Thesis Marieke Goedhart

On 27 June 2019 (10:00) Marieke Goedhart defended her PhD thesis 'The vascular bone marrow niche as immunological and hematopoietic hotspot' at the University of Amsterdam.

Promotor: Prof Ellen van der Schoot MD PhD
Copromotores: Martijn Nolte PhD and Carlijn Voermans PhD
Venue: Agnietenkapel, University of Amsterdam

Summary

Cover thesis Marieke Goedhart

Both hematopoietic stem cells and immune cells in the bone marrow localize in close proximity to the bone marrow vasculature, suggesting possible interactions between hematopoiesis and the immune response in the vascular bone marrow niche. In this thesis, we therefore focus on the vascular bone marrow niche as an immunological and hematopoietic hotspot. 
We study the role of the vascular bone marrow niche in the bone marrow entry of hematopoietic stem- and progenitor cells. We show that VE-cadherin is crucial for the regulation of bone marrow vascular permeability and bone marrow directed migration of hematopoietic progenitor cells. Next, we identify an important role for the CXCR4-CXCL12 axis for CD8+ T bone marrow entry and subsequent localization in vascular bone marrow niches that support their survival. In addition, we study the capacity of the vascular bone marrow niche to support hematopoiesis under inflammatory challenge, as well as its ability to translate inflammatory signals to hematopoietic output.
We conclude that IFN-y negatively affects the maintenance and survival of bone marrow MSCs, and does not improve their hematopoietic support function. In addition, we suggest an important role for bone marrow dendritic cells as translators between infection and hematopoiesis, in particular in anti-fungal immunity. This thesis therefore identifies opportunities for crosstalk between hematopoiesis and immunity in the bone marrow, and invites further investigations into the organization of the vascular bone marrow niche that will be of significance for our understanding of hematopoiesis and immunological memory in both health and disease.

Chapters

Chapter 1
General Introduction

Chapter 2
VE-cadherin regulates homing of hematopoietic stem and progenitor cells to the bone marrow

Chapter 3
CXCR4, but not CXCR3, drives CD8 T cell entry into and migration through the murine bone marrow Abstract

Chapter 4
Interferon-gamma impairs maintenance and alters hematopoietic support of bone marrow mesenchymal stromal cells Abstract

Chapter 5
Bone marrow harbors a unique population of dendritic cells that promotes granulopoiesis upon exposure to fungal antigens

Chapter 6
General Discussion