scholarly journals The Long-lasting Radioprotective Effect of Caffeic Acid in Mice Exposed to Total Body Irradiation by Modulating Reactive Oxygen Species Generation and Hematopoietic Stem Cell Senescence-Accompanied Long-term Residual Bone Marrow Injury

2019 ◽  
Vol 10 (6) ◽  
pp. 1320
Author(s):  
Hyun-Jaung Sim ◽  
Govinda Bhattarai ◽  
Joshua Lee ◽  
Jeong-Chae Lee ◽  
Sung-Ho Kook
Keyword(s):  
Reactive Oxygen Species ◽  
Bone Marrow ◽  
Stem Cell ◽  
Caffeic Acid ◽  
Total Body Irradiation ◽  
Reactive Oxygen Species Generation ◽  
Oxygen Species ◽  
Hematopoietic Stem ◽  
Total Body

Total Body Irradiation Causes Residual Bone Marrow Injury by Induction of Persistent Oxidative Stress in Murine Hematopoietic Stem Cells.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3209-3209
Author(s):  
Yong Wang ◽  
Lingbo Liu ◽  
Senthil Kumar Pazhanisamy ◽  
Aimin Meng ◽  
Daohong Zhou
Keyword(s):  
Oxidative Stress ◽  
Bone Marrow ◽  
Total Body Irradiation ◽  
Molecular Mechanisms ◽  
Conflicts Of Interest ◽  
Tissue Injury ◽  
Hematopoietic Stem ◽  
Chronic Oxidative Stress ◽  
Total Body

Abstract Abstract 3209 Poster Board III-146 Ionizing radiation (IR) and/or chemotherapy cause not only acute tissue injury but also have late effects including long-term bone marrow (BM) suppression. The induction of residual BM injury is primarily attributable to induction of hematopoietic stem cell (HSC) senescence. However, neither the molecular mechanisms by which IR and/or chemotherapy induce HSC senescence have been clearly defined, nor has an effective treatment been developed to ameliorate the injury, which were investigated in the present study using a total body irradiation (TBI) mouse model. The results showed that exposure of mice to 6.5 Gy TBI induced a persistent increase in reactive oxygen species (ROS) production in HSCs only for up to 8 weeks, primarily via up-regulation of NADPH oxidase 4 (NOX4). This finding provides the foremost direct evidence demonstrating that in vivo exposure to IR causes persistent oxidative stress selectively in a specific population of BM hematopoietic cells (HSCs). The induction of chronic oxidative stress in HSCs was associated with sustained increases in oxidative DNA damage, DNA double strand breaks, inhibition of HSC clonogenic function, and induction of HSC senescence but not apoptosis. Treatment of the irradiated mice with N-acetyl-cysteine (NAC) after TBI significantly attenuated IR-induced inhibition of HSC clonogenic function and reduction of HSC long-term engraftment after transplantation. These findings suggest that selective induction of chronic oxidative stress in HSCs by TBI leads to induction of HSC senescence and residual BM injury and that antioxidant therapy may be used as an effective strategy to mitigate IR- and chemotherapy-induced residual BM injury. Disclosures No relevant conflicts of interest to declare.

scholarly journals Busulfan and total body irradiation as antihematopoietic stem cell agents in the preparation of patients with congenital bone marrow disorders for allogenic bone marrow transplantation

Blood ◽  
1984 ◽  
Vol 64 (4) ◽  
pp. 852-857
Author(s):  
R Parkman ◽  
JM Rappeport ◽  
S Hellman ◽  
J Lipton ◽  
B Smith ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Bone Marrow Transplantation ◽  
Total Body Irradiation ◽  
Interstitial Pneumonitis ◽  
Marrow Transplantation ◽  
Allogeneic Bone ◽  
Hematopoietic Stem ◽  
Total Body ◽  
Bone Marrow Disorders

The capacity of busulfan and total body irradiation to ablate hematopoietic stem cells as preparation for the allogeneic bone marrow transplantation of patients with congenital bone marrow disorders was studied. Fourteen patients received 18 transplants; busulfan was used in the preparatory regimen of eight transplants and total body irradiation in the regimens of six transplants. Sustained hematopoietic ablation was achieved in six of eight patients prepared with busulfan and in all six patients prepared with total body irradiation. Three patients prepared with total body irradiation died with idiopathic interstitial pneumonitis, whereas no patients receiving busulfan developed interstitial pneumonitis. The optimal antihematopoietic stem cell agent to be used for the preparation of patients with congenital bone marrow disorder for bone marrow transplantation is not certain.

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

Blood ◽  
2012 ◽  
Vol 119 (15) ◽  
pp. 3629-3637 ◽  
Author(s):  
Hongmei Shen ◽  
Hui Yu ◽  
Paulina H. Liang ◽  
Haizi Cheng ◽  
Richard XuFeng ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Total Body Irradiation ◽  
Bystander Effect ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Hematopoietic Stem ◽  
Clinical Scenarios ◽  
Accelerated Proliferation ◽  
Conditioning Regimens ◽  
Total Body

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 (∼ 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.

scholarly journals Total body irradiation selectively induces murine hematopoietic stem cell senescence

Blood ◽  
2006 ◽  
Vol 107 (1) ◽  
pp. 358-366 ◽  
Author(s):  
Yong Wang ◽  
Bradley A. Schulte ◽  
Amanda C. LaRue ◽  
Makio Ogawa ◽  
Daohong Zhou
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Total Body Irradiation ◽  
Chemotherapeutic Agents ◽  
Sublethal Dose ◽  
Self Renewal ◽  
Hematopoietic Stem ◽  
Murine Hematopoietic Stem Cell ◽  
Total Body

Abstract Exposure to ionizing radiation (IR) and certain chemotherapeutic agents not only causes acute bone marrow (BM) suppression but also leads to long-term residual hematopoietic injury. This latter effect has been attributed to damage to hematopoietic stem cell (HSC) self-renewal. Using a mouse model, we investigated whether IR induces senescence in HSCs, as induction of HSC senescence can lead to the defect in HSC self-renewal. It was found that exposure of C57BL/6 mice to a sublethal dose (6.5 Gy) of total body irradiation (TBI) resulted in a sustained quantitative and qualitative reduction of LKS+ HSCs. In addition, LKS+ HSCs from irradiated mice exhibited an increased expression of the 2 commonly used biomarkers of cellular senescence, p16Ink4a and SA-β-gal. In contrast, no such changes were observed in irradiated LKS- hematopoietic progenitor cells. These results provide the first direct evidence demonstrating that IR exposure can selectively induce HSC senescence. Of interest, the induction of HSC senescence was associated with a prolonged elevation of p21Cip1/Waf1, p19Arf, and p16Ink4a mRNA expression, while the expression of p27Kip1 and p18Ink4c mRNA was not increased following TBI. This suggests that p21Cip1/Waf1, p19Arf, and p16Ink4a may play an important role in IR-induced senescence in HSCs.

MRP1 Plays a Role in Regulating Hematopoietic Stem Cell Oxidative Stress and Differentiation Via MRP1-Dependent Gsh Efflux

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1223-1223
Author(s):  
Cassandra J Reiling ◽  
Dianna Howard ◽  
Christian M Paumi
Keyword(s):  
Oxidative Stress ◽  
Reactive Oxygen Species ◽  
Stem Cell ◽  
Oxygen Species ◽  
Self Renewal ◽  
Hematopoietic Stem ◽  
Intracellular Ros ◽  
Intracellular Oxidative Stress

Abstract Abstract 1223 Hematopoietic stem cells (HSCs) are currently used therapeutically to treat diseases such as leukemia; however, a greater understanding in both the molecular and environmental requirements for HSCs self-renewal will hopefully increase the success rate of these therapeutic uses. It is increasingly evident that reactive oxygen species (ROS) and cellular oxidative stress play an important role in HSC self-renewal and differentiation. Therefore a better understanding of intracellular oxidative stress regulation is critical to increasing transplant success and increasing successful treatment of Leukemia. Our studies take aim at determining the role of multidrug resistance-associated protein 1 (MRP1) in regulating intracellular ROS in HSC's. MRP1 is expressed at slightly higher levels in HSCs than in mature blood cells. The expression pattern of MRP1 in HSCs suggests a possible role in hematopoietic stem cell integrity and differentiation. A major function of MRP1 is to help maintain the oxidative balance of the cell by transporting reduced glutathione (GSH), oxidized glutathione (GSSG), and glutathione-4-hydroxy-nonenal (HNE-SG) conjugates out of the cell. We have hypothesized that MRP1-dependent efflux of GSH and GSSG in HSC increases intracellular reactive oxygen species (ROS) resulting in a loss of self-renewing and increased differentiation of HSCs. In our current studies we have used C57BL/6 FVB and Mrp1-disrupted FVB [Mrp1 (−/−)] mice to investigate the role of MRP1 in HSC differentiation. Our experiments have revealed an increase in LT-HSC and ST-HSC and a corresponding decrease in MPP's in the MRP1 −/− mice as compared to WT matched controls. To determine if MRP1 plays a role in regulating HSC intracellular oxidative stress levels via GSH and GSSG efflux, we measured cellular oxidative stress as a function of DCF-DA and relative GSH levels as a function of glutathione-monochlorobimane (GS-MCB) conjugate fluorescence by flow cytometry. Our studies revealed higher intracellular ROS in WT mice as compared to MRP1 −/− mice and decreased GS-MCB in our WT mice as compared to the MRP1 −/− mice. Taken together the DCF-DA and MCB assays support our hypothesis that MRP1-dependent efflux of GSH/GSSG decreases cellular GSH resulting in higher level of ROS. Our hypothesis is further supported by analysis of lineage marked cells (Lin+), which showed a distinct differentiation pattern between the cells derived from WT and MRP1−/− bone marrow (BM). These studies are supported by results from colony forming cell (CFC) assays. Interestingly, analysis of whole blood did not result in a robust phenotype with regards to leukocytes; however, we found an increase in the number of platelets in MRP1−/− mice when compared to the WT. The increase in platelets is an intriguing result under further investigation. In light of our recent results we have initiated long-term transplant assays to determine if MRP1 does indeed play a role in HSC differentiation and self-renewal. If our hypothesis is true as suggested by our current studies then we expect that expression of MRP1 will negatively effect the ability of HSC's to successfully transplant in the long-term. Overall our data supports our hypothesis that MRP1-dependent efflux of GSH and GSSG in HSC increases intracellular ROS thereby decreasing HSC self-renewing potential and increasing HSC differentiation. Disclosures: No relevant conflicts of interest to declare.

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