Endothelial Progenitor Cells (EPCs) as Gene Carrier System for Rat Model of Human Glioma

Abstract

BackgroundDue to their unique property to migrate to pathological lesions, stem cells are used as a delivery vehicle for therapeutic genes to tumors, especially for glioma. It is critically important to track the movement, localization, engraftment efficiency and functional capability or expression of transgenes of selected cell populations following transplantation. The purposes of this study were to investigate whether 1) intravenously administered, genetically transformed cord blood derived EPCs can carry human sodium iodide symporter (hNIS) to the sites of tumors in rat orthotopic model of human glioma and express transgene products, and 2) whether accumulation of these administered EPCs can be tracked by different in vivo imaging modalities.Methods and ResultsCollected EPCs were cultured and transduced to carry hNIS. Cellular viability, differential capacity and Tc-99m uptake were determined. Five to ten million EPCs were intravenously administered and Tc-99-SPECT images were acquired on day 8, to determine the accumulation of EPCs and expression of transgenes (increase activity of Tc-99m) in the tumors. Immunohistochemistry was performed to determine endothelial cell markers and hNIS positive cells in the tumors. Transduced EPCs were also magnetically labeled and accumulation of cells was confirmed by MRI and histochemistry. SPECT analysis showed increased activity of Tc-99m in the tumors that received transduced EPCs, indicative of the expression of transgene (hNIS). Activity of Tc-99m in the tumors was also dependent on the number of administered transduced EPCs. MRI showed the accumulation of magnetically labeled EPCs. Immunohistochemical analysis showed iron and hNIS positive and, human CD31 and vWF positive cells in the tumors.ConclusionEPC was able to carry and express hNIS in glioma following IV administration. SPECT detected migration of EPCs and expression of the hNIS gene. EPCs can be used as gene carrier/delivery system for glioma therapy as well as imaging probes.

Application of Umbilical Cord Blood Derived Stem Cells in Diseases of the Nervous System

“…We found that EF1 and CMV promoters are ideal for high level expression of transgene [89]. Recently, we have determine the migration and accumulation of genetically altered EPCs where UCB derived EPCs transduced to carry human sodium iodide symporter (hNIS) gene and injected into glioma bearing rats and we observed their migration to tumor site and functional expression of transgenes [91]. These experiments clearly highlight the capability of EPCs as gene delivery vehicles.…”

“…Tumor invasive properties of EPCs allow its possibility to use them as gene delivery vehicles to tumors [87–89]. EPCs based gene delivery offers several advantages over traditional gene therapy based on vectors or virus due to EPCs’ ability to cross tumor blood brain barrier (TBBB) and also their extended homing properties at the disease site [90,91]. Vascular endothelial growth factor (VEGF) gene delivery through EPCs enhances the proliferation and migration of human aortic endothelial cells following ultrasonic microbubble transfection (UMT) [92].…”

Endothelial Progenitor Cells Combined with Cytosine Deaminase-Endostatin for Suppression of Liver Carcinoma

“…The EPCs can be used as part of a gene carrier/delivery system for glioma therapy and imaging probes. 31 Santarelli et al 32 used mouse tumor models to demonstrate that the BMderived EPCs are greatly mobilized into the bloodstream, and specifically migrate to tumor tissues.…”

A new mosaic pattern in glioma vascularization: exogenous endothelial progenitor cells integrating into the vessels containing tumor-derived endothelial cells

“…Owing to their unique property of migration to pathological lesions, stem cells are considered to be used as a delivery vehicle for therapeutic genes to tumors, especially for glioma [11 -13]. EPCs, a subpopulation of pluripotent hematopoietic stem cells (HSCs), could migrate actively to glioma [14-16], being incorporated directly in the neovasculature with high specificity [17-19].…”