Progenitors Mobilized by Gamma-Tocotrienol as an Effective Radiation Countermeasure

Vijay K Singh,Patricia L P Romaine,Stephen Y Wise,Victoria L Newman,Jessica Scott,Thomas M Seed,Amit Verma,Thomas B Elliott,Oluseyi O Fatanmi,Zoran Ivanovic

doi:10.1371/journal.pone.0114078

Vijay K Singh, Patricia L P Romaine + Show 8 more

Open Access

https://doi.org/10.1371/journal.pone.0114078

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Abstract

The purpose of this study was to elucidate the role of gamma-tocotrienol (GT3)-mobilized progenitors in mitigating damage to mice exposed to a supralethal dose of cobalt-60 gamma-radiation. CD2F1 mice were transfused 24 h post-irradiation with whole blood or isolated peripheral blood mononuclear cells (PBMC) from donors that had received GT3 72 h prior to blood collection and recipient mice were monitored for 30 days. To understand the role of GT3-induced granulocyte colony-stimulating factor (G-CSF) in mobilizing progenitors, donor mice were administered a neutralizing antibody specific to G-CSF or its isotype before blood collection. Bacterial translocation from gut to heart, spleen and liver of irradiated recipient mice was evaluated by bacterial culture on enriched and selective agar media. Endotoxin in serum samples also was measured. We also analyzed the colony-forming units in the spleens of irradiated mice. Our results demonstrate that whole blood or PBMC from GT3-administered mice mitigated radiation injury when administered 24 h post-irradiation. Furthermore, administration of a G-CSF antibody to GT3-injected mice abrogated the efficacy of blood or PBMC obtained from such donors. Additionally, GT3-mobilized PBMC inhibited the translocation of intestinal bacteria to the heart, spleen, and liver, and increased colony forming unit-spleen (CFU-S) numbers in irradiated mice. Our data suggests that GT3 induces G-CSF, which mobilizes progenitors and these progenitors mitigate radiation injury in recipient mice. This approach using mobilized progenitor cells from GT3-injected donors could be a potential treatment for humans exposed to high doses of radiation.

Highlights

Radiological and nuclear mass-casualty events are significant threats to civilian populations and deployed members of the military
Disasters that occurred at the Chernobyl Nuclear Power Plant in 1986 and more recently at the Fukushima Daiichi Nuclear Power Plant in 2011 highlight the need for effective treatments to contend with the damaging effects of ionizing radiation [1,2,3,4]
The primary objective of this study was to determine the radiomitigative efficacy of GT3-mobilized progenitors when transfused into mice 24 h following a potentially lethal 11 Gy 6 ̊Co c-radiation exposure

Summary

Introduction

Radiological and nuclear mass-casualty events are significant threats to civilian populations and deployed members of the military. In the worst possible scenario, such a bomb or an improvised nuclear device would be detonated in an urban setting, inciting fear and panic, but an array of medical problems and deaths resulting from the initial blast, intense heat and subsequent radioactive fallout. Those affected would be in need of immediate medical treatment [6,7]. Significant acute radiation injury in humans occurs at whole-body doses above 1 Gy, with symptoms getting progressively more severe as the level of radiation exposure increases [8]. To date there have been no suitable countermeasures approved for use by the U.S Food and Drug administration (US FDA) for the treatment of ARS

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