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Whereas multiple growth-promoting cytokines have been demonstrated to be involved in regulation of the hemopoietic stem cell (HSC) pool, the potential role of negative regulators is less clear. However, IFN-gamma, if overexpressed, can mediate bone marrow suppression and has been directly implicated in a number of bone marrow failure syndromes, including graft-vs-host disease. Whether IFN-gamma might directly affect the function of repopulating HSCs has, however, not been investigated. In the present study, we used in vitro conditions promoting self-renewing divisions of human HSCs to investigate the effect of IFN-gamma on HSC maintenance and function. Although purified cord blood CD34(+)CD38(-) cells underwent cell divisions in the presence of IFN-gamma, cycling HSCs exposed to IFN-gamma in vitro were severely compromised in their ability to reconstitute long-term cultures in vitro and multilineage engraft NOD-SCID mice in vivo (>90% reduced activity in both HSC assays). In vitro studies suggested that IFN-gamma accelerated differentiation of targeted human stem and progenitor cells. These results demonstrate that IFN-gamma can negatively affect human HSC self-renewal.

Type

Journal article

Journal

J Immunol

Publication Date

15/01/2005

Volume

174

Pages

752 - 757

Keywords

ADP-ribosyl Cyclase, ADP-ribosyl Cyclase 1, Animals, Antigens, CD, Antigens, CD34, Cell Differentiation, Cell Lineage, Cells, Cultured, Clone Cells, Dose-Response Relationship, Immunologic, Fetal Blood, Growth Inhibitors, Hematopoietic Stem Cell Transplantation, Hematopoietic Stem Cells, Humans, Immunophenotyping, Interferon-gamma, Membrane Glycoproteins, Mice, Mice, Inbred NOD, Mice, SCID