Hematopoietic stem cells (HSCs) are multipotent, self-renewing cells responsible for the production of all blood cell types throughout the life of an individual. Despite their location within the adult bone marrow, HSCs are generated during development from specialized endothelial cells called hemogenic endothelial cells in the main embryonic arteries (dorsal aorta, umbilical and vitelline arteries), an evolutionary conserved mechanism within vertebrate species. HSCs arise through a process called endothelial-to-hematopoietic transition, a lineage switch which is tightly regulated in time and space and polarized to the ventral side of the embryonic aorta. In this respect, HSC production is also thought to rely on a specialized microenvironment localized underneath the aortic floor that would promote the lineage switch and constitute a niche for the first HSCs. Taken together, HSC formation encompasses intrinsic cues i.e., cell autonomous and extrinsic cues that constitute an unresolved paradigm for cell and developmental biology and a challenge for regenerative medicine, as clinical de novo formation of HSCs is an unmet goal.
 

I investigate these intrinsic and extrinsic regulations using complementary in vitro and in vivo approaches in the avian embryo, which is a reliable and accessible vertebrate model, and using human iPSCs.
On one hand, I am developing an in vitro system that allows mesodermal cells to differentiate into endothelial cells, then into hemogenic endothelial cells, and finally into hematopoietic cells. This system will be used to detect the discrete cellular differentiation steps leading to HSC formation using single cell RNA sequencing technology. The main goal is to elucidate the initial steps of HSC formation to eventually optimize in vitro culture systems for clinical grade HSC production.
On the other hand, I use microsurgical techniques to alter the normal microenvironment of the aorta, the cradle of HSC formation, and evaluate the consequences for HSC development. Combining these ablation experiments with spatial transcriptomic approaches will decipher the role of the aortic environment in the formation of the first HSCs.

Laurent Yvernogeau is invited by Pascal Maire.