Laurent YVERGONEAU
Institut de Biologie Paris Seine ; UMR 7622 - Developmental Biology Laboratory
Invité par : Frédéric Mazurier
Dissecting the first steps leading to hematopoietic stem cell emergence: lessons from the chicken embryo
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 embryonic development from specialized endothelial cells called hemogenic endothelial cells of the main arteries (dorsal aorta, umbilical and vitelline arteries), an evolutionary strongly 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 i.e., cell autonomous and extrinsic cues that constitute a still unsolved paradigm for cell and developmental biology and a challenge for the regenerative medicine since clinical grade de novo formation of HSC is a goal still not reached.
I am investigating these intrinsic and extrinsic regulations using complementary in vitro and in vivo approaches in the avian embryo, a reliable and amenable vertebrate model.
On one hand, I am developing an in vitro system, which allows to differentiate mesodermal cells into endothelial cells, then into hemogenic endothelial cells and finally into hematopoietic cells. This system is used to capture the discrete cellular differentiation steps leading to HSC generation using single cell RNA-sequencing technology; the main goal being to elucidate the first steps controlling HSC generation to ultimately optimize in vitro culture systems for clinical-grade HSC production.
On the other hand, I am using micro-surgery techniques to modify the normal microenvironment of the aorta, the cradle of HSC, and evaluate the consequences on HSC emergence. Combining these ablation/graft surgery experiments with transcriptomic approaches will unravel to role of the surroundings of the aorta in the generation of the first HSCs.
The general objective of our project focuses on understanding the determination and maintenance of the intestinal epithelium, more specifically during cryptogenesis. Research on intestinal crypts has mostly focused on stem cell asymmetric divisions in terms of fate or rate of proliferation. However, research on the physiological regulation of crypt development, dynamics and cycle is still in its infancy. In recent studies, we have implemented intestinal organoid cultures, their high-resolution imaging and genetic manipulations to study crypt dynamics, and we address the mechanisms regulating the crypt organization and dynamics, and their contribution to tissue homeostasis. By combining tools from histology, advanced cell biology, tissue engineering, biophysics and computational modelling, our project reveals the collective behavior of intestinal epithelial cells in their close-to-nature environment. Gathering expertise from different fields brings conceptual advances allowing to decipher the mechanisms at play in intestinal epithelium homeostasis in normal and pathological conditions, processes that are driving forces in cell and developmental biology.
