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

SUBMITTER: McCabe A

PROVIDER: S-EPMC4693298 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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Macrophage-Lineage Cells Negatively Regulate the Hematopoietic Stem Cell Pool in Response to Interferon Gamma at Steady State and During Infection.

McCabe Amanda A Zhang Yubin Y Thai Vinh V Jones Maura M Jordan Michael B MB MacNamara Katherine C KC

Stem cells (Dayton, Ohio) 20150522 7

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 rescu ...[more]

PMID: 25880153

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Project description:BackgroundNeovascular age-related macular degeneration (nAMD) commonly causes vision loss from aberrant angiogenesis, termed choroidal neovascularization (CNV). Macrophages are heterogeneous cells that are necessary for experimental CNV, present in human CNV samples, and can display diverse functions, which are dependent upon both their origin and tissue microenvironment. Despite these associations, choroidal macrophage heterogeneity remains unexplored.MethodsWe performed multi-parameter flow cytometry on wildtype (WT) and Ccr2-/- mice after laser injury to identify macrophage subtypes, and determine which subsets originate from classical monocytes. To fate map tissue resident macrophages at steady state and after laser injury, we used the Cx3cr1CreER/+ ; Rosa26zsGFP/+ mouse model. We reanalyzed previously published single-cell RNA-seq of human choroid samples from healthy and nAMD patients to investigate human macrophage heterogeneity, disease association, and function.ResultsWe identified 4 macrophage subsets in mice: microglia, MHCII+CD11c-, MHCII+CD11c+, and MHCII-. Microglia are tissue resident macrophages at steady state and unaffected by laser injury. At steady state, MHCII- macrophages are long lived, tissue resident macrophages, while MHCII+CD11c- and MHCII+CD11c+ macrophages are partially replenished from blood monocytes. After laser injury, MHCII+CD11c- macrophages are entirely derived from classical monocytes, MHCII- macrophages originate from classical monocytes (90%) and an expansion of tissue resident macrophages (10%), and MHCII+CD11c+ macrophages are derived from classical monocytes (70%), non-classical monocytes (10%), and an expansion of tissue resident macrophages (20%). Single-cell RNA-seq analysis of human choroid found 5 macrophage subsets: two MHCII+CD11C- and three MHCII+CD11C+ populations. One MHCII+CD11C+ subset was 78% derived from a patient with nAMD. Differential expression analysis identified up-regulation of pro-angiogenic gene expression in one MHCII+CD11C- and two MHCII+CD11C+ subsets, including the disease-associated cluster. The upregulated MHCII+CD11C- pro-angiogenic genes were unique compared to the increased MHCII+CD11C+ angiogenesis genes.ConclusionsMacrophage origin impacts heterogeneity at steady state and after laser injury in mice. Both mice and human patients demonstrate similar macrophage subtypes. Two discrete pro-angiogenic macrophage populations exist in the human choroid. Targeting specific, pro-angiogenic macrophage subsets is a potential novel therapeutic for nAMD.

Dataset Information

Macrophage-Lineage Cells Negatively Regulate the Hematopoietic Stem Cell Pool in Response to Interferon Gamma at Steady State and During Infection.

Publications

Macrophage-Lineage Cells Negatively Regulate the Hematopoietic Stem Cell Pool in Response to Interferon Gamma at Steady State and During Infection.

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