Cookies on this website
We use cookies to ensure that we give you the best experience on our website. If you click 'Continue' we'll assume that you are happy to receive all cookies and you won't see this message again. Click 'Find out more' for information on how to change your cookie settings.
Skip to main content

Molecular dissection of blood cell fate determination.

Porcher lead image
Single molecule mRNA FISH reveals co-expression of distinct gene expression programmes (hematopoietic (red); paraxial (green); cardiac (blue)) in single ES cell-derived mesodermal cells

Our aims are two-fold: (i) to understand the molecular mechanisms underlying specification of the blood lineage from mesodermal cells and (ii) to model blood stem cell development in vitro.

(i) Molecular mechanisms underlying lineage specification

 During development, mesodermal cells differentiate into several lineages such as the blood, cardiac and paraxial tissues. Despite an established understanding of cell movements during gastrulation, the exact molecular mechanisms driving lineage fate decisions and the developmental relationship between lineages are still unclear. This is essential information not only for a better understanding of these fundamental mechanisms, but also to gain further insight into the mechanistic bases underlying congenital diseases and to define the optimum culture conditions supporting the development or lineage-fated cells from pluripotent stem cells for therapeutic purposes.

To study these questions, we take  complementary approaches. First, we examine the function and mechanisms of action of the basic helix-loop-helix transcription factor and oncoprotein SCL/TAL1. SCL, originally identified by virtue of its involvement in T-cell Acute Lymphoblastic Leukaemia (T-ALL), is essential to confer blood fate to mesodermal cells and offers an excellent entry point for mechanistic studies of cell fate determination. Second, using in vivo lineage tracing and single cell mRNA sequencing approaches, we characterise the earliest lineage-committed progenitors in developing embryos and investigate the intricate developmental relationships between blood and alternative mesodermal lineages. Third, we build the gene regulatory networks that control expression of key regulators of blood development.

To address these questions, we use state-of-the-art technologies: lineage tracing and single cell approaches, single molecule mRNA imaging, high-throughput genomic and transcriptomic assays (such as ATAC-, ChIP- and RNA-seq to document chromatin accessibility and protein:DNA interactions and gene expression), proteomics studies and structural biology. A large part of our work uses in vitro differentiation assays of embryonic stem (ES) cells.

(ii) Modelling blood stem cell development in vitro

Over the past decade, numerous efforts have been deployed to produce the elusive blood (haematopoietic) stem cell (HSC) in vitro from pluripotent stem cells (PSCs) for mechanistic and therapeutic purposes. However, none of the differentiation cultures developed so far have been able to produce long-term repopulating HSCs, the cells with self-renewal and multilineage potentialities that give rise to the entire blood system when transplanted into a host organism. This is likely to reflect the lack of critical signalling molecules supporting HSC development in the current differentiation cultures. We aim to carefully recapitulate haematopoietic development in serum-free mouse and human PSC differentiation cultures, as it happens during embryonic development. To do this, we apply our knowledge of the signalling pathways controlling HSC development into in vitro differentiation protocols for a tight control of the stepwise development of PSCs towards HSCs. Ultimately, our goal is to translate our findings to the clinical setting.

 

********************************************************

POST-DOCTORAL POSITION AVAILABLE

Position in Structural and Stem Cell Biology

https://www.recruit.ox.ac.uk/pls/hrisliverecruit/erq_jobspec_version_4.jobspec?p_id=139214

******************************************************** 

Please do contact us for more information on current vacancies and projects.

 

Our team

Collaborations

Professor Roger Patient, Weatherall Institute of Molecular Medicine, University of Oxford, UK

Professor Paresh Vyas, Weatherall Institute of Molecular Medicine, University of Oxford, UK

Dr Denis Ptchelkine, Weatherall Institute of Molecular Medicine, University of Oxford, UK

Related research themes