografts with hMSC-IFN-beta significantly increase animal survival compared with controls (P < 0.05). We conclude that hMSCs can integrate into human gliomas after intravascular or local delivery, that this engraftment may be mediated by growth factors, and that this tropism of hMSCs for human gliomas can be exploited to therapeutic advantage.