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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
5F30HL112552-02
Application #
8610807
Study Section
Special Emphasis Panel (ZRG1-F10A-S (20))
Program Officer
Chang, Henry
Project Start
2012-04-01
Project End
2015-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
2
Fiscal Year
2013
Total Cost
$28,465
Indirect Cost
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130