Integrative single-cell transcriptomic to identify novel mediator of human blood progenitor proliferation at The University of Edinburgh

Integrative single-cell transcriptomic to identify novel mediator of human blood progenitor proliferation

Deadline: Monday 27th November 2023, 5pm 

1st Supervisor: Dr Antonella Fidanza 

About the Project

Hematopoietic stem and progenitor cells (HSPCs) develop exclusively during embryonic life, sustaining blood and immune cell production for the organism’s lifespan. They emerge in different anatomical regions before migrating into the fetal liver, where they proliferate. Hence, understanding the molecular mechanisms that control the proliferation of these cells within the fetal liver will aid their ex vivo expansion in the laboratory. We have performed a machine learning-based comparison of iPSCs derived progenitor cells with those present in the human fetal liver and identified candidate transcription factors1, such as EGR1, JUN, JUNB and FOS, previously associated with cell proliferation that were expressed at a lower level in vitro, supporting the hypothesis of defective proliferation capacity.

This multidisciplinary project aims to:

1. Identify secreted molecules that could be used to expand HSPCs. To do this we will screen published human fetal liver single-cell transcriptomic datasets 2,3 for putative secretory molecules using single cell-to-cell interaction prediction models. We have developed an analytical pipeline based on a neural network that allows for the identification of corresponding cell types between datasets. Using this we will integrate the available fetal liver atlases and identify consistent putative cell-to-cell interactions between blood progenitors and their niche.
2. Validate cell-cell interactions with candidate secreted factors (eg cytokines) and/or small molecules that modulate associated signalling pathways using our iPSCs model.
3. Assess the function of the transcription factor EGR1 in the context of HSPC expansion. To do this, tamoxifen-inducible EGR1-ERT2 iPSCs lines will be generated by genome editing. These cell lines will be differentiated into HSPCs to assess proliferative capacity. If significant effects are observed, we will identify downstream targets of EGR1 using CHiP-seq Altogether this project will explore the fetal liver niche and identify transcription factors and novel signalling molecules that are involved in supporting HSPCs production and proliferation. This multidisciplinary pipeline will use bioinformatics, stem cells models of human development and in vivo validation to provide a robust approach into niche modelling.

References

Please see full advert description for reference details.

Funding Notes

This opportunity is open to UK and international students and provides funding covering stipend and UK level tuition fees. The University of Edinburgh covers the difference between home and international fees meaning that the EASTBIO DTP offers fully-funded studentships to all appointees. Please see full advert description for further funding details.

Applications

Please review the full advert description here for details on the application process.