Gamma-Tocotrienol Protects Hematopoietic Stem and Progenitor Cells in Mice after Total-Body Irradiation

Abstract

We analyzed the radioprotective effects of gamma-tocotrienol (GT3) on hematopoietic stem cells (HSCs) and progenitor cells (HPCs) in sublethally irradiated mice. Flow cytometry analysis indicated that radiation depleted HPCs (c-Kit(+), Lin(-)) to 40% at days 2 and 4 after total-body irradiation (TBI) in all treatment groups. The HPC numbers in GT3-treated mice recovered almost completely (90%) at day 7 but remained depleted in vehicle-treated mice (30%) even at day 13 after TBI. An in vitro colony-forming assay on sorted HSCs (Lin(-), Sca1(+), c-Kit(+)) indicated that TBI reduced the number of colonies to 40% and 50% at day 17 and 60, respectively, in vehicle-treated groups compared to unirradiated controls (naïve). GT3-treated irradiated mice maintained higher numbers of colonies (86% and 80% compared to naïve mice), thereby preserving the self-renewable capacity of HSCs. Histopathology of sternal bone marrow indicated more regenerative microfoci for myeloid cells and megakaryocytes and higher overall cellularity in GT3-treated mice compared to vehicle controls at days 7 and 13 after TBI. GT3 treatment also reduced the frequency of micronucleated erythrocytes significantly in irradiated mice. Our results demonstrate that GT3 protected hematopoietic tissue by preserving the HSCs and HPCs and by preventing persistent DNA damage.

Gamma-tocotrienol, a radiation prophylaxis agent, induces high levels of granulocyte colony-stimulating factor

“…We demonstrated recently that gamma-tocotrienol (GT3) protected mice from radiation-induced hematopoietic syndrome, reduced neutropenia and thrombocytopenia, and protected bone marrow stem and progenitor cells [17,18]. GT3 also significantly reduced instant and persistent damage in the hematopoietic tissue as observed by micronucleus assay, and thereby reducing the risk of oxidative-stress induced longterm damage [18].…”

γ-Tocotrienol Protects against Mitochondrial Dysfunction and Renal Cell Death

“…GT3 ameliorates intestinal injury, enhances recovery of the intestine after irradiation, decreases vascular oxidative stress, and improves survival in animals subjected to total body irradiation (Felemovicius et al, 1995;Kulkarni et al, 2010;Berbée et al, 2011). GT3-conferred protection and reduction of mortality are associated with accelerated recovery of hematopoietic progenitor and white blood cells, neutrophils, monocytes, platelets, and reticulocytes after lethal radiation doses in mice (Ghosh et al, 2009;Kulkarni et al, 2010). It is noteworthy that the radioprotective action of GT3 against vascular injury is mediated through a HMG-CoA reductase-dependent mechanism (Berbée et al, 2011).…”

Radiation Countermeasures: Current Status

“…It also shows protection by up regulation of A20, the inhibitor of NF-κB in case there is basal level of expression of NF-κB, up regulation of anti-apoptotic genes and down regulation of pro-apoptotic genes bak-1 both at the transcriptional and translational level in the intestine 24,25 . GT3 protects normal tissues from hematopoietic and GI injuries by protecting hematopoietic stem and progenitor cells and epithelial crypt cells of intestine from the DNA damage caused by ionising radiation 26,27 .…”