An acute negative bystander effect of γ-irradiated recipients on transplanted hematopoietic stem cells

Abstract

Ultimate success of hematopoietic stem cell transplantation (HSCT) depends not only on donor HSCs themselves but also on the host environment. Total body irradiation is a component in various host conditioning regimens for HSCT. It is known that ionizing radiation exerts "bystander effects" on nontargeted cells and that HSCs transplanted into irradiated recipients undergo proliferative exhaustion. However, whether irradiated recipients pose a proliferation-independent bystander effect on transplanted HSCs is unclear. In this study, we found that irradiated mouse recipients significantly impaired the long-term repopulating ability of transplanted mouse HSCs shortly (ϳ 17 hours) after exposure to irradiated hosts and before the cells began to divide. There was an increase of acute cell death associated with accelerated proliferation of the bystander hematopoietic cells. This effect was marked by dramatic down-regulation of c-Kit, apparently because of elevated reactive oxygen species. Administration of an antioxidant chemical, N-acetylcysteine, or ectopically overexpressing a reactive oxygen species scavenging enzyme, catalase, improved the function of transplanted HSCs in irradiated hosts. Together, this study provides evidence for an acute negative, yet proliferation-independent, bystander effect of irradiated recipients on transplanted HSCs, thereby having implications for HSCT in both experimental and clinical scenarios in which total body irradiation is involved. (Blood. 2012;119(15):3629-3637) IntroductionHematopoietic stem cell transplantation (HSCT) may provide cures for many congenital diseases, immunodeficiencies, and hematopoietic or nonhematopoietic malignancies. 1 However, the broader use of HSCT in patients is hindered in part by the limited number of HSCs contained in each harvest. This issue may prove especially problematic in cases when HSCs are collected from human cord blood, where the number of HSCs per harvest is not sufficient for an adult patient. 2 Successful HSC engraftment depends not only on the dosage and quality of transplanted HSCs but also the conditioning of recipients. Given the current unsatisfactory status of ex vivo HSC expansion, manipulating the bone marrow (BM) microenvironment or the stem cell niche has been thought to be an attractive strategy [3][4][5][6] to improve the outcome of HSCT.On transplantation, HSCs go through a series of processes, including homing, lodgment, proliferation, and differentiation, all of which are important determinants for short-and long-term engraftment. One of the major factors that may impact these processes is the conditioning regimen administered to the HSCT recipient before transplantation to reduce the chances of graft rejection and in the case of cancer treatment, to reduce the burden of disease and to make niches available for donor stem cells. Of particular interest is the effects of total body irradiation (TBI) on these processes as this remains a component in many HSCT conditioning regimens and has been associated with a number of eff...

Total body irradiation causes long-term mouse BM injury via induction of HSC premature senescence in an Ink4a- and Arf-independent manner

“…31 In addition, damage to the HSC niche, such as induction of BM stromal cell senescence, and a negative bystander effect of TBI on HSCs, also play a role in IR-induced residual BM injury. 32,33 Our studies also revealed that only a small fraction of HSCs became senescent at a time after TBI. This may be in part attributable to the immunosurveillance of senescent cells by immune cells that can rapidly remove senescent cells to prevent the accumulation of senescent cells in vivo.…”

Catalase Inhibits Ionizing Radiation-Induced Apoptosis in Hematopoietic Stem and Progenitor Cells

“…Previous studies, including those from our laboratory, indicated that acute BM radiation injury is, at least in part, attributable to the induction of apoptosis in HSPCs [3,6,18], suggesting that inhibition of IR-induced apoptosis may be an effective approach to protecting BM radiation injury. CAT is an extremely potent antioxidant We and others have demonstrated that IR-induced ROS play a critical role in radiation tissue injury [10][11][12][18][19][20]. IR induces ROS production in irradiated cells as a consequence of radiolysis of water, which can cause DNA damage, ultimately leading to apoptosis and/or cellular senescence.…”

“…It has been shown that ectopic overexpression of CAT can protect a variety of tissues against oxidative stress-induced damage in animal models [19][20][21]. Furthermore, there is evidence indicating that CAT treatment may preserve hematopoietic stem cell (HSC) selfrenewal in long-term BM cultures [22].…”

Leukemic marrow infiltration reveals a novel role for Egr3 as a potent inhibitor of normal hematopoietic stem cell proliferation

“…Consequently, it exerts a significant bystander effect on transplanted cells in marrow. 12 Thus, transplant protocols involving the use of TBI do not accurately reflect the conditions in leukemia patients. In addition, previous studies have focused on only one or a few HSC/HPC subsets, and they lacked data on the impact of leukemic hosts on the whole spectrum of different subsets of HSCs and HPCs in vivo.…”