Expression of interferon-gamma by stromal cells inhibits murine long-term repopulating hematopoietic stem cell activity

Several lines of evidence suggest that overexpression of interferon gamma ( IFN-gamma) in the marrow microenvironment may play a role in the pathogenes is of marrow suppression in aplastic anemia. We previously showed that over expression of IFN-gamma by marrow stromal cells inhibits human long-term cu lture initiating fell activity assayed in vitro to a much greater degree th an the addition of soluble IFN-gamma. The effect of IFN-gamma on true repop ulating stem cells assayed in vivo has not been studied previously, We comp ared the effect of co-culture of murine marrow cells in the presence of str omal cells transduced with a retroviral vector expressing murine IFN-gamma vs stromal cells transduced with a control neo vector, Using a murine conge nic competitive repopulation assay, there was significantly less long-term repopulating stem cell activity remaining after culture on mIFN-gamma-expre ssing stroma as compared to control stroma, We also investigated the effect of directly transducing murine hone marrow cells with the mIFN-gamma or co ntrol vector, Marrow cells transduced with either vector were transplanted into W/W-v recipient mice. The percentage of vector-containing cells in the mIFN-gamma mice was significantly lower than in the control mice, suggesti ng that mIFN-gamma-transduced primitive cells may not have survived culture , or that mIFN-gamma directly decreases gene transfer into repopulating cel ls, Despite no significant differences in white or red blood cells in the m ice transplanted with the mIFN-gamma-transduced cells, the number of bone m arrow colony-forming unit-C 16 weeks after transplantation was significantl y lower in the IFN-gamma group. These data indicate that ectopic or overexp ression of mIFN-gamma, especially by marrow microenvironmental elements, ma y have a marked effect on primitive hematopoiesis as assayed in vivo. Publi shed by Elsevier Science Inc.