Page 264 - 2014 Printable Abstract Book
P. 264
Furthermore, radiation-induced inflammation was significantly attenuated across multiple hippocampal
subfields in animals receiving iPS-derived hNSCs at 4 weeks after IRR. These studies expand our prior
findings to demonstrate that protracted stem cell grafting provides improved cognitive benefits following
irradiation that are associated with reduced neuroinflammation. [Support: NIH-NINDS, R01 NS074388581,
C.L.L.]
(PS4-48) Mitigation of total body irradiation-induced long-term bone marrow injury and genomic
instability via induction of selective depletion of senescent hematopoietic stem cells and expansion of
1; 2
1
1
1
1
normal hematopoietic stem cells. Lijian Shao ; Hongliang Li ; Wei Feng ; Jianhui Chang ; Yi Luo ; Rupak
1
2
Pathak ; Martin Hauer-Jensen 1; 3 ; Aimin Meng ; and Daohong Zhou, 1 Division of Radiation Health,
1
Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR ;
Institute of Radiation Medicine, Peking Union Medical College & Chinese Academy of Medical Sciences
2
3
(PUMC & CAMS), Tianjin, China ; and Central Arkansas Veterans Healthcare System, Little Rock, AR
Our previous studies have shown that exposure of mice to a sublethal dose (6 Gy) of total body
irradiation (TBI) induces not only acute hematopoietic radiation syndrome but also long-term bone
marrow (LT-BM) suppression and hematopoietic genomic instability. The induction of LT-BM suppression
is mainly attributed to the induction of hematopoietic stem cell (HSC) senescence. Senescent HSCs
induced by TBI exhibit sustained increases in reactive oxygen species (ROS) production, DNA double strand
breaks (DSBs), unstable chromosomal aberrations, ATM and p53 activation, p16, p21 and ARF expression,
and significant decreases in cell proliferation, self-renewal, and long-term repopulating ability. However,
in the present study we found that HSCs are heterogenic in response to ionizing radiation (IR). Not all HSCs
undergo senescence after TBI, because a few HSCs from irradiated mice appear normal. They have normal
reproductive function as HSCs from un-irradiated mice and ability to generate long-term engraftment
after single HSC transplantation and serial transplantation. More importantly, we found that single
administration of 5-fluorouracil (150 mg/kg, ip) to mice 2 months after TBI depletes senescent HSCs but
induces clonal expansion of these “normal” HSCs probably via stimulating HSC cycling and niche
competition. This results in a significant improvement in HSC function and attenuation of TBI-induced LT-
BM injury and hematopoietic genomic instability. These findings provide the first evidence of HSC
heterogeneity in response to IR and a novel strategy to exploit this heterogeneity to mitigate IR-induced
long-term adverse effects on the hematopoietic system by selectively depleting senescent HSCs while
expanding normal HSCs.
(PS4-49) Low dose particle radiation affects long-term survival of bone marrow progenitor cell
2
1
3
2
1
populations. Sharath P. Sasi ; Daniel Park ; Maria A. Zuriaga ; Kenneth Walsh ; Xinhua Yan ; David A.
3
Goukassian, GeneSys Research Institute, Cardiovascular Research Center, Boston, MA ; Boston University
1
3
2
School of Medicine, Boston, MA ; and Tufts University School of Medicine, Boston, MA
Radiation-induced decreases in the number of bone marrow (BM)-derived endothelial progenitor
cell (BM-EPCs) and their lineage precursors which include Early- and Late-Multi-Potent Progenitor cells (E-
MPPs and L-MPPs) could contribute to the pathogenesis of ischemic and vascular diseases. We examined
the effect of full-body single dose of proton (1H) at 0.5 Gy, 1 GeV and 0.15 Gy, 1 GeV/nucleon of iron
(56Fe) - ionizing radiation (IR) on survival and proliferation of BM-EPCs. The survival of E-MPPs and L-MPPs
262 | P a g e
subfields in animals receiving iPS-derived hNSCs at 4 weeks after IRR. These studies expand our prior
findings to demonstrate that protracted stem cell grafting provides improved cognitive benefits following
irradiation that are associated with reduced neuroinflammation. [Support: NIH-NINDS, R01 NS074388581,
C.L.L.]
(PS4-48) Mitigation of total body irradiation-induced long-term bone marrow injury and genomic
instability via induction of selective depletion of senescent hematopoietic stem cells and expansion of
1; 2
1
1
1
1
normal hematopoietic stem cells. Lijian Shao ; Hongliang Li ; Wei Feng ; Jianhui Chang ; Yi Luo ; Rupak
1
2
Pathak ; Martin Hauer-Jensen 1; 3 ; Aimin Meng ; and Daohong Zhou, 1 Division of Radiation Health,
1
Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR ;
Institute of Radiation Medicine, Peking Union Medical College & Chinese Academy of Medical Sciences
2
3
(PUMC & CAMS), Tianjin, China ; and Central Arkansas Veterans Healthcare System, Little Rock, AR
Our previous studies have shown that exposure of mice to a sublethal dose (6 Gy) of total body
irradiation (TBI) induces not only acute hematopoietic radiation syndrome but also long-term bone
marrow (LT-BM) suppression and hematopoietic genomic instability. The induction of LT-BM suppression
is mainly attributed to the induction of hematopoietic stem cell (HSC) senescence. Senescent HSCs
induced by TBI exhibit sustained increases in reactive oxygen species (ROS) production, DNA double strand
breaks (DSBs), unstable chromosomal aberrations, ATM and p53 activation, p16, p21 and ARF expression,
and significant decreases in cell proliferation, self-renewal, and long-term repopulating ability. However,
in the present study we found that HSCs are heterogenic in response to ionizing radiation (IR). Not all HSCs
undergo senescence after TBI, because a few HSCs from irradiated mice appear normal. They have normal
reproductive function as HSCs from un-irradiated mice and ability to generate long-term engraftment
after single HSC transplantation and serial transplantation. More importantly, we found that single
administration of 5-fluorouracil (150 mg/kg, ip) to mice 2 months after TBI depletes senescent HSCs but
induces clonal expansion of these “normal” HSCs probably via stimulating HSC cycling and niche
competition. This results in a significant improvement in HSC function and attenuation of TBI-induced LT-
BM injury and hematopoietic genomic instability. These findings provide the first evidence of HSC
heterogeneity in response to IR and a novel strategy to exploit this heterogeneity to mitigate IR-induced
long-term adverse effects on the hematopoietic system by selectively depleting senescent HSCs while
expanding normal HSCs.
(PS4-49) Low dose particle radiation affects long-term survival of bone marrow progenitor cell
2
1
3
2
1
populations. Sharath P. Sasi ; Daniel Park ; Maria A. Zuriaga ; Kenneth Walsh ; Xinhua Yan ; David A.
3
Goukassian, GeneSys Research Institute, Cardiovascular Research Center, Boston, MA ; Boston University
1
3
2
School of Medicine, Boston, MA ; and Tufts University School of Medicine, Boston, MA
Radiation-induced decreases in the number of bone marrow (BM)-derived endothelial progenitor
cell (BM-EPCs) and their lineage precursors which include Early- and Late-Multi-Potent Progenitor cells (E-
MPPs and L-MPPs) could contribute to the pathogenesis of ischemic and vascular diseases. We examined
the effect of full-body single dose of proton (1H) at 0.5 Gy, 1 GeV and 0.15 Gy, 1 GeV/nucleon of iron
(56Fe) - ionizing radiation (IR) on survival and proliferation of BM-EPCs. The survival of E-MPPs and L-MPPs
262 | P a g e
