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Comparative Effects of Insulin-Like Growth Factor II (IGF-II) and IGF-II Mutants Specific for IGF-II/CIM6-P or IGF-I Receptors on in Vitro Hematopoiesis

^a Transplantation Therapy Section, National Cancer Institute, Bethesda, Maryland, USA;
^b Otsuka America Pharmaceutical Company, Rockville, Maryland, USA;
^c Daiichi Pharmaceutical Company, LTD, Molecular Biology Research Laboratory, Tokyo, Japan;
^d Immune Cell Biology Program, Naval Medical Research Institute, Bethesda, Maryland, USA;
^e Holland Laboratories, Molecular Biology Laboratory, American Red Cross, Rockville, Maryland, USA

Key Words. Colony-forming units for granulocytes-macrophages (CFU-GM) • Burst-forming units-erythroid (BFU-E) • Insulin-like growth factor II (IGF-II) • Megakaryocyte • Interleukin 3 • c-kit ligand

Dr. Gretchen N. Schwartz, Bldg. 10, Rm. 12N226, Transplantation Therapy Section, Medicine Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.

This report presents the results of studies investigating the effect of insulin-like growth factor II (IGF-II) on the proliferation and differentiation of CD34⁺ bone marrow cells in serum-substituted liquid cultures. Bone marrow cells were enriched for CD34⁺ cells and then placed in liquid cultures supplemented with either interleukin 3 (IL-3) or IL-3 and c-kit ligand with and without the addition of IGF-II. When CD34⁺ cells were incubated with IL-3, cellularity increased throughout four weeks of culture. Cellularity was twofold greater when cultures also contained IGF-II. IGF-II also promoted an increase in cellularity in cultures with IL-3 and c-kit ligand. In combination with IL-3 or IL-3 and c-kit ligand, IGF-II promoted an earlier differentiation of granulocytes, as well as an increase in the number of megakaryocyte lineage cells. There were approximately two-fold more colony-forming units for granulocytes and macrophages (CFU-GM) and burst-forming units for erythroid cells (BFU-E) in cultures containing both IL-3 and IGF-II than in cultures with IL-3 alone. These results demonstrate that in cytokine-supplemented media, physiological concentrations of IGF-II augmented both the proliferation and differentiation of CD34⁺ bone marrow cells while maintaining a greater number of progenitor cells. To identify the receptors through which IGF-II enhances in vitro hematopoiesis, IGF-II was substituted with one of the mutant forms of IGF-II that selectively interacts with either IGF-II/CIM6-P receptors or with IGF-I and insulin receptors. The results with the mutant forms of IGF-II demonstrate that IGF-II augments in vitro hematopoiesis primarily through its interaction with IGF-I and possibly insulin receptors, rather than IGF-II/CIM6-P receptors.

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