Human Bone Marrow–Derived Mesenchymal Stem Cells in the Treatment of Gliomas

Abstract

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-1A, 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-B (hMSC-IFN-B). In vitro coculture and Transwell experiments showed the efficacy of hMSC-IFN-B against human gliomas. In vivo experiments showed that treatment of human U87 intracranial glioma xenografts with hMSC-IFN-B 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. (Cancer Res 2005; 65(8): 3307-18)

The anti-glioma effect of suicide gene therapy using BMSC expressing HSV/TK combined with overexpression of Cx43 in glioma cells

“…Several studies have shown that mesenchymal stem cells have ability to track and envelop infiltrating glioma cells like NSCs, as described in this study. [3][4][5][6] Therefore, BMSCs might be a rational substitute for NSCs as promising therapeutic gene delivery vehicles for tumor because of a good tropism for malignant glioma.…”

“…[1][2][3] BMSCs are well suited for clinical application because they are easily obtained from patients themselves and the autologous transplantation is possible to avoid immunologic incompatibilities. Of the various progenitor cells that exist in bone marrow, BMSCs are particularly attractive for clinical use because they can be easily isolated and expanded in culture, and genetically manipulated using currently available molecular techniques.…”

“…[4][5][6] BMSCs have been genetically modified to express interferon-b with potent tropism for disseminating glioma cells and show strong anti-tumor effects both in vitro and in vivo. 3 Herpes simplex virus thymidine kinase (HSV-TK)/ ganciclovir (GCV) suicide gene therapy has been considered as one of the most promising therapeutic strategies for malignant gliomas. Theorectically, it can be used for various malignant tumors no matter what changes of molecular pathology they have.…”

HSV-1 amplicon viral vector-mediated gene transfer to human bone marrow-derived mesenchymal stem cells

“…16,25 To investigate whether the transduction with pHGCX HSV-1 amplicon viral vector will alter the tumor tropism of BM-hMSCs, in vitro migration chamber assays were performed. In the presence of either conditioned medium from NHAs or medium alone, both the naı¨ve and pHGCX-transduced BM-hMSCs did not migrate toward the underside of the membrane.…”

“…[14][15][16] This approach would obviate the need for long-term selection of stable clones that may potentially lead to senescence, lost of multilineage differentiation capacity and lost of migratory potential of BM-hMSCs. The development of an efficient gene delivery vector to achieve high expression of therapeutic genes in BM-hMSCs is needed.…”