Elucidating the birth of haematopoietic stem cells

Lead Research Organisation: University of Oxford

Abstract

Hematopoietic stem cells (HSCs) are important cells from a biological and therapeutic perspective. They are responsible for the life-long production of all blood cells. Our work focuses on the first origins of HSCs during their initial generation in the embryo. We aim to obtain a better understanding of the molecules and mechanisms that are involved in HSC generation, function and maintenance. The transcription factor Runx1 was shown to play a critical role in HSC generation in the embryo. In humans, mutations and translocations of RUNX1 are found in approximately 25% of acute leukaemias, indicating the importance of RUNX1 also for the maintenance of normal haematopoiesis. In our studies we will examine how Runx1 exerts its crucial role in the first HSCs of the embryo, by identification of the genes and pathways regulated by Runx1, and by identification of the pathways that regulate Runx1 expression. These studies are expected to increase our insight into the biology of HSCs, and can contribute to a better understanding of leukaemogenesis and ultimately the development of new therapies.

Technical Summary

This programme aims to delineate the cellular and molecular events that regulate definitive hematopoietic stem cell (HSC) generation in the mammalian embryo. Obtaining a mechanistic understanding of this process as it occurs in vivo is challenging, but critical to the design of rational approaches to improve current HSC-based therapies and develop new ones. This programme also relates to broader fundamental questions in developmental biology, i.e. how genes are regulated, and how different types of adult stem cells are generated. The entry point for our studies of the hematopoietic system is the transcription factor Runx1, a master regulator of HSC emergence. There are three specific aims: 1) Comprehensive identification and characterization of Runx1 cis-regulatory elements and trans-acting factors in developmental haematopoiesis. 2) Characterization of the process of endothelial-to-haematopoietic transition (EHT). 3) Identification and characterization of Runx1 transcriptional target genes in developmental haematopoiesis.
 
Description John Fell Fund
Amount £53,340 (GBP)
Organisation University of Oxford 
Sector Academic/University
Country United Kingdom
Start 04/2017 
End 03/2018
 
Description LLR project grant
Amount £229,117 (GBP)
Organisation Leukaemia and Lymphoma Research 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2011 
End 06/2014
 
Description Weizmann-UK joint research program grant
Amount $50,000 (USD)
Organisation Weizmann Institute of Science 
Sector Academic/University
Country Israel
Start 04/2013 
End 03/2015
 
Title Reporter constructs 
Description Runx1 enhancer and promoter constructs 
Type Of Material Technology assay or reagent 
Year Produced 2006 
Provided To Others? Yes  
Impact Has been instrumental for in vivo and in vitro studies of blood cell development. 
 
Title Reporter mouse ESC lines 
Description Mouse ESC reporter lines 
Type Of Material Cell line 
Year Produced 2017 
Provided To Others? No  
Impact Allows identification of cells specified to the blood cell lineage 
 
Title Reporter mouse lines 
Description Enhancer-reporter mouse lines. 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Year Produced 2007 
Provided To Others? Yes  
Impact These lines facilitate the identification, isolation and characterisation of specific stages of the developing blood lineage. 
 
Title E11.5 expression data 
Description Expression data of endothelium and hematopoietic cluster cells in wild type and Steel mutant E11.5 mouse AGM and vitelline and umbilical arteries. 
Type Of Material Database/Collection of data 
Year Produced 2018 
Provided To Others? Yes  
Impact PMID 30166337 
URL https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi
 
Title E8.5 EHT expression data 
Description Affymetrix microarray expression data of sorted endothelium, hemogenic endothelium and hematopoietic progenitors isolated from E8.5 mouse concepti. 
Type Of Material Database/Collection of data 
Year Produced 2013 
Provided To Others? Yes  
Impact PMID 24326267 
URL https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE52075
 
Title Expression and ATAC-seq data of E8.5 to E10.5 EHT 
Description Mini-bulk RNA-seq and ATAC-seq on cells undergoing EHT in the mouse PAS/AGM and vitelline and umbilical arteries 
Type Of Material Database/Collection of data 
Year Produced 2018 
Provided To Others? No  
Impact Manuscript in preparation. Data will be made publicly available with published paper. 
 
Description Chromatin analysis 
Organisation University of Oxford
Department Weatherall Institute of Molecular Medicine (WIMM)
Country United Kingdom 
Sector Academic/University 
PI Contribution Experimental and intellectual
Collaborator Contribution Experimental and intellectual
Impact paper to be submitted
Start Year 2016
 
Description Developmental hematopoiesis 
Organisation University of Edinburgh
Department Institute of Stem Cell Research Edinburgh
Country United Kingdom 
Sector Academic/University 
PI Contribution intellectual and experimental
Collaborator Contribution intellectual and experimental
Impact publication
Start Year 2012
 
Description Gene regulation; WIS-UK 
Organisation Weizmann Institute of Science
Country Israel 
Sector Academic/University 
PI Contribution Intellectual and experimental
Collaborator Contribution Intellectual and experimental
Impact ongoing
Start Year 2013
 
Description Gene regulatory networks 
Organisation University of Cambridge
Department Cambridge Institute for Medical Research (CIMR)
Country United Kingdom 
Sector Academic/University 
PI Contribution Intellectual and experimental
Collaborator Contribution Intellectual and experimental
Impact Publications; joint grant (Australia)
Start Year 2006
 
Description Gene regulatory networks 
Organisation University of New South Wales
Country Australia 
Sector Academic/University 
PI Contribution Intellectual and experimental
Collaborator Contribution Intellectual and experimental
Impact Publications; joint grant (Australia)
Start Year 2006
 
Description Live imaging 
Organisation Helmholtz Zentrum München
Country Germany 
Sector Academic/University 
PI Contribution Intellectual and practical
Collaborator Contribution Intellectual and practical
Impact PMID 24326267
Start Year 2010
 
Description Progenitors 
Organisation University of Oxford
Department Weatherall Institute of Molecular Medicine (WIMM)
Country United Kingdom 
Sector Academic/University 
PI Contribution intellectual and practical
Collaborator Contribution intellectual and practical
Impact publications
Start Year 2009
 
Description macrophages 
Organisation King's College London
Country United Kingdom 
Sector Academic/University 
PI Contribution Intellectual and practical
Collaborator Contribution Intellectual and practical
Impact publication
Start Year 2014
 
Description reprogramming 
Organisation Icahn School of Medicine at Mount Sinai
Country United States 
Sector Academic/University 
PI Contribution intellectual and practical
Collaborator Contribution intellectual and practical
Impact publication
Start Year 2013
 
Description Cheltenham Science Festival 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact My postdoc attended the MRC stand and explained nutrition to the public.

Positive feedback from the public.
Year(s) Of Engagement Activity 2013
 
Description MHU stand at MRC centenary event 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact My student was participating in explaining science to the public.

Positive feedback from the public.
Year(s) Of Engagement Activity 2013
 
Description Student work experience 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Pupils went on to pursue a career in science.

Pupils visit lab every year.
Year(s) Of Engagement Activity 2010,2011,2015,2016,2017,2018