INTERFERON-GAMMA SELECTIVELY INHIBITS VERY PRIMITIVE CD34(2-) AND NOTMORE MATURE CD34+CD38+ HUMAN HEMATOPOIETIC PROGENITOR CELLS()CD38()

To assess the effects of interferon gamma (IFN-gamma) on very primitiv e hematopoietic progenitor cells, CD34(2+)CD38(-) human bone marrow ce lls were isolated and cultured in a-two-stage culture system, consisti ng of a primary liquid culture phase followed by a secondary semisolid colony assay. CD34(2+)CD38(-) cells needed at least the presence of i nterleukin 3 (IL-3) and kit ligand (KL) together with either IL-1, IL- 6, or granulocyte-colony-stimulating factor (G-CSF) in the primary liq uid phase in order to proliferate and differentiate into secondary col ony-forming cells (CFC). Addition of IFN-gamma to the primary liquid c ultures inhibited cell proliferation and generation of secondary CFC i n a dose-dependent way. This was a direct effect since it was also see n in primary single cell cultures of CD34(2+) CD38(-) cells. The proli feration of more mature CD34(+) CD38(+) cells, however, was not inhibi ted by IFN-gamma, demonstrating for the first time that IFN-gamma is a specific and direct hematopoietic stem cell inhibitor. IFN-gamma, mor eover, preserves the viability of CD34(2+)CD38(-) cells in the absence of other cytokines. IFN-gamma could, therefore, play a role in the pr otection of the stem cell compartment from exhaustion in situations of hematopoietic stress and may be useful as stem cell protecting agent against chemotherapy for cancer.