title: Approaches to utilize mesenchymal progenitor cells as cellular vehicles.
abstract: Mammalian cells represent a novel vector approach for gene delivery that overcomes major drawbacks of viral and nonviral vectors and couples cell therapy with gene delivery. A variety of cell types have been tested in this regard, confirming that the ideal cellular vector system for ex vivo gene therapy has to comply with stringent criteria and is yet to be found. Several properties of mesenchymal progenitor cells (MPCs), such as easy access and simple isolation and propagation procedures, make these cells attractive candidates as cellular vehicles. In the current work, we evaluated the potential utility of MPCs as cellular vectors with the intent to use them in the cancer therapy context. When conventional adenoviral (Ad) vectors were used for MPC transduction, the highest transduction efficiency of MPCs was 40%. We demonstrated that Ad primary-binding receptors were poorly expressed on MPCs, while the secondary Ad receptors and integrins presented in sufficient amounts. By employing Ad vectors with incorporated integrin-binding motifs (Ad5lucRGD), MPC transduction was augmented tenfold, achieving efficient genetic loading of MPCs with reporter and anticancer genes. MPCs expressing thymidine kinase were able to exert a bystander killing effect on the cancer cell line SKOV3ip1 in vitro. In addition, we found that MPCs were able to support Ad replication, and thus can be used as cell vectors to deliver oncolytic viruses. Our results show that MPCs can foster expression of suicide genes or support replication of adenoviruses as potential anticancer therapeutic payloads. These findings are consistent with the concept that MPCs possess key properties that ensure their employment as cellular vehicles and can be used to deliver either therapeutic genes or viruses to tumor sites.
authors.affiliation: Division of Human Gene Therapy, Department of Medicine, University of Alabama at Birmingham, 35294, USA. larisa.pereboeva@ccc.uab.edu
authors.forename: L
authors.initials: L
authors.lastname: Pereboeva
authors.forename: S
authors.initials: S
authors.lastname: Komarova
authors.forename: G
authors.initials: G
authors.lastname: Mikheeva
authors.forename: V
authors.initials: V
authors.lastname: Krasnykh
authors.forename: D T
authors.initials: DT
authors.lastname: Curiel
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002470:Cell Survival; D003470:Culture Media / Q000494:pharmacology; D005434:Flow Cytometry; D018014:Gene Transfer Techniques; D017930:Genes, Reporter; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors; D049452:Green Fluorescent Proteins; D006367:HeLa Cells; D006801:Humans; D007763:Lac Operon; D008156:Luciferases / Q000378:metabolism; D008164:Luminescent Proteins / Q000378:metabolism; D008648:Mesoderm / Q000166:cytology*; D013234:Stem Cells; D013997:Time Factors
chemical_list: D003470:Culture Media; D008164:Luminescent Proteins; D049452:Green Fluorescent Proteins; D008156:Luciferases