A gene delivery system with a human artificial chromosome vector based on migration of mesenchymal stem cells towards human glioblastoma HTB14 cells

Abstract

Mesenchymal stem cells (MSCs) have been expected to become useful gene delivery vehicles against human malignant gliomas when coupled with an appropriate vector system, because they migrate towards the lesion. Human artificial chromosomes (HACs) are non-integrating vectors with several advantages for gene therapy, namely, no limitations on the size and number of genes that can be inserted. We investigated the migration of human immortalized MSCs bearing a HAC vector containing the herpes simplex virus thymidine kinase gene (HAC-tk-hiMSCs) towards malignant gliomas in vivo. Red fluorescence protein-labeled human glioblastoma HTB14 cells were implanted into a subcortical region in nude mice. Four days later, green fluorescence protein-labeled HAC-tk-hiMSCs were injected into a contralateral subcortical region (the HTB14/HAC-tk-hiMSC injection model). Tropism to the glioma mass and the route of migration were visualized by fluorescence microscopy and immunohistochemical staining. HAC-tk-hiMSCs began to migrate toward the HTB14 glioma area via the corpus callosum on day 4, and gathered around the HTB14 glioma mass on day 7. To test whether the delivered gene could effectively treat glioblastoma in vivo, HTB14/HAC-tk-hiMSC injected mice were treated with ganciclovir (GCV) or PBS. The HTB14 glioma mass was significantly reduced by GCV treatment in mice injected with HAC-tk-hiMSCs. It was confirmed that gene delivery by our HAC-hiMSC system was effective after migration of MSCs to the glioma mass in vivo. Therefore, MSCs containing HACs carrying an anticancer gene or genes may provide a new tool for the treatment of malignant gliomas and possibly of other tumor types.

Stem Cell-Mediated Delivery of Therapies in the Treatment of Glioma

“…Likewise NSC, mesenchymal stem cells (MSC) migrate towards glioma lesions and may be taken into consideration as gene delivery vehicles against human malignant gliomas [25]. Human bone marrow-derived MSC (hMSC) have been used as a cellular vehicle for the targeted delivery and local production of TRAIL at the glioma tumour site [26].…”

Terapia génica: opción terapéutica para neoplasias, infecciones y enfermedades monogénicas

“…Esto disminuiría la anormal tolerancia del tumor y favorecería la inmunidad, tanto contra las células tumorales que expresan B7, como contra las células del tumor original. 46,47 Éstas y otras estrategias se han ensayado frente a diferentes neoplasias, como cáncer de ovario, 48,49 melanoma, 50-52 cáncer de mama, 50 glioblastoma, 53,54 carcinoma hepatocelular 55 y neuroblastoma, 56 entre muchas otras. Cabe destacar que, al día de hoy, los protocolos oncológicos de TG están dirigidos a pacientes con metástasis, más que contra las neoplasias primarias.…”

Mesenchymal stem cells as therapeutic agents and in gene delivery for the treatment of glioma

“…Recently, HSV-tk-engineered MSCs in combination with systemic administration of ganciclovir have been used in the treatment of C6 glioma (Amano et al, 2009;Uchibori et al, 2009;Chang et al, 2010) and Panc02 pancreatic cancer (Zischek et al, 2009). When coupled with the HSV-tk-ganciclovir prodrug cancer gene therapy system, with delivery by either implantation into the opposite hemisphere or injection into xenografts, EC-MSCs have been demonstrated to inhibit U87 and HTB14 tumor growth and to prolong the survival of mice (Kinoshita et al, 2010;Bak et al, 2011;de Melo et al, 2015). Additionally, Matuskova et al (2010) have demonstrated the formation of gap junctions between AT-MSCs and human glioblastoma cells (8-MG-BA, 42-MG-BA, and U-118).…”