From Quiescent to Proliferating

Science Signaling  21 Apr 2009:
Vol. 2, Issue 67, pp. ec141
DOI: 10.1126/scisignal.267ec141

Interferon-α (IFN-α), one family of type I interferons, are well known for inhibiting cell proliferation in vitro and are used clinically to treat certain forms of cancer, including various leukemias and lymphomas. Essers et al. report an unexpected proliferative response of mouse hematopoietic stem cells (HSCs) to either IFN-α or poly(I:C) (polyriboinosinic-polyribocytidylic acid), which mimics the effects of infection by an RNA virus and triggers type I IFN production. HSCs in mice treated with either poly(I:C) or recombinant IFN-α exited from the quiescent state and transiently proliferated. HSCs from Ifnar−/− mice, which lack the type I IFN receptor, failed to proliferate in response to either signal, showing that the poly(I:C) response is mediated by stimulation of type I IFNs. When reconstituted into irradiated mice, Ifnar−/− HSCs reconstituted the blood system of the recipients, and when mixed populations of bone marrow cells were transplanted into host mice, the Ifnar−/− cells were retained (no competitive disadvantage) and even proliferated when coinjected with a high proportion of wild-type cells (95:5; wild type:Ifnar−/−). Thus, type I IFN signaling is not required for HSC function but is required for the transient proliferative response to IFN-α or poly(I:C). The proliferative response required signaling through STAT1 (signal transducer and activator of transcription 1), as evidenced by loss of the response in Stat1−/− mice, and involved activation of the phosphoinositide 3-kinase pathway, as evidenced by increased Akt phosphorylation. IFN-α–stimulated cells also exhibited increased transcription and abundance of the protein Sca-1 (stem cell antigen 1) at the cell surface and neither IFN-α nor poly(I:C) stimulated HSC proliferation in Sca1−/− mice. Repeated exposure of HSCs to signals that trigger proliferation may deplete the stem cell pool. Indeed, treatment of mice with mixed populations of HSCs (wild-type and Ifnar−/−) with poly(I:C) resulted in the eventual loss of the wild-type HSCs, which suggests that chronic IFN-α stimulation did indeed deplete the stem cell pool, providing an advantage to the Ifnar−/− cells. Shifting the HSC pool from a dormant or quiescent state to a proliferating state makes mice more susceptible to chemotherapeutic agents such as 5-flurouracil (5-FU). When wild-type mice were exposed to poly(I:C) before exposure to 5-FU, a regimen was established that resulted in complete lethality of 5-FU due to severe anemia. Thus, the authors postulate that IFN-α priming may increase the effectiveness of some chemotherapeutic regimens.

M. A. G. Essers, S. Offner, W. E. Blanco-Bose, Z. Waibler, U. Kalinke, M. A. Duchosal, A. Trumpp, INFα activates dormant haematopoietic stem cells in vivo. Nature 458, 904–908 (2009). [PubMed]