Gamma-tocotrienol protects hematopoietic stem and progenitor cells in mice after total-body irradiation.
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.
Kulkarni
Shilpa
S
a Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20889, USA.
Ghosh
Sanchita P
SP
Satyamitra
Merriline
M
Mog
Steven
S
Hieber
Kevin
K
Romanyukha
Lyudmila
L
Gambles
Kristen
K
Toles
Raymond
R
Kao
Tzu-Cheg
TC
Hauer-Jensen
Martin
M
Kumar
K Sree
KS
D000818:Animals; D002839:Chromans / Q000494:pharmacology*; D004249:DNA Damage; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D005434:Flow Cytometry; D006412:Hematopoietic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects*; D008297:Male; D051379:Mice; D015162:Micronucleus Tests; D011837:Radiation-Protective Agents / Q000494:pharmacology*; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000494:pharmacology; D014916:Whole-Body Irradiation
D002839:Chromans; D011837:Radiation-Protective Agents; D014810:Vitamin E; C013649:plastochromanol 8