Ontogeny of haematopoietic stem cells

Our specific aims are to

1. Phenotypically characterize and visualize primary definitive HSCs in the early embryo
2. Identify embryonic ancestor cells which develop into HSCs
3. Identify routes and mechanisms of hematopoietic stem cell migration
4. Identify and characterize transcription and growth factors as well as extracellular signaling and matrix molecules responsible for the process of initiation, expansion and migration of HSCs.
5. Based on the knowledge of mechanisms underlying development of HSCs in vivo, develop new protocols for generation of definitive long-term repopulating HSCs from ES cells (so far attempts to achieve this by different laboratories without employing genetic intervention have been unsuccessful).

Background

Haematopoietic stem cells (HSCs) developing in the embryo ultimately give rise to the adult haematopoietic system. The main direction of our research is to investigate cellular and molecular mechanisms involved in the generation and expansion of primitive hematopoietic stem cells (HSC) in the mammalian embryo.

Approach and progress

We broadly use methods to perform embryo manipulations and experimental haematology techniques such as advanced cell culture and flow cytometry for the analysis of the early biology of HSCs, including investigating the lineage relationship between endothelial and HSC cells. We have recently identified a specific niche for HSC development in the AGM region. We have developed new culture methods which allow us to dramatically expand HSCs in vitro and analyse intercellular interactions involved in HSC development. Several transgenic/ knockout/reporter mice have been generated in this laboratory, which we use for genetic analysis of HSC development (e.g. Runx1, Flk1, HoxB4 etc.). Microarray analysis is used for gene expression profiling in sites of embryonic development of HSCs. We are applying our functional analysis of HSC development in the embryo to develop new protocols enabling the in vitro generation of HSCs from ES cells.

Recent publications

• J. Senserrich, A. Batsivari, S. Rybtsov, S. Gordon-Keylock, C. Souilhol, F. Buchholz, D. Hills, S. Zhao, A. Medvinsky. (2018). Analysis of Runx1 Using Induced Gene Ablation Reveals Its Essential Role in Pre-liver HSC Development and Limitations of an In Vivo Approach. Stem Cell Reports 11, 784–794.

• McGarvey AC, Rybtsov S, Souilhol C, Tamagno S, Rice R, Hills D, Godwin D, Rice D, Tomlinson SR, Medvinsky A.  2017.  A molecular roadmap of the AGM region reveals BMPER as a novel regulator of HSC maturation.J Exp Med. 214(12):3731-3751.

• Batsivari A, Rybtsov S, Souilhol C, Binagui-Casas A, Hills D, Zhao S, Travers P, Medvinsky A.  2017.  Understanding Hematopoietic Stem Cell Development through Functional Correlation of Their Proliferative Status with the Intra-aortic Cluster Architecture. Stem Cell Reports. 8(6):1549-1562.

• Souilhol C, Lendinez JG, Rybtsov S, Murphy F, Wilson H, Hills D, Batsivari A, Binagui-Casas A, McGarvey AC, H MacDonald R et al..  2016.  Developing HSCs become Notch independent by the end of maturation in the AGM region.Blood. 128(12):1567-77.

• Ciau-Uitz A, Patient R, Medvinsky A.  2016.  Ontogeny of the Hematopoietic System. In: Ratcliffe, M.J.H. (Editor in Chief), Encyclopedia of Immunobiology, Vol. 1, pp. 1–14. Encyclopedia of Immunobiology. Vol 1

• Souilhol C, le Gonneau C, Lendinez JG, Batsivari A, Rybtsov S, Wilson H, Morgado-Palacin L, Hills D, Taoudi S, Antonchuk J et al..  2016.  Inductive interactions mediated by interplay of asymmetric signalling underlie development of adult haematopoietic stem cells.Nat Commun. 7:10784.

• Rybtsov S, Ivanovs A, Zhao S, Medvinsky A.  2016.  Concealed expansion of immature precursors underpins acute burst of adult HSC activity in foetal liver.Development. 143(8):1284-9.

• Rybtsov S, Batsivari A, Bilotkach K, Paruzina D, Senserrich J, Nerushev O, Medvinsky A.  2014.  Tracing the Origin of the HSC Hierarchy Reveals an SCF-Dependent, IL-3-Independent CD43(-) Embryonic Precursor.Stem Cell Reports. 3(3):489-501.