Alexander Medvinsky Research Group

Ontogeny of haematopoietic stem cells

Haematopoietic stem cells (HSCs) developing in the embryo give rise to the adult haematopoietic system. We investigate cellular and molecular mechanisms underpinning HSC generation in the mammalian embryo.

Professor Alexander Medvinsky

Group Leader

Contact details

Our question

Image of green and purple dots representing cells and a close up square of the image in the corner — Endothelial-to-hematopoietic transition (EHT) in E11 dorsal aorta

It was thought in the past that mammalian HSCs arise from the embryonic yolk sac. Our studies, however, showed the actual origin of HSCs is inside the embryo, in the intra-embryonic aorta-gonad-mesonephros (AGM) region. This presented an exciting opportunity to answer outstanding questions about how these important stem cells first emerge during development: what are the signalling mechanisms underlying formation of the first HSCs in the AGM region? What causes these cells to later relocate to the foetal liver and finally to the bone marrow of the developing animal? Which specific environment drives their development? Despite progress made by different groups, we are still far from understanding this process in its entirety. Notably, it has not been possible to generate fully functional HSCs from pluripotent (ES/iPS) cells in the lab without genetic manipulations.

Progress and methodology

Our in vivo studies of the embryo are complemented by continuous efforts to model the processes governing HSC formation in vitro, to make it amenable for analysis. This approach has proven to be highly successful in understanding dynamic stages involved in HSC maturation. We broadly use embryo manipulations, imaging, molecular biology, gene editing, experimental haematology and bioinformatics approaches.

We have identified the AGM region as the key HSC niche both in the mouse and human embryos (Medvinsky et al., Nature 1993; Medvinsky and Dzierzak, Cell, 1996; Ivanovs et al., J. Exp. Med. 2011; Ivanovs et al., Stem Cell Reports, 2014). In this research, novel methods are developed which allow us to recapitulate and analyse the process of early HSC development in vitro (Taoudi et al., Cell Stem Cell, 2008; Rybtsov et al., J Exp Med., 2011; Rybtsov et al., Stem Cell Reports, 2014). The investigation includes inductive interactions and asymmetric signalling within the AGM region that underlie HSC development (McGarvey et al., J Exp Med., 2017; Souilhol et al., Nat. Comm., 2016; Crosse et al., Cell Stem Cell, 2020). We explore the potential role of physical cues in this process. Building on expertise in in vivo and ex vivo analysis, we also employ human ES cell haematopoietic differentiation to model key processes, with the ultimate goal of generating HSCs in the petri dish.

Publications

Group Members

Moira Ross (Project Manager)

Sabrina Gordon-Keylock (Postdoctoral Research Associate)

Dipta Sengupta (Postdoctoral Research Associate)

Pallavi Chinnu Varghese (Postdoctoral Research Associate)

Marta Amador Molina (PhD Student)

Adelle Greene (PhD Student)

Alexandre Meier (PhD Student)

Marlene Ring (PhD Student)

Louise Adamson (Research Technician)

Antonios Minopetros (Research Technician)

Xiaoyan Zou (Technician)

Funders

Medical Research Council (MRC)

Biotechnology and Biological Sciences Research Council (BBSRC)

This article was published on 2024-02-26