Macrophage-lineage cells negatively regulate the hematopoietic stem cell pool in response to interferon gamma at steady state and during infection

Abstract

Bone marrow (BM) resident macrophages (Mφs) regulate hematopoietic stem cell (HSC) mobilization; however, their impact on HSC function has not been investigated. We demonstrate that depletion of BM resident Mφs increases HSC proliferation as well as the pool of quiescent HSCs. At the same time, during bacterial infection where BM resident Mφs are selectively increased we observe a decrease in HSC numbers. Moreover, strategies that deplete or reduce Mφs during infection prevent HSC loss and rescue HSC function. We previously found that the transient loss of HSCs during infection is interferon-gamma (IFNγ)-dependent. We now demonstrate that IFNγ signaling specifically in Mφs is critical for both the diminished HSC pool and maintenance of BM resident Mφs during infection. In addition to the IFNγ-dependent loss of BM HSC and progenitor cells (HSPCs) during infection, IFNγ reduced circulating HSPC numbers. Importantly, under infection conditions AMD3100 or G-CSF-induced stem cell mobilization was impaired. Taken together, our data show that IFNγ acts on Mφs, which are a negative regulator of the HSC pool, to drive the loss in BM and peripheral HSCs during infection. Our findings demonstrate that modulating BM resident Mφ numbers can impact HSC function in vivo, which may be therapeutically useful for hematologic conditions and refinement of HSC transplantation protocols. Stem Cells 2015;33:2294-2305