SSA - The roles of bone marrow stromal-derived thrombopoietin in HSC niche self-renewal

Lead Research Organisation: University of York
Department Name: Biology

Abstract

Background: Haematopoiesis occurs predominantly within the bone marrow and is orchestrated by the direct and indirect interactions of many different cell types to tightly regulate proliferation, self-renewal and differentiation of haematopoietic stem cells (HSCs). Recent findings suggest that bone marrow stromal cells (BMSCs) are critical in regulating the HSC niche through direct cell-cell contact and paracrine signalling. Although many factors regulate HSC maintenance, thrombopoietin (TPO) is one of the three key haematopoietic cytokines able to directly control HSC self-renewal. A number of groups have shown that BMSCs release TPO in the picomolar range, which might be sufficient to regulate HSC self-renewal in the niche. However, the role of BMSC-derived TPO in the HSC microenvironment is unknown.
Objectives:
1. Establish which BMSC subsets produce TPO
2. Determine the effects of TPO-producing BMSCs on HSC self-renewal in vitro
3. Determine the roles of BMSC-derived TPO on haematopoiesis in vivo
Novelty: Defining the precise roles of stromal cells in the HSC niche is a novel and cutting-edge area of research combining imaging technologies with gene expression analysis and in vitro and in vivo models.
Timeliness: Understanding the molecular and cellular mechanisms regulating stem cell niches is essential to understanding homeostasis of blood and other adult organs and tissues all key to understanding the healthy aging process, a BBSRC/RCUK priority area.
Experimental Approach: Using flow cytometry for specific markers and Cxcl12-DS-red transgenic mice we will determine which specific group of BMSCs express TPO as determined by western blot and qPCR analysis. We will then develop a co-culture system to determine the ability of TPO-producing BMSCs to support HSCs in vitro in addition to 4D-multiphoton imaging of the TPO+-BMSC HSC niche in vivo. Finally, using Tpo-null GM mice, we will characterise the importance of BMSC-derived TPO on haematopoiesis in vivo using bone marrow chimeras.

Publications

10 25 50

Studentship Projects

Project Reference Relationship Related To Start End Student Name
BB/M011151/1 30/09/2015 29/09/2023
1792472 Studentship BB/M011151/1 30/09/2016 30/03/2021 Oliver Herd
 
Description 1) Thrombopoietin (TPO) is not produced by bone marrow stromal cells at the protein level. TPO is instead produced by the liver and travels through the circulation to the bone marrow where it is involved in haematopoiesis and haematopoietic stem cell self-renewal

2) A mouse model of chronic immune thrombocytopenia reveals that haematopoietic stem cells are not functionally compromised. Blood production is increased due to an increase in the number of functional haematopoietic stem cells and these are supported by an adapting bone marrow microenvironment (stromal cell expansion and vasculature changes)
Exploitation Route Further research in humans (ITP patients). WQhat are the long term effects of the bone marrow changes?
Sectors Pharmaceuticals and Medical Biotechnology

URL https://ashpublications.org/blood/article/134/Supplement_1/222/426030/An-Adapting-Bone-Marrow-Niche-Creates-a-Nurturing
 
Description Patient group 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Members of the public visited the university and attended presentations from members of the Genever lab, followed by guided tours
Year(s) Of Engagement Activity 2018
 
Description Patient group workshop 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Members of the York Haematology Support Group attended the University of York where members of the Hitchcock lab gave an overview of our research followed by a tour of the technology facility and lab space
Year(s) Of Engagement Activity 2018