Gene therapy represents a promising treatment alternative for patients with malignant gliomas. Nevertheless, in the setting of these highly infiltrative tumors, transgene delivery remains a challenge. Indeed, viral vehicles tested in clinical trials often target only those tumor cells that are adjacent to the injection site. In this study, we examined the feasibility of using human mesenchymal stem cells (hMSC) to deliver a replication-competent oncolytic adenovirus (CRAd) in a model of intracranial malignant glioma. To do so, CRAds with a chimeric 5/3 fiber or RGD backbone with or without CXCR4 promoter driving E1A were examined with respect to replication and toxicity in hMSC, human astrocytes, and the human glioma cell line U87MG by quantitative polymerase chain reaction and membrane integrity assay. CRAd delivery by virus-loaded hMSC was then evaluated in vitro and in an in vivo model of mice bearing intracranial U87MG xenografts. Our results show that hMSC are effectively infected by CRAds that use the CXCR4 promoter. CRAd-CXCR4-RGD had the highest replication, followed by CRAd-CXCR4 -5/3, in hMSC, with comparable levels of toxicity. In U87MG tumor cells, CRAd-CXCR4 -5/3 showed the highest replication and toxicity. Virus-loaded hMSC effectively migrated in vitro and released CRAds that infected U87MG glioma cells. When injected away from the tumor site in vivo, hMSC migrated to the tumor and delivered 46-fold more viral copies than injection of CRAd-CXCR4 -5/3 alone. Taken together, these results indicate that hMSC migrate and deliver CRAd to distant glioma cells. This delivery strategy should be explored further, as it could improve the outcome of oncolytic virotherapy for glioma. STEM CELLS 2008;26:831-841 Disclosure of potential conflicts of interest is found at the end of this article.

Inflammatory bowel diseases (IBD) are a complex group of diseases involving alterations in mucosal immunity and gastrointestinal physiology during both initiation and progressive phases of the disease. At the core of these alterations are endothelial cells, whose continual adjustments in structure and function coordinate vascular supply, immune cell emigration, and regulation of the tissue environment. Expansion of the endothelium in IBD (angiogenesis), mediated by inflammatory growth factors, cytokines and chemokines, is a hallmark of active gut disease and is closely related to disease severity. The endothelium in newly formed or inflamed vessels differs from that in normal vessels in the production of and response to inflammatory cytokines, growth factors, and adhesion molecules, altering coagulant capacity, barrier function and blood cell recruitment in injury. This review examines the roles of the endothelium in the initiation and propagation of IBD pathology and distinctive features of the intestinal endothelium contributing to these conditions.

Injected hMSCs transduced with CRAds suppressed the growth of pulmonary metastases, presumably through viral amplification in the hMSCs. Thus, hMSCs may be an effective platform for the targeted delivery of CRAds to distant cancer sites such as metastatic breast cancer.

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