レオナード シュルツ ジャクソン研究所, 研究員
ロナルド ハ゜ラシアス バーゼル免疫学研究所, 研究員
マックス クーハ゜ー アラバマ州立大学, 医学部, 教授
OGAWA Minetaro Institute for Medical Immunology, Kumamoto Univ. Medical School., 医学部, 助手 (70194454)
HAYASHI Shin-Ichi Institute for Medical Immunology, Kumamoto Univ. Medical School, 医学部, 助手 (50208617)
COOPER Max D. Howard Hughes Medical Institute Research Laboratory, University of Albama at Bir
PALACIOS Ronald Basel Institute for Immunology
SHULTZ Reonard D. The Jackcon Laboratories.
|Budget Amount *help
¥3,200,000 (Direct Cost : ¥3,200,000)
Fiscal Year 1990 : ¥3,200,000 (Direct Cost : ¥3,200,000)
Experimental hematology has now a list of growth factors, which contains nearly 20 distinct molecules acting on the cells of various blood cell lineages. Although it is important to list as many hematopoietc growth factors as possible, however, it become more difficult to have a clear image of hematopoietic system in toto as the number of molecules involved in the system increases. The major purpose of this international collaboratory project is pave a way towards a simplified model of hematopoietic system.
During the course of this project, two growth factor/receptor systems have been demonstrated to constitute the core structure of hematopoietic system. One is c-fms/M-CSF system, and the other is c-kit/SCF system.
First, in collaboration with Dr. L. D. Schultz in Jackson Laboratory, we have demonstrated that a mutation, osteopetrosis(op), is a single nucleotide insertion within M-CSF coding region, by which biological activity of M-CSF is abrogated. Further histological examination ind
icated that macrophage generation is maintained in the absence of M-CF. On the other hand, osteoclast generation whuch is indispensable for preparing bone cavity, is absolutely dependent on M-CSF. Noting a simple fact that there is no intramarrow hematopoiesis without bone cavity, c-fms/M-CSF system may well be a essential system for maintaining the intramarrow hematopoiesis.
Even in the presence of bone cavity, however, no intramarrow hematopoiesis is maintained if the system supporting self-renewal of stem cell is absent. Since Previous phenotype analysis of mutant mice defective in the functions of c-kit or its ligand suggested that this system could constitute the core tructue for hematopoietic stem cell self-renewal. To test this possibility, we have estabished hybridomas which secrete anti-c-kit moneclonal antibody. Using one of these mAb which can block c-kit function, we investigated the role of c-kit/SCF system in intramarrow hematopoiesis. Our result indicated that the self-renewal of myeloid and erythroid stem cells requires c-kit/SCF absolutely. In collaboration with Dr. Max Cooper in Alabama Univ., Frirtz Melchers, and Drs. Ronald Palacios, Fritz Melchers, and Antonius Rolink in Basel Institute for Immunology, we also demonstrated that c-kit isexpressed on the surface of early lymphocyte Precursors cell lines. Taken together, it is clear that c-kit/SCF system constitutes a core molecular structure for the self-renewal of all kinds of hematopoietic stem cells including lymphoid stem cells.
From these results, we are proposing a simplified model that receptor type tyrosine kinases and their ligands form a core structure of intramarrow hematopoiesis, and other cytokine receptor family molecules and their ligands are placed around this core structure, Probably Playing a role for ensuring the flexibility of hematopoietic system. This model might well be testable by investigating phylogenical and ontogenical development of hematopoietic system, and the investigation along this line is currently carried out in our laboratory. Less