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Date of Award
Doctor of Philosophy (PhD)
The production of hematopoietic cells in the bone marrow is tightly and dynamically regulated in response to environmental stimuli. In response to infection, the bone marrow increases granulopoiesis at the expense of lymphopoiesis. The mechanisms mediating this shift are poorly understood. We show that treatment with granulocyte-colony stimulating factor (G-CSF), which is often induced during infection, results in marked decline of B lymphocytes at multiple stages of bone marrow B cell development. Transgenic mouse models show that G-CSF acts in a non-cell intrinsic fashion through cells of the monocyte-macrophage lineage to suppress B lymphopoiesis by downregulating important B trophic factors including CXCL12, KIT ligand, FLT3 ligand, interleukin-6, interleukin-7, IGF-1, and BAFF, resulting in B cell mobilization and apoptosis. G-CSF reprograms CXCL12-abundant reticular (CAR) cells, bipotent adipogenic-osteogenic stromal cells that are a key component of the B cell niche, increasing osteogenic potential and downregulating the production of CXCL12, interleukin-7, and KIT ligand. G-CSF also decreases osteoblast number, disrupting an additional B niche population and source of key B cell developmental cytokines. These data show that G-CSF reprograms bone marrow stromal cells to alter the bone marrow microenvironment to actively suppress B lymphopoiesis. To further explore the role of stromal cell-derived CXCL12 in B lymphopoiesis, we examined mice in which Cxcl12 was conditionally deleted in different stromal cell populations. Deletion of Cxcl12 using Dmp1-Cre (targeting osteolineage cells) does not disrupt bone marrow B lymphopoiesis. Deletion of Cxcl12 using OC-Cre (targeting osteolineage cells and vascular smooth muscle cells) results in an isolated loss of mature nave B cells in the bone marrow due to a homing defect following peripheral maturation. Deletion of Cxcl12 using Osx-Cre (targeting CAR cells) results in an early loss of bone marrow B cells beginning with pre-pro-B cells. Deletion of Cxcl12 using Prx1-Cre (targeting mesenchymal progenitors) results in severe suppression of B lymphopoiesis, including a loss of CLP, the upstream progenitor of B, T, and NK cells. These data suggest that CXCL12 from different stromal cell populations in the bone marrow regulates distinct stages of B lymphopoiesis.
Chair and Committee
Daniel C. Link
Timothy Ley, Matthew Walter, Deepta Bhattacharya, Eugene Oltz,
Day, Ryan Brent, "Granulocyte-Colony Stimulating Factor Reprograms the Bone Marrow Microenvironment to Suppress B Lymphopoiesis" (2016). Arts & Sciences Electronic Theses and Dissertations. 791.
Available for download on Thursday, March 08, 2018