Porcher Group: Molecular Dissection of Blood Cell Fate Determination
We study the developmental origin and trajectory of the blood stem cell lineage, and the transcriptional and epigenetic mechanisms underlying specification of this lineage from mesoderm. We use this information to model development of blood stem cells in vitro for regenerative medicine purposes.
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 of lineage-fated cells from pluripotent stem cells for therapeutic purposes.
To study these questions, we take complementary approaches. First, 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. Second, 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. 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: in vivo lineage tracing, single molecule mRNA imaging, high-throughput genomic and transcriptomic assays (such as ATAC-, ChIP- and single cell RNA-seq to document chromatin accessibility, protein:DNA interactions and gene expression), proteomics studies and structural biology. A large part of our work uses in vitro differentiation assays of human and mouse 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.
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