ORCID

https://orcid.org/0000-0001-8811-1319

Date of Award

Summer 8-15-2018

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Molecular Genetics & Genomics)

Degree Name

Doctor of Philosophy (PhD)

Degree Type

Dissertation

Abstract

The bone marrow niche is an important microenvironment for the regulation of normal and malignant hematopoiesis. The first discovered niche component is mesenchymal stromal cells, which are the major source for the production and secretion of multiple niche factors. Mesenchymal stromal cells are heterogeneous and various transgenes have been used to target non-identical but overlapping subpopulations. To further characterize the heterogeneity of mesenchymal stromal cells, we tested the targeting specificity of three tissue-specific Cre-recombinase transgenes. We show that in addition to osteoblasts, Ocn-Cre targets a majority of Cxcl12-abundant reticular (CAR) cells and arteriolar pericytes. Surprisingly, Dmp1-Cre also targets a subset of CAR cells, in which expression of osteoblast-lineage genes is enriched. Moreover, a new tissue-specific Cre-recombinase, Tagln-Cre efficiently targets osteoblasts, a majority of CAR cells, and both venous sinusoidal and arteriolar pericytes. These observations highlight the heterogeneity of mesenchymal stromal cells in the bone marrow and provide tools to interrogate this heterogeneity. To further analyze the functional heterogeneity of mesenchymal stromal cells, we assessed the function of CXCL12 from different subsets of mesenchymal stromal cells on B lymphopoiesis. We show that CXCL12 from Ocn-Cre targeted stromal cells is particularly important for the regulation of mature naive B cells and memory B cells, potentially through the regulation of their homing and/or retention. This suggests that B cell development requires distinct niches at different stages and Ocn-Cre targeted stromal cells may represent a specific niche for late-stage B cell development. Besides mesenchymal stromal cells, this thesis also assesses the function of a recently identified resident population of murine bone marrow classical dendritic cells (BM cDCs). We show that BM cDC ablation results in a secondary, non-cell autonomous loss of BM macrophages. And more importantly, BM cDCs regulate hematopoietic progenitor and stem cell (HSPC) trafficking through a macrophage independent pathway, at least in part, through its regulation of sinusoidal CXCR2 signaling and vascular permeability. These findings suggest BM cDCs may serve as a novel bone marrow niche component regulating HSPCs. Collectively, this thesis improves on the overall understanding of the bone marrow niche and provides insights with significant relevance to both basic and clinical research.

Language

English (en)

Chair and Committee

Daniel C. Link

Committee Members

Timothy J. Ley, Grant A. Challen, Fanxin Long, Roberto Civitelli,

Comments

Permanent URL: 2019-02-14

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