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The Role of the Tissue Inhibitor of ...

Weiss, Ashley Rebecca.

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The Role of the Tissue Inhibitor of Metalloproteinase Family in the Bone Marrow Niche.

Record Type:	Electronic resources : Monograph/item
Title/Author:	The Role of the Tissue Inhibitor of Metalloproteinase Family in the Bone Marrow Niche./
Author:	Weiss, Ashley Rebecca.
Published:	Ann Arbor : ProQuest Dissertations & Theses, : 2018,
Description:	350 p.
Notes:	Source: Dissertations Abstracts International, Volume: 80-01, Section: B.
Contained By:	Dissertations Abstracts International80-01B.
Subject:	Molecular biology. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=10789452
ISBN:	9780438190399

The Role of the Tissue Inhibitor of Metalloproteinase Family in the Bone Marrow Niche.
Weiss, Ashley Rebecca.

The Role of the Tissue Inhibitor of Metalloproteinase Family in the Bone Marrow Niche. - Ann Arbor : ProQuest Dissertations & Theses, 2018 - 350 p.

Source: Dissertations Abstracts International, Volume: 80-01, Section: B.

Thesis (Ph.D.)--University of Toronto (Canada), 2018.

This item must not be sold to any third party vendors.

Proper host defense is dependent on the constant supply of a variety of different innate and adaptive immune cells, all of which originate from multipotent hematopoietic stem cells (HSCs). HSCs can differentiate into all immune lineages, as well as self-renew to sustain themselves throughout life. Fate decisions of HSCs are largely directed by extracellular signals received in their specialized microenvironment: the bone marrow niche. The metalloproteinases are a family of extracellular proteases responsible for degrading components of the extracellular matrix, as well as clipping and shedding growth factors, cytokines and their receptors, impacting signaling within tissues. The four mammalian tissue inhibitors of metalloproteinases (TIMP1-4) inhibit metalloproteinase activity. The TIMP-metalloproteinase axis is therefore uniquely positioned to impact both structural and molecular aspects of tissue niches. However, functional redundancy within the TIMP family exists due to overlapping expression patterns and shared proteinase targets. This thesis investigates the effects of completely unleashed metalloproteinase activity on hematopoiesis, using mice genetically deficient in all four TIMP family members ("TIMPless" mice). In Chapter 2, we survey immune cells and organs in TIMPless mice, uncovering a specific B cell developmental defect. In Chapter 3, we identify striking structural deformities in the bone marrow vasculature of TIMPless mice, as well as deficiencies in osteoblasts and perivascular cells. We identify molecular alterations in the TIMP-deficient bone marrow niche, including a deficit in VEGF and mislocalization in CXCL12. Finally, Appendix I describes a robust method to co-culture developing B cells with primary bone marrow-derived stromal cells, indicating the strength of TIMP-deficient stroma in supporting B lymphopoiesis in vitro. Overall, this thesis provides new evidence for essential in vivo activities of metalloproteinases and TIMPs in hematopoiesis, stimulating the need to continue studying the impact of these critical enzymes in stem cell niches.

ISBN: 9780438190399Subjects--Topical Terms:

517296
Molecular biology.

The Role of the Tissue Inhibitor of Metalloproteinase Family in the Bone Marrow Niche.
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245 1 4 $a The Role of the Tissue Inhibitor of Metalloproteinase Family in the Bone Marrow Niche.
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500 $a Advisor: Khokha, Rama.
502 $a Thesis (Ph.D.)--University of Toronto (Canada), 2018.
506 $a This item must not be sold to any third party vendors.
520 $a Proper host defense is dependent on the constant supply of a variety of different innate and adaptive immune cells, all of which originate from multipotent hematopoietic stem cells (HSCs). HSCs can differentiate into all immune lineages, as well as self-renew to sustain themselves throughout life. Fate decisions of HSCs are largely directed by extracellular signals received in their specialized microenvironment: the bone marrow niche. The metalloproteinases are a family of extracellular proteases responsible for degrading components of the extracellular matrix, as well as clipping and shedding growth factors, cytokines and their receptors, impacting signaling within tissues. The four mammalian tissue inhibitors of metalloproteinases (TIMP1-4) inhibit metalloproteinase activity. The TIMP-metalloproteinase axis is therefore uniquely positioned to impact both structural and molecular aspects of tissue niches. However, functional redundancy within the TIMP family exists due to overlapping expression patterns and shared proteinase targets. This thesis investigates the effects of completely unleashed metalloproteinase activity on hematopoiesis, using mice genetically deficient in all four TIMP family members ("TIMPless" mice). In Chapter 2, we survey immune cells and organs in TIMPless mice, uncovering a specific B cell developmental defect. In Chapter 3, we identify striking structural deformities in the bone marrow vasculature of TIMPless mice, as well as deficiencies in osteoblasts and perivascular cells. We identify molecular alterations in the TIMP-deficient bone marrow niche, including a deficit in VEGF and mislocalization in CXCL12. Finally, Appendix I describes a robust method to co-culture developing B cells with primary bone marrow-derived stromal cells, indicating the strength of TIMP-deficient stroma in supporting B lymphopoiesis in vitro. Overall, this thesis provides new evidence for essential in vivo activities of metalloproteinases and TIMPs in hematopoiesis, stimulating the need to continue studying the impact of these critical enzymes in stem cell niches.
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