Regulation of hematopoietic regeneration in the aging marrow by bone

Columbia University Health Sciences, New York NY

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Abstract

Project Summary Emergency myelopoiesis (EM) is induced to rapidly expand the myeloid compartment in response to injury, commonly acute inflammation or chronic inflammatory stress accumulating in the bone marrow (BM). The importance of the BM microenvironment in this process is emerging along with the understanding of how HSPCs respond to cytokines. However, the initiating signals that enforce and control lineage trajectories are not well understood. Whether bone cells, among the niche, contribute to the control of EM is also not known. During the previous funding cycle, we identified Lipocalin-2 (LCN2) as an innate immune protein and inflammatory marker secreted in response to inflammatory stress mainly by osteoblasts; and that LCN2 is essential in the anti- inflammatory cascade and protection from lethality. We now find that mice lacking Lcn2 in osteoblast (Lcn2osb-/- mice) show reduced neutrophil chemotaxis in the blood, indicating a defective myeloid response. The BM contains granulocyte-macrophage progenitors (GMPs), which give rise to neutrophils and monocytes. During EM, GMPs undergo enhanced proliferation and differentiation, leading to the increased production of mature myeloid cells. However, whereas LPS challenge increased GMPs in wild type mice, it did not affect GMP numbers in the BM of Lcn2osb-/- mice. These results suggest that bone-derived LCN2 is required to mount GMP response during acute inflammatory challenge and plays a critical role in EM by regulating the proliferation of GMPs. Based on these and other preliminary data we propose that LCN2 is an essential component of the EM pathway needed to stimulate production and maturation of myeloid cells in the BM following inflammatory stress and fight infection. Circulating LCN2 acts on HSPCs in the BM modulating their immunophenotype and subsequent function. To address this hypothesis, we will: Examine the effect of LCN2 inactivation in osteoblasts on the complete HSPC lineage in steady state and during hematopoietic injury (serial 5FU injections, chronic IL- 1 delivery, LPS challenge) and during aging; Model inflammatory injury to trace HSPC differentiation and map the effect of LCN2 on the clonal expansion of HSPCs during inflammation-induced EM; Determine whether glutamate signaling regulates LCN2 availability during inflammatory injury as a means of mounting EM activation; and how this response is altered during aging. These studies will establish bone LCN2 as a regulator of EM and can identify its critical transcriptional targets and the regulatory steps that can be targeted to mount a robust inflammatory response, improve clinical outcomes in younger and older adults; and inform therapeutic strategies during inflammation.