Age Dependence of Hematopoietic Progenitor Survival and Chemokine Family Gene Induction after Gamma Irradiation in Bone Marrow Tissue in C3H/He Mice

Age at exposure is a critical factor that influences the risk of radiation-induced leukemia, which arises from hematopoietic stem and progenitor cells. However, little is known about the effect of age on the radiation response of these cells. In this study, we examined the radiation response of hematopoietic stem and progenitor cells in infant (1-week-old), juvenile (3-week-old), and adult (8- and 14-week-old) C3H/He mice, which are susceptible to radiation-induced myeloid leukemia. We first observed an age-dependent increase in the radioresistance of hematopoietic stem and progenitor cells after in vivo irradiation. However, in vitro irradiation of progenitor cells did not show any age differences, suggesting that radiation sensitivity in vivo is dependent on the bone marrow microenvironment rather than to intrinsic properties of progenitors themselves. Expression profiles of bone marrow tissues identified chemokine and cytokine family genes, whose expression differed between infant and adult tissues at time points before and after irradiation. Among the selected thirteen cytokines reported to be radioprotective, we observed increased expression of Csf1, Csf2, Cxcl12, Fgf1, Fgf7, Il1a, Il1b and Kitl after irradiation, mostly in adult tissues. Specifically, Csf2, Fgf1 and Il1b expression, as revealed by qPCR, were significantly enhanced in adult bone marrow tissue after irradiation, but were unresponsive to irradiation in infant tissue. These results suggest that the higher susceptibility of infant hematopoietic stem and progenitor cells to the cell killing effect of ionizing radiation may be attributed to a failure to induce a subset of radioprotective cytokines in the immature bone marrow microenvironment.

[1]  Y. Shimada,et al.  Unique Characteristics of Radiation-Induced Apoptosis in the Postnatally Developing Small Intestine and Colon of Mice , 2009, Radiation research.

[2]  N. Aksenova,et al.  Effects of early therapeutic administration of interleukin-1beta on survival rate and bone marrow haemopoiesis in irradiated mice. , 2010, Acta medica.

[3]  D. Richardson,et al.  Ionizing Radiation and Leukemia Mortality among Japanese Atomic Bomb Survivors, 1950–2000 , 2009, Radiation research.

[4]  O. Niwa,et al.  Chromosome Aberrations do not Persist in the Lymphocytes or Bone Marrow Cells of Mice Irradiated In Utero or Soon after Birth , 2007, Radiation research.

[5]  D. Bonnet,et al.  Age‐Dependent Increase in Side Population Distribution Within Hematopoiesis: Implications for Our Understanding of the Mechanism of Aging , 2007, Stem cells.

[6]  B. Mignotte,et al.  FGF1 inhibits p53-dependent apoptosis and cell cycle arrest via an intracrine pathway , 2005, Oncogene.

[7]  W. Anderson,et al.  Soluble factor(s) from bone marrow cells can rescue lethally irradiated mice by protecting endogenous hematopoietic stem cells. , 2005, Experimental hematology.

[8]  H. Yonekawa,et al.  Intestinal tumorigenesis in Min mice is enhanced by X-irradiation in an age-dependent manner. , 2005, Journal of radiation research.

[9]  A. Vacek,et al.  Action of granulopoiesis-stimulating cytokines rhG-CSF, rhGM-CSF, and rmGM-CSF on murine haematopoietic progenitor cells for granulocytes and macrophages (GM-CFC). , 2005, Physiological research.

[10]  K. Akashi,et al.  Enforced Granulocyte/Macrophage Colony-stimulating Factor Signals Do Not Support Lymphopoiesis, but Instruct Lymphoid to Myelomonocytic Lineage Conversion , 2003, The Journal of experimental medicine.

[11]  P. Bourin,et al.  Short-term injection of antiapoptotic cytokine combinations soon after lethal gamma -irradiation promotes survival. , 2003, Blood.

[12]  F. Wolber,et al.  Roles of spleen and liver in development of the murine hematopoietic system. , 2002, Experimental hematology.

[13]  J. Jaffrezou,et al.  Kit signaling inhibits the sphingomyelin-ceramide pathway through PLC gamma 1: implication in stem cell factor radioprotective effect. , 2002, Blood.

[14]  K. Mita,et al.  Spectrum of Znfn1a1 (Ikaros) Inactivation and its Association with Loss of Heterozygosity in Radiogenic T-Cell Lymphomas in Susceptible B6C3F1 Mice , 2002, Radiation research.

[15]  Thomas D. Schmittgen,et al.  Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. , 2001, Methods.

[16]  P. Okunieff,et al.  Keratinocyte Growth Factors Radioprotect Bowel and Bone Marrow But Not KHT Sarcoma , 2001, American journal of clinical oncology.

[17]  C. Baum,et al.  Myelopoietin, an engineered chimeric IL-3 and G-CSF receptor agonist, stimulates multilineage hematopoietic recovery in a nonhuman primate model of radiation-induced myelosuppression. , 2000, Blood.

[18]  M. Le Bousse-Kerdilès,et al.  Chemokine SDF-1 enhances circulating CD34(+) cell proliferation in synergy with cytokines: possible role in progenitor survival. , 2000, Blood.

[19]  G. Haan,et al.  Dynamic Changes in Mouse Hematopoietic Stem Cell Numbers During Aging , 1999 .

[20]  I. Weissman,et al.  In vivo proliferation and cell cycle kinetics of long-term self-renewing hematopoietic stem cells. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[21]  G. Wagemaker,et al.  A single dose of thrombopoietin shortly after myelosuppressive total body irradiation prevents pancytopenia in mice by promoting short-term multilineage spleen-repopulating cells at the transient expense of bone marrow-repopulating cells. , 1998, Blood.

[22]  A. Gratwohl,et al.  FLT-3 ligand provides hematopoietic protection from total body irradiation in rabbits. , 1998, Blood.

[23]  K. Yoshida,et al.  Calorie restriction reduces the incidence of myeloid leukemia induced by a single whole-body radiation in C3H/He mice. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[24]  P. Okunieff,et al.  Acidic fibroblast growth factor (FGF1) increases survival and haematopoietic recovery in total body irradiated C3H/HeNCr mice. , 1997, Cytokine.

[25]  J. Boice.  Cancer following irradiation in childhood and adolescence. , 1996, Medical and pediatric oncology. Supplement.

[26]  F. Finkelman,et al.  IL-12 protects bone marrow from and sensitizes intestinal tract to ionizing radiation. , 1994, Journal of immunology.

[27]  C. Snapper,et al.  Synergy of IL-1 and stem cell factor in radioprotection of mice is associated with IL-1 up-regulation of mRNA and protein expression for c-kit on bone marrow cells. , 1994, Journal of immunology.

[28]  H. Dohy,et al.  Cancer incidence in atomic bomb survivors. Part III. Leukemia, lymphoma and multiple myeloma, 1950-1987. , 1994, Radiation research.

[29]  I. Weissman,et al.  Functional heterogeneity is associated with the cell cycle status of murine hematopoietic stem cells , 1993, The Journal of cell biology.

[30]  S. Sasaki.  Influence of the age of mice at exposure to radiation on life-shortening and carcinogenesis. , 1991, Journal of radiation research.

[31]  K. Yoshida,et al.  Radiation-induced myeloid leukemia in C3H/He mice and the effect of prednisolone acetate on leukemogenesis. , 1991, Radiation research.

[32]  P. Rubin,et al.  Interleukin 1 alpha stimulates hemopoiesis but not tumor cell proliferation and protects mice from lethal total body irradiation. , 1991, International journal of radiation oncology, biology, physics.

[33]  J. Talmadge,et al.  Protective, restorative, and therapeutic properties of recombinant colony-stimulating factors. , 1989, Blood.

[34]  J. Talmadge,et al.  Protective, restorative, and therapeutic properties of recombinant human IL-1 in rodent models. , 1988, Journal of immunology.

[35]  B. Modan,et al.  Mortality after radiotherapy for ringworm of the scalp. , 1988, American journal of epidemiology.

[36]  R. Doll,et al.  Long term mortality after a single treatment course with X-rays in patients treated for ankylosing spondylitis. , 1987, British Journal of Cancer.

[37]  R. Neta,et al.  Interleukin 1 is a radioprotector. , 1986, Journal of immunology.

[38]  J. Denekamp,et al.  Cell kinetics and radiation biology. , 1986, International journal of radiation biology and related studies in physics, chemistry, and medicine.

[39]  R. Mole.  Radiation-induced acute myeloid leukemia in the mouse: experimental observations in vivo with implications for hypotheses about the basis of carcinogenesis. , 1986, Leukemia research.

[40]  S. Fred,et al.  Radiation sensitivity and proliferative recovery of hemopoietic stem cells in weanling as compared to adult mice. , 1967, Radiation research.

[41]  J. Till,et al.  A direct measurement of the radiation sensitivity of normal mouse bone marrow cells. , 1961, Radiation research.

[42]  A. Upton,et al.  Influence of Age at Time of Irradiation on Induction of Leukemia and Ovarian Tumors in RF Mice , 1960, Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine.

[43]  L. Hempelmann,et al.  Leukemia in children exposed to ionizing radiation. , 1959, The New England journal of medicine.