Abstract
Human mesenchymal stem cells (MSCs) have emerged as attractive cellular vehicles to deliver therapeutic genes for ex-vivo therapy of diverse diseases; this is, in part, because they have the capability to migrate into tumor or lesion sites. Previously, we showed that MSCs could be utilized to deliver a bacterial cytosine deaminase (CD) suicide gene to brain tumors. Here we assessed whether transduction with a retroviral vector encoding CD gene altered the stem cell property of MSCs. MSCs were transduced at passage 1 and cultivated up to passage 11. We found that proliferation and differentiation potentials, chromosomal stability and surface antigenicity of MSCs were not altered by retroviral transduction. The results indicate that retroviral vectors can be safely utilized for delivery of suicide genes to MSCs for ex-vivo therapy. We also found that a single retroviral transduction was sufficient for sustainable expression up to passage 10. The persistent expression of the transduced gene indicates that transduced MSCs provide a tractable and manageable approach for potential use in allogeneic transplantation.
Highlights
Mesenchymal stem cells (MSCs) have been utilized for the treatment of diverse diseases, including neuropathies such as Parkinson’s disease,[1] Huntington’s disease,[2] multiple sclerosis,[3,4] amyotrophic lateral sclerosis,[5] ischemic stroke,[6,7] and non-neurological diseases such as myocardial infarction,[8,9] and graft-versus-host diseases.[10]
The results indicate that retroviral vectors can be safely utilized for delivery of suicide genes to MSCs for ex-vivo therapy
Our results suggest that retroviral vectors provide efficient tools to deliver suicide genes to MSCs for ex-vivo gene therapy of cancers
Summary
Mesenchymal stem cells (MSCs) have been utilized for the treatment of diverse diseases, including neuropathies such as Parkinson’s disease,[1] Huntington’s disease,[2] multiple sclerosis,[3,4] amyotrophic lateral sclerosis,[5] ischemic stroke,[6,7] and non-neurological diseases such as myocardial infarction,[8,9] and graft-versus-host diseases.[10]. As MSCs are highly migratory to lesion and tumor sites,[16] it has been suggested they can be used as cellular vehicles to deliver therapeutic genes to target tissues for ex-vivo therapy and to overcome targeting problems of conventional gene therapy. To tailor MSCs to be more disease-specific or to modify them as gene carriers, viral vectors are frequently utilized to introduce therapeutic genes into MSCs. Previously, we showed that MSCs could be utilized as a cellular vehicle to deliver a cytosine deaminase (CD) gene to brain tumors.[17] CD genes are naturally expressed in bacteria and fungi, but absent in humans. We showed that MSCs infected with a retroviral vector expressing an Escherichia coli CD gene could migrate toward brain tumors and suppress tumor growth through bystander
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