Neutropenia, a deficiency in certain white blood cells, is a common side effect of chemotherapy that exposes patients to a high risk of death from opportunistic infections. Existing methods to restore neutrophils, including G-CSF administration and granulocyte infusions, have not produced a clear improvement in outcome, and new approaches are needed. White blood cells are the product of bone marrow hematopoietic stem and progenitor cells (HSPCs) that can be triggered to divide and differentiate by circulating inflammatory signals. Our prior work shows that the inflammatory cytokine interferon gamma (IFNg) is a potent stimulus for hematopoietic stem cell (HSC) division and myeloid differentiation. Yet persistent IFNg exposure inhibits HSC self-renewal, eventually leading to bone marrow failure. Whether HSCs or their progeny, the multipotent progenitors (MPPs), are equally responsive to IFNg is unknown. Furthermore, a lack of molecular understanding of signaling pathways induced by IFNg to promote HSPC differentiation poses a barrier to utilizing proimmune functions of IFNg while preventing deleterious effects. In preliminary work we identify genes induced in HSCs upon IFNg stimulation, and we show by gain- and loss-of-function studies that an exemplary gene can critically regulate HSPC differentiation. Thus we hypothesize that IFNg-induced transcriptional changes can be used to activate quiescent HSCs to produce more neutrophils, resulting in improved recovery from infection. The rationale is that regulated induction of specific IFNg targets in HSCs may enhance short-term myelopoiesis without disrupting long-term bone marrow function.
Three aims are designed to characterize the kinetics, mechanism, and outcome of IFNg-dependent HSPC differentiation.
In Aim 1, we will measure the contribution of HSCs versus MPPs to circulating granulocytes after IFNg stimulation using lineage-tracing, thereby revealing which of these HSPC subtypes is most potent as a source of neutrophils.
In Aim 2, we will evaluate IFNg-inducible factors for their role in HSPC differentiation using loss of function, xenotransplant, and functional biochemical studies. Finally, in Aim 3, we will test the utility of IFNg-induced HSPC myeloid differentiation in pathogen clearance using a mouse model of Group A Streptococcal myositis. Studies in Aim 3 will be informed by, but not dependent on, results of Aims 1 and 2. These studies will provide critical mechanistic data needed to design novel stem cell-based therapies for neutropenic fever and may reveal new insights into bone marrow failure syndromes that result from excessive inflammation.
New strategies to boost immune cell production are needed to prevent and treat opportunistic infections in patients with suppressed immune systems. We previously demonstrated that inflammatory signals such as interferon gamma push bone marrow stem cells to produce more immune cells. In this proposal, we will quantify how interferon gamma promotes immune cell production and evaluate whether bone marrow stem cells can be adapted to improve immunity.
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| Tashi, Tsewang; Swierczek, Sabina; Kim, Soo Jin et al. (2018) Pegylated interferon Alfa-2a and hydroxyurea in polycythemia vera and essential thrombocythemia: differential cellular and molecular responses. Leukemia 32:1830-1833 |
| Yan, Hannah; Baldridge, Megan T; King, Katherine Y (2018) Hematopoiesis and the bacterial microbiome. Blood 132:559-564 |
| Morales-Mantilla, Daniel E; King, Katherine Y (2018) The Role of Interferon-Gamma in Hematopoietic Stem Cell Development, Homeostasis, and Disease. Curr Stem Cell Rep 4:264-271 |
| King, Katherine Y (2017) Saving Stem Cells after Stress. Cell Stem Cell 21:709-710 |
| Kadmon, Claudine S; Landers, Cameron T; Li, Haiyan S et al. (2017) MicroRNA-22 controls interferon alpha production and erythroid maturation in response to infectious stress in mice. Exp Hematol 56:7-15 |
