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The Journal of Immunology, 2005, 174: 752-757.
Copyright © 2005 by The American Association of Immunologists

IFN-{gamma} Negatively Modulates Self-Renewal of Repopulating Human Hemopoietic Stem Cells1

Liping Yang, Ingunn Dybedal, David Bryder, Lars Nilsson, Ewa Sitnicka, Yutaka Sasaki and Sten Eirik W. Jacobsen2

Hemopoietic Stem Cell Laboratory, Lund Strategic Research Center for Stem Cell Biology and Cell Therapy, Lund University, Lund, Sweden

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.




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