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ORCID

https://orcid.org/0000-0001-5491-528X

Date of Award

Spring 5-15-2016

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Molecular Cell Biology)

Degree Name

Doctor of Philosophy (PhD)

Degree Type

Dissertation

Abstract

Hematopoiesis is the process in which blood cells develop from hematopoietic stem and progenitor cells (HSPCs). In the healthy adult, the majority of HSPCs reside in specialized microenvironments surrounding the vasculature within the bone marrow, collectively referred to as the HSPC niche. In response to various forms of stimuli, including the administration of certain pharmacologic agents, the regulatory functions of niches are altered and allow HSPCs to exit the bone marrow and enter the periphery through a process known as mobilization. Granulocyte-colony stimulating factor (G-CSF) is the prototypic agent used clinically to mobilize HSPCs into the blood where they can be harvested for stem cell transplantation to treat a variety of hematologic conditions. However, the mechanisms by which G-CSF-induced signaling affect niche function to mobilize HSPCs are not completely understood.

Our lab has previously shown that G-CSF signaling in monocytic cells is sufficient to induce a normal mobilization response of HSPCs. We first focused on identifying which of the monocytic cell subtypes in the bone marrow monocytes, macrophages, and myeloid dendritic cells (MDCs) are targeted by G-CSF. We identified MDCs as a previously uncharacterized cell type that localizes to perivascular HSPC niches in the bone marrow. G-CSF treatment results in a marked loss of MDCs from the bone marrow. Moreover, conditional ablation of MDCs results in HSPC mobilization and suppresses CXCL12 expression in arteriolar endothelial cells, a key stromal cell type of the HSPC niche, indicating a novel role for MDCs in regulating HSPC niche function.

Our preliminary data suggests that monocyte-lineage activation of TGF- signaling in the bone marrow may mediate G-CSFs effects on bone marrow stromal cells. To test this hypothesis, we conditionally deleted Tgfbr2 from bone marrow mesenchymal progenitors and found altered hematopoiesis and stromal cell architecture. Further work will be required to fully characterize the changes in the stromal cell development in the marrow, how these changes alter the HSPC niche, and how they affect HSPC maintenance.

Language

English (en)

Chair and Committee

Daniel C. Link

Committee Members

Khunghee Choi, Roberto Civitelli, Timothy J. Ley, Fanxin Long,

Comments

Permanent URL: https://doi.org/10.7936/K71R6NSK

Available for download on Friday, May 15, 2116

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