Porcher Group: Developmental Control of Blood Cell Fate Determination

catherine.porcher@imm.ox.ac.uk

MRC MHU

We study the transcriptional, epigenetic and environmental signals specifying the blood stem cell lineage during embryonic development. This knowledge is used to model the development of blood stem cells in vitro for basic research and regenerative medicine purposes.

Domains of expression of lineage-affiliated markers by single molecule mRNA detection in day 8 mouse embryo (future dorsal aorta in red and green, surrounded by distinct niche cells). Image from David Grainger, PhD student.

During embryonic development, blood cell fate determination initiates in mesodermal endothelial cell progenitors (angioblasts) at gastrulation. Despite an established understanding of cell movements during gastrulation, the molecular mechanisms driving blood specification in a subset of angioblasts and the developmental relationships between blood and specialised endothelial cells/blood vessels are poorly understood. Our main goal is to identify the intrinsic and extrinsic cues conferring blood cell identity to angioblasts as the embryo develops. This provides a framework to study the developmental trajectory of haematopoietic stem cells (HSCs, the cells with self-renewal and multilineage potentialities that give rise to the entire blood system) and to explore the origin of blood diseases arising during embryonic development.

We use complementary approaches: advanced single molecule RNA FISH imaging informs on the spatial organisation of angioblasts and their environmental niches; single cell genomics/transcriptomics assays and functional analyses identify permissive and instructive mechanisms and regulators of blood specification. An important aspect of our work examines the function of the transcription factor and oncoprotein SCL/TAL1 and its protein partners, essential to confer blood fate to mesodermal cells. Finally, we use in vivo lineage tracing approaches (CRISPR/CAS9-based genetic barcode recording systems) to track lineage histories and reconstruct developmental relationships between blood, endothelial and related mesodermal lineages.

Over the past two decades, numerous efforts have been deployed to produce HSCs in vitro from pluripotent stem cells (PSCs) for mechanistic and therapeutic purposes. None of the differentiation cultures developed so far have been able to produce transgene-free, long-term repopulating HSCs. This is likely to reflect the lack of critical signalling molecules supporting HSC development in current differentiation cultures. The knowledge gain from our studies (and that of others) will inform protocols aimed at recapitulating the stepwise differentiation trajectory of the HSC lineage in serum-free mouse and human PSC in vitro differentiation cultures, as it happens during embryonic development.

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