Generating blood stem and progenitor cells from haemogenic endothelium

Lead Research Organisation: University of Oxford
Department Name: UNLISTED

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

Stem cells are crucial in tissue homeostasis, regeneration and repair. The current interest in stem cell-based therapies has emphasised the importance of understanding how tissue specific stem cells are specified in development. Here, we aim to obtain a mechanistic understanding of the birth of blood stem cells in mouse development. We will build on our previous work in which we have made advances towards unravelling the cis-regulatory complexity of Runx1, a critical regulator of the endothelial-to-haematopoietic transition (EHT), and obtained important new insights on the timeline and process of early haematopoietic commitment. In this programme we will continue our analysis of the Runx1 cis-regulatory logic through application of state-of-the-art technologies, and identify upstream regulators that converge on these cis-elements. In addition, we aim to identify the gene regulatory network that underlies blood stem and progenitor generation in vivo, through genome wide expression and chromatin analyses of primary mouse embryo cells. Together with studies into the developmental origin of the haemogenic endothelium, these experiments will shed light on the spatiotemporal factors and signals that are active in haematopoietic specification and differentiation from gastrulation onwards. This knowledge will inform the development of robust in vitro models for generating definitive haemogenic endothelium and blood stem and progenitor cells from ESC/iPSCs.

Publications

10 25 50

Related Projects

Project Reference Relationship Related To Start End Award Value
MC_UU_00016/1 31/03/2017 30/03/2022 £3,035,000
MC_UU_00016/2 Transfer MC_UU_00016/1 31/03/2017 30/03/2022 £3,411,000
MC_UU_00016/3 Transfer MC_UU_00016/2 31/03/2017 30/03/2022 £1,366,000
MC_UU_00016/4 Transfer MC_UU_00016/3 31/03/2017 30/03/2020 £3,017,000
MC_UU_00016/5 Transfer MC_UU_00016/4 31/03/2017 30/03/2020 £497,000
MC_UU_00016/6 Transfer MC_UU_00016/5 31/03/2017 30/03/2022 £2,530,000
MC_UU_00016/7 Transfer MC_UU_00016/6 31/03/2017 30/03/2022 £2,018,000
MC_UU_00016/8 Transfer MC_UU_00016/7 31/03/2017 30/03/2018 £1,131,000
MC_UU_00016/9 Transfer MC_UU_00016/8 31/03/2017 30/03/2022 £2,500,000
MC_UU_00016/10 Transfer MC_UU_00016/9 31/03/2017 30/03/2018 £1,171,000
MC_UU_00016/11 Transfer MC_UU_00016/10 31/03/2017 30/03/2022 £1,387,000
MC_UU_00016/12 Transfer MC_UU_00016/11 31/03/2017 30/03/2022 £446,000
 
Description Research Degrees
Geographic Reach Local/Municipal/Regional 
Policy Influence Type Participation in a guidance/advisory committee
 
Description John Fell Fund
Amount £53,340 (GBP)
Organisation University of Oxford 
Sector Academic/University
Country United Kingdom
Start 03/2017 
End 03/2018
 
Description NHMRC-National Health and Medical Research Council of Australia
Amount $618,190 (AUD)
Funding ID APP1160110 
Organisation National Health and Medical Research Council 
Sector Public
Country Australia
Start 01/2019 
End 06/2022
 
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 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 E9.5 single cell expression data 
Description Single cell expression data of cells undergoing EHT and cells from the caudal part isolated from E9.5 wild type and Ncx1 null embryos. The 10x single cell RNA sequencing (scRNA-seq) data of E9.5 wild-type and Ncx1-/- caudal parts (CPs) have been deposited in the EMBL-EBI data repository with the accession number ArrayExpress: E-MTAB-10945. The Smart-Seq2 scRNA-seq data of wild-type and Ncx1-/- cells undergoing EHT have been deposited in the EMBL-EBI data repository with the accession number ArrayExpress: E-MTAB-8362. 
Type Of Material Database/Collection of data 
Year Produced 2021 
Provided To Others? Yes  
Impact New insights into pathways affecting HSC development. 
 
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 published
Start Year 2016
 
Description Development 
Organisation University of Oxford
Department Sir William Dunn School of Pathology
Country United Kingdom 
Sector Academic/University 
PI Contribution Intellectual and practical
Collaborator Contribution Intellectual and practical
Impact Paper published.
Start Year 2018
 
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 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 CR NR Oxford Science and Ideas Festival 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Running of the Blood Factory stand. People enjoyed putting the different components of blood together.
Year(s) Of Engagement Activity 2018
 
Description DO PubHD 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact The idea behind PubHD is for PhD students across all disciplines to give a 10 minute accessible talk without visual aids in a pub. Members of the audience seemed interested especially in how the research could help understanding disease mechanisms in leukaemia.
Year(s) Of Engagement Activity 2018
 
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