Phenotypic and functional changes induced in hematopoietic stem/progenitor cells after gamma-ray radiation exposure.
Ionizing radiation (IR) exposure causes rapid and acute bone marrow (BM) suppression that is reversible for nonlethal doses. Evidence is accumulating that IR can also provoke long-lasting residual hematopoietic injury. To better understand these effects, we analyzed phenotypic and functional changes in the stem/progenitor compartment of irradiated mice over a 10-week period. We found that hematopoietic stem cells (HSCs) identified by their repopulating ability continued to segregate within the Hoechst dye excluding "side population (SP)" early after IR exposure. However, transient phenotypic changes were observed within this cell population: Sca-1 (S) and c-Kit (K) expression levels were increased and severely reduced, respectively, with a concurrent increase in the proportion of SP(SK) cells positive for established indicators of the presence of HSCs: CD150 and CD105. Ten weeks after IR exposure, expression of Sca-1 and c-Kit at the SP cell surface returned to control levels, and BM cellularity of irradiated mice was restored. However, the c-Kit(+)Sca-1(+)Lin(-/low) (KSL) stem/progenitor compartment displayed major phenotypic modifications, including an increase and a severe decrease in the frequencies of CD150(+)Flk2(-) and CD150(-)Flk2(+) cells, respectively. CD150(+) KSL cells also showed impaired reconstituting ability, an increased tendency to apoptosis, and accrued DNA damage. Finally, 15 weeks after exposure, irradiated mice, but not age-matched controls, allowed engraftment and significant hematopoietic contribution from transplanted congenic HSCs without additional host conditioning. These results provide novel insight in our understanding of immediate and delayed IR-induced hematopoietic injury and highlight similarities between HSCs of young irradiated and old mice.
Simonnet
Arthur J
AJ
Institute of Emerging Diseases and Innovative Therapies, Functional Bioengineering Laboratory, Commissariat à l'Energie Atomique, Evry, France.
Nehmé
Johnny
J
Vaigot
Pierre
P
Barroca
Vilma
V
Leboulch
Philippe
P
Tronik-Le Roux
Diana
D
D000818:Animals; D000950:Antigens, Ly / Q000378:metabolism / Q000528:radiation effects; D017209:Apoptosis / Q000528:radiation effects; D001854:Bone Marrow Cells / Q000528:radiation effects; D002453:Cell Cycle / Q000528:radiation effects; D005434:Flow Cytometry; D005720:Gamma Rays / Q000009:adverse effects*; D015870:Gene Expression / Q000528:radiation effects*; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000528:radiation effects*; D008565:Membrane Proteins / Q000378:metabolism / Q000528:radiation effects; D051379:Mice; D010641:Phenotype; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism / Q000528:radiation effects
D000950:Antigens, Ly; C074650:Ly6a protein, mouse; D008565:Membrane Proteins; D019009:Proto-Oncogene Proteins c-kit