Successful Mitigation of Radiation Injuries in Mice using Mesenchymal Stem Cells Genetically Modified to Secrete Extracellular Superoxide Dismutase

Weiwen Deng, Aly S Abdel-Mageed

doi:10.4172/2157-7633.1000288

Abstract

Oxidative stress is a major determinant for radiation-induced tissue injuries. We present a novel method that harnesses the power of migration of mesenchymal stem cells (MSCs) to radiation injured tissues and adenovirusmediated extracellular superoxide dismutase (ECSOD) gene therapy for oxidative stress. This report demonstrates for the first time that intravenous administration of MSCs genetically modified to secrete ECSOD at 24 hours after radiation exposure can improve survival from 10% to 52%, extend lifespan for 207 days, retard cataract formation for 39 days, and prevent carcinogenesis in mice. For proof-of-concept, we further demonstrate for the first time that human MSCs can be genetically modified with adenoviral vector to secrete high levels of biologically active ECSOD. Our findings suggest that mesenchymal stem cell-based antioxidant gene therapy has the potential for mitigation of radiation injuries in humans as a consequence of radiological and nuclear emergencies, space radiation exposure, and cancer radiotherapy toxicity.

Highlights

Exposure to high doses of ionizing radiation can lead to radiation injuries such as death, lifespan shortening, cataract formation, or carcinogenesis [1,2,3,4,5]
To study the persistence of Extracellular superoxide dismutase (ECSOD) transgene expression in vitro, mouse MSCs (mMSCs) were transduced with Ad5CMVECSOD and the cells were cultured for 35 days
To determine whether intravenous administration of ECSODMSCs can mitigate delayed effects of acute radiation exposure such as lifespan shortening, cataractogenesis, and carcinogenesis [2,3,4,5], mice that had survived for 35 days were monitored for survival, cataract formation, and carcinogenesis over their remaining lifespan

Summary

Introduction

Exposure to high doses of ionizing radiation can lead to radiation injuries such as death, lifespan shortening, cataract formation, or carcinogenesis [1,2,3,4,5]. This finding demonstrates for the first time that intravenous administration of ECSOD-MSCs improves survival in irradiated mice, suggesting its clinical potential for mitigation of potentially lethal complications of acute radiation syndrome [1,9]. To test the hypothesis that ECSOD-MSCs can mitigate delayed effects of acute radiation exposure, we conducted the following study and our data showed for the first time that intravenous administration of ECSOD-MSCs at 24 hours after radiation exposure extended lifespan, retarded cataract formation, and prevented carcinogenesis in mice.

Results

Conclusion