Simonnet Arthur J, Nehmé Johnny, Vaigot Pierre, Barroca Vilma, Leboulch Philippe, Tronik-Le Roux Diana
Institute of Emerging Diseases and Innovative Therapies, Functional Bioengineering Laboratory, Commissariat à l'Energie Atomique, Evry, France.
Stem Cells. 2009 Jun;27(6):1400-9. doi: 10.1002/stem.66.
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.
电离辐射（IR）暴露会导致快速且急性的骨髓（BM）抑制，对于非致死剂量而言这种抑制是可逆的。越来越多的证据表明，IR还可引发持久的残留造血损伤。为了更好地理解这些效应，我们分析了受辐照小鼠的干细胞/祖细胞区室在10周时间内的表型和功能变化。我们发现，通过其重建能力鉴定的造血干细胞（HSCs）在IR暴露后早期继续在Hoechst染料排除的“侧群（SP）”内分离。然而，在这个细胞群体中观察到了短暂的表型变化：Sca-1（S）和c-Kit（K）的表达水平分别升高和严重降低，同时对于HSCs存在的既定指标呈阳性的SP（SK）细胞比例增加：CD150和CD105。IR暴露10周后，SP细胞表面的Sca-1和c-Kit表达恢复到对照水平，且受辐照小鼠的骨髓细胞数量得以恢复。然而，c-Kit(+)Sca-1(+)Lin(-/low)（KSL）干细胞/祖细胞区室表现出主要的表型改变，包括CD150(+)Flk2(-)和CD150(-)Flk2(+)细胞频率分别增加和严重降低。CD150(+) KSL细胞还表现出重建能力受损、凋亡倾向增加以及累积的DNA损伤。最后，暴露15周后，受辐照小鼠而非年龄匹配的对照，在没有额外宿主预处理的情况下允许移植的同基因HSCs植入并产生显著的造血贡献。这些结果为我们理解IR诱导的即时和延迟造血损伤提供了新的见解，并突出了年轻受辐照小鼠和老年小鼠的HSCs之间的相似性。
