The objective of this research is to define the role of niche-specific production of CXCL12 in B lymphopoiesis. In response to infection, there is a dramatic increase in neutrophil production (granulopoiesis) in the bone marrow at the expense of other cell lineages, including B cells. Granulocyte colony-stimulating factor (G-CSF) is the principal cytokine mediating this switch from B lymphopoiesis to granulopoiesis. Our preliminary data show that treatment of mice with G-CSF for 5 days leads to a 10-fold decrease in bone marrow B cells. The loss of B cells is most striking at the mature B cell stage but extends to at least the pro-B stage of development. Preliminary studies of G-CSF receptor (G-CSFR)-/- bone marrow chimeras demonstrate that G-CSF-induced B cell suppression occurs in a non-cell intrinsic fashion. Consistent with this observation, G-CSF treatment is associated with marked alterations in the bone marrow microenvironment, including decreased CXCL12/SDF1 expression and loss of mature osteoblasts. Previous studies show that B cell progenitors are in direct contact with CXCL12 expressing stromal cells and that loss of CXCL12 signaling is associated with impaired B lymphopoiesis. Moreover, our preliminary data show that B lymphopoiesis is impaired in mice with an osteoblast-specific deletion of CXCL12. Based on these data, we hypothesize that loss of CXCL12 expression by osteoblast lineage cells is the central event mediating G- CSF-induced B cell suppression. This hypothesis raises several important questions that will be addressed in this proposal: 1) what is the stage of osteoblast maturation that produces CXCL12 and regulates B lymphopoiesis and does endothelial CXCL12 expression play any role;and 2) how does CXCL12 regulate B lymphopoiesis. The following specific aims are proposed.
Aim 1 : Analyze the effect of CXCL12 deletion in osteolineage or endothelial cells on B lymphopoiesis.
Aim 2 : Analyze the role of niche-specific CXCL12 production on B cell bone marrow localization, proliferation, and survival.
This project will benefit public health by providing insight into the development of the immune system, specifically how antibody-producing B cells develop. The project will explore how the drug granulocyte colony- stimulating factor and the signaling molecule CXCL12 regulate B cell production and number. This understanding may be useful in treating people who have leukemia derived from B cells.
|Day, Ryan B; Bhattacharya, Deepta; Nagasawa, Takashi et al. (2015) Granulocyte colony-stimulating factor reprograms bone marrow stromal cells to actively suppress B lymphopoiesis in mice. Blood 125:3114-7|
|Greenbaum, Adam; Hsu, Yen-Michael S; Day, Ryan B et al. (2013) CXCL12 in early mesenchymal progenitors is required for haematopoietic stem-cell maintenance. Nature 495:227-30|