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Analysis of biomechanical forces in the embryonic development of haematopoietic stem cells

Reference	BB/W003236/1
Principal Investigator / Supervisor	Professor Alexander Medvinsky
Co-Investigators / Co-Supervisors	Dr Pierre Bagnaninchi
Institution	University of Edinburgh
Department	Sch of Biological Sciences
Funding type	Research
Value (£)	722,655
Status	Current
Type	Research Grant
Start date	01/04/2022
End date	31/03/2025
Duration	36 months

Abstract

The first haematopoietic stem cells (HSCs) emerge during the endothelial-to-haematopoietic transition (EHT) within the dorsal aorta of the embryonic AGM region. We have been able to recapitulate HSC development in mouse AGM cultures, but in vitro derivation of transplantable HSCs from embryonic stem (ES) cells without genetic modifications remains problematic. This clearly indicates that there is insufficient knowledge of mechanisms underlying EHT/ HSC development. We propose that this could be explained by a failure to recapitulate in vitro the key physical cues acting within the embryo. This hypothesis is based on various lines of evidence obtained in our laboratory. EHT/HSC development is dorso-ventrally polarised and occurs within the ventral domain of the dorsal aorta (AoV) (Taoudi et al., 2007). Spatial transcriptome profiling identified ventrally polarised secreted factors that can promote HSC development (McGarvey et al., 2016; Crosse et al., 2020). We recently determined that the physical stiffness of the AoV region is different from the adjacent AGM domains and we obtained evidence that this can be caused by tissue compression during embryogenesis. Importantly, experimental compression results in upregulation of several HSC-promoting secreted factors. These observations led us to hypothesise that EHT/ HSC development in vivo requires specific physical conditions that trigger essential molecular signalling. Our main objective is to identify the molecular mechanisms by which compressive forces direct HSC formation from the endothelium during EHT. This interdisciplinary project combines bioengineering, physics and stem cell biology and links macro movements of the developing embryo with local AoV-specific physical cues and signalling that trigger EHT/HSC development. Our study will fill an important gap in our knowledge and, in the longer term, will inform new protocols for the generation of transplantable human HSCs.

Summary

Blood stem cells (also known as haematopoietic stem cells, HSCs) can generate all types of blood cells in the body throughout our lifetime. HSCs are the most extensively studied stem cell type and serve as a model for analysis of other types of stem cell. HSCs are widely used in clinics to treat blood disorders. The importance of these potent "immortal" cells in the organism attracts considerable attention both from the scientific community and the general public. Despite significant progress in this field, the exact mechanisms whereby HSCs emerge in the embryo remain poorly understood. Knowing how the body first generates HSCs will help us to develop strategies for growing and producing these cells in the laboratory. It is known that HSCs first emerge in the embryo from the large vessel called the dorsal aorta, through a process called endothelial-to-haematopoietic transition (EHT). Despite progress in this area, it has not been possible to generate HSCs from pluripotent embryonic stem cells (ESCs) in the laboratory without drastic genetic intervention. This is despite the fact that ESCs can generate all cell types of the body. This deficiency of EHT in cells growing under laboratory conditions could be caused by our inability to exactly reproduce conditions that exist in the developing embryo. Here we propose to focus on physical forces that have come under increasing attention in the past two decades as a key player in regulating embryo development, tissue architecture and function. We propose that physical cues existing in the embryo play an important role during EHT and HSC development and that the failure to reproduce key physical forces acting in the embryo may result in deficient blood development in vitro. We will investigate the physical environment of the embryonic dorsal aorta where HSCs are known to develop and establish how these physical cues switch on important genes during EHT and HSC development, and conversely, we will investigate how some genes may impact the physical characteristics of the dorsal aorta. This is a multidisciplinary project which combines biomedical engineering, physics, stem cell biology and bioinformatics. We will integrate a complex picture of physical and molecular interactions of the cell lineage that develops into HSCs with their environment. Our study will reveal fundamental mechanisms that drive development of the blood system and in the longer term may pave a way to the generation of transplantable human HSCs for clinical settings.

Committee	Research Committee C (Genes, development and STEM approaches to biology)
Research Topics	X – not assigned to a current Research Topic
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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