Vol. 10, Issue 11, 3633-3642, November 1999

Chimeric Cytokine Receptor Can Transduce Expansion Signals in Interleukin 6 Receptor  (IL-6R)-, IL-11R-, and gp130-low to -negative Primitive Hematopoietic Progenitors

Mineo Takagi,^* Takanori Nakamura,^* Toshie Sawada,^* Azusa Kaneko,^* Manabu Nozaki-Ukai, Tatsutoshi Nakahata, Takashi Yokota,^* and Toshio Heike^*§

Departments of  ^*Stem Cell Regulation and  Clinical Oncology and  Laboratory Animal Research Center, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan

We generated transgenic mice expressing chimeric receptors, which comprise extracellular domains of the human granulocyte-macrophage colony-stimulating factor (hGM-CSF) receptor and transmembrane and cytoplasmic domains of the mouse leukemia inhibitory factor receptor. In suspension cultures of lineage-negative (Lin), 5-fluorouracil-resistant bone marrow cells of the transgenic mice, a combination of hGM-CSF and stem cell factor (SCF) induced exponential expansions of mixed colony-forming unit. The combination of hGM-CSF and SCF was effective on enriched, LinSca-1⁺c-kit⁺ progenitors and increased either mixed colony-forming unit or cobblestone area-forming cells. In case of stimulation with hGM-CSF and SCF, interleukin-6 (IL-6) and SCF, or IL-11 and SCF, the most efficient expansion was achieved with hGM-CSF and SCF. When LinSca-1⁺c-kit⁺CD34 further enriched progenitors were clone sorted and individually incubated in the presence of SCF, hGM-CSF stimulated a larger number of cells than did IL-6, IL-6 and soluble IL-6 receptor (IL-6R), or IL-11. These data suggest the presence of IL-6R-, IL-11R-, and gp130-low to -negative primitive hematopoietic progenitors. Such primitive progenitors are equipped with signal transduction molecules and can expand when these chimeric receptors are genetically introduced into the cells and stimulated with hGM-CSF in the presence of SCF.