| Co-Investigator(Kenkyū-buntansha) |
INOUE Tohru National Institute of Health Science, Toxicology, Chairman, 毒性部, (研究職)部長 (50100110)
FUNABIKI Tetsunori Yokohama City Univ., School of Med., Instructor, 医学部, 助手 (20264616)
IKUTA Koichro Yokohama City Univ., School of Med., Assistant Professor, 医学部, 講師 (80159590)
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| Research Abstract |
We investigated possible changes in hematopoiesis in p53-deficient mice [p53(-)] in comparison with those in wild-type controls. There was no difference in the numbers of peripheral blood cells and marrow nucleated cells, while the frequency of hematopoietic progenitors in marrow of p53(-) seems to have increased. The number of HPP-CFC in p53(-) marrow, 2 days after injection of 5FU,markedly increased. Then, we examined the effect of TGF-beta on hematopoietic progenitors, and found that the proliferation of megakaryocyte-progenitors was markedly inhibited by TGF-beta, whereas erythroid and granulocyte-macrophage progenitors were not significantly inhibited. TGF-beta also completely inhibited the growth of HPP-CFC.It is interesting that in the p53(-), the inhibitory action of TGF-beta on the HPP-CFC was incompletely abolished, which suggests that there is a subpopulation of HPP-CFC less sensitive to the regulation by TGF-beta. In contrast to HPP-CFC,the CFU-Mk in the p53(-) remained inhibited by TGF-beta. Thus, HPP-CFC might be regulated by TGF-beta through their signal pathways which are linked to p53. CFU-S and CFU-GM in p53(-) after graded doses of irradiation showed a flatter survival curve. According to the end-labeling for spleen colonies, p53(-) showed rather high incidence of apoptosis, which was not modulated by irradiation. These results showed a possible mechanism escaped from the radiation-induced apoptosis due to lack of p53 gene also in hematopoietic stem cells. In vivo kinetics studies revealed that CFU-GM in p53(-) rapidly proliferated after the start of labeling by BrdUrd but the size of growing fraction of CFU-GM was same as that in the control mice. In conclusion, the stem cell kinetics should be altered by disruption of p53 gene, but the numbers of differentiated cells in peripheral blood are corrected by unknown regulating mechanisms.
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