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Dissecting the role of novel haematopoietic regulators in Haematopoietic Stem Cells


College of Medical and Dental Sciences

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Dr R Monteiro No more applications being accepted Competition Funded PhD Project (Students Worldwide)

About the Project

Applications are invited for a 4-year fully-funded/self-funded PhD Studentship starting October 2021

Background

Blood is made up of different cell types with different functions, such as carrying oxygen (red blood cells), help with wound healing (platelets) and fighting infections (white blood cells). These cells arise from Haematopoietic stem cells (HSCs) that live in our bone marrow. They are generated during embryonic development, arising from the haemogenic endothelium (HE), a specialized subset of endothelial cells located in the floor of the main embryonic artery. A major bottleneck in the production of HSCs in vitro for substitution therapies is to determine the right conditions that mimic the embryo microenvironment and induce a HE-like intermediate that can differentiate into HSCs. The Monteiro lab uses the zebrafish model to investigate the formation of HSCs in the early embryo(1-6).

Project 1 We have recently demonstrated that haematopoietic gene expression in the HE requires input from the transcription factor Gata2a, followed by the Notch signalling pathway that rescues embryonic haematopoiesis in the absence of Gata2a. In this project, we will use a combination of classical developmental biology, transgenesis and gene editing, together with transcriptional profiling and computational tools to identify novel haematopoietic factors that are targeted both by Gata2a and Notch signalling in the HE and study how they shape haematopoiesis in embryonic development and in homeostasis in the adult. Project 2 A major player in determining haematopoietic fates is the Notch signalling pathway(7). We and others have recently uncovered evidence suggesting that establishing the (aortic) arterial cell fate is a pre-requisite for the formation of HSCs from HE(1,8).

We aim to study the role of the Notch ligand Dll4 in the formation of the precursors to HSCs in the embryo. First, the student will use an existing transgenic line(1) to isolate arterial and haemogenic cells to compare gene expression between wildtype and dll4 loss of function by scRNAseq. They will then generate transgenic lines to enable them to perform lineage tracing and identify the haematopoietic cell populations that derive from arterial or haemogenic cells. Characterization of these haematopoietic cells will be accomplished by single cell transcriptional profiling of the labelled cells. Zebrafish is very amenable to genetic modifications including generation of gene mutations and transgenic reporters for live imaging or isolation of specific cellular lineages for downstream molecular analyses. These projects are collaborations with a bioinformatics lab and ample opportunity for training will be provided. A better understanding of the factors that generate and maintain a healthy haematopoietic system in a whole organism is critical both to design new approaches to generating stem cells in vitro but also to help design effective interventions when haematopoiesis is perturbed in diseases such as leukaemias.

Person Specification

Applicants should have a strong interest in developmental biology, haematopoiesis or transcriptomics. They should hold or realistically expect to obtain at least an Upper Second Class Honours Degree in Genetics, Biological Sciences or related subjects. How to apply Applicants are encouraged to contact Dr Rui Monteiro directly ([Email Address Removed]) to discuss the project before applying. This project can be found in the Theme ‘Understanding the rules of life’, under ‘Stem cells’ (https://warwick.ac.uk/fac/cross_fac/mibtp/pgstudy/phd_opportunities/stem_cells). Detailed instructions for applicants, academic requirements and eligibility criteria can be found in the University of Birmingham and University of Warwick websites: https://www.birmingham.ac.uk/research/activity/mibtp/index.aspx https://warwick.ac.uk/mibtp/

Funding Notes

The Midlands Integrative Biosciences Training Partnership (MIBTP) is a BBSRC-funded doctoral training partnership between the universities of Warwick, Birmingham and Leicester. Successful applicants will be funded by the BBSRC, including UK fees and stipend. International students are eligible to apply, but the BBSRC does not cover international fees. Please see application details and eligibility criteria on: https://warwick.ac.uk/fac/cross_fac/mibtp/pgstudy/phd_opportunities/application/ More details about the program on: https://warwick.ac.uk/mibtp/ https://www.birmingham.ac.uk/research/activity/mibtp/index.aspx

References

1 Bonkhofer, F. et al. Blood stem cell-forming haemogenic endothelium in zebrafish derives from arterial endothelium. Nat Commun 10, 3577, doi:10.1038/s41467-019-11423-2 (2019).

2 Ciau-Uitz, A., Monteiro, R., Kirmizitas, A. & Patient, R. Developmental hematopoiesis: ontogeny, genetic programming and conservation. Exp Hematol 42, 669-683, doi:10.1016/j.exphem.2014.06.001 (2014).

3 Dobrzycki, T., Krecsmarik, M., Bonkhofer, F., Patient, R. & Monteiro, R. An optimised pipeline for parallel image-based quantification of gene expression and genotyping after in situ hybridisation. Biol Open 7, doi:10.1242/bio.031096 (2018).

4 Dobrzycki, T. et al. Deletion of a conserved Gata2 enhancer impairs haemogenic endothelium programming and adult Zebrafish haematopoiesis. Commun Biol 3, 71, doi:10.1038/s42003-020-0798-3 (2020).

5 Monteiro, R. et al. Transforming Growth Factor beta Drives Hemogenic Endothelium Programming and the Transition to Hematopoietic Stem Cells. Dev Cell 38, 358-370, doi:10.1016/j.devcel.2016.06.024 (2016).

6 Monteiro, R., Pouget, C. & Patient, R. The gata1/pu.1 lineage fate paradigm varies between blood populations and is modulated by tif1gamma. Embo J 30, 1093-1103, doi:10.1038/emboj.2011.34 (2011).

7 Butko, E., Pouget, C. & Traver, D. Complex regulation of HSC emergence by the Notch signaling pathway. Dev Biol 409, 129-138, doi:10.1016/j.ydbio.2015.11.008 (2016).

8 Uenishi, G. I. et al. NOTCH signaling specifies arterial-type definitive hemogenic endothelium from human pluripotent stem cells. Nat Commun 9, 1828, doi:10.1038/s41467-018-04134-7 (2018).
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