A newly created mouse cell line now allows scientists to watch—and genetically manipulate—the moment embryonic blood vessel cells transform into blood cells, a process previously hidden inside developing embryos. This matters because the body’s earliest blood cells arise from a rare, short-lived cell type called the haemogenic endothelium. Researchers have struggled to study this transition in the lab because true haemogenic endothelial cells are scarce and difficult to maintain. Without a reliable supply, efforts to grow blood stem cells from pluripotent stem cells for therapies—such as bone marrow transplants or cellular immunotherapies—remain inefficient and labour-intensive. If this research succeeds, it will produce the first comprehensive map of the gene regulatory networks and signalling pathways that drive blood cell formation. The team plans to use genome-wide CRISPR screens, single-cell RNA sequencing, and proteomics to identify master regulators of the transition. This fundamental knowledge could serve as a blueprint for creating similar human cell lines, enabling scalable platforms to generate blood cells for transplantation, transfusion, and immunotherapy. The work is primarily curiosity-driven, but deeper understanding of how endothelial cells commit to blood fates has the potential to transform how therapeutic blood cells are manufactured.
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The generation of mature blood cells and haematopoietic stem cells (HSCs) has been a longstanding goal in stem cell biology, developmental biology, and biotechnology due to their critical roles in clinical applications such as bone marrow transplantation, transfusions, and cellular immunotherapy. A crucial component in blood cell development is the haemogenic endothelium (HE), a rare and transient endothelial cell population found in the embryonic vasculature. During the Endothelial-to-Haematopoietic Transition (EHT), HE cells lose their endothelial characteristics, activate haematopoietic transcriptional programs, and transform into blood cells. This process is essential for haematopoiesis, providing a direct and practical target for generating all blood cell lineages. Pluripotent embryonic stem (ES) cells and induced pluripotent stem cells (iPSCs) offer promising starting points for achieving this goal. However, their differentiation into specific blood cell types remains inefficient, requiring labor-intensive protocols and extensive culture to produce functional cells. These protocols often depend on enriched HE-like populations, where true HE cells are scarce. This scarcity limits our ability to fully understand the EHT process and hampers the development of efficient, scalable protocols for generating therapeutic blood cells. To address these challenges, we successfully established a novel murine HE (mHE) cell line using transient expression of a unique combination of transcription factors. This cell line demonstrates robust expansion capacity and undergoes definitive haematopoiesis upon withdrawal of ectopic gene expression. The mHE cell line generates multi-lineage haematopoietic progenitors and mature blood cells, as demonstrated through flow cytometry, colony-assays, gene expression profiling, and cytospin analysis. This mHE cell line provides an unprecedented opportunity to study EHT with enhanced precision and scalability. Using this system, we plan to perform genome-wide CRISPR screens to identify new master regulators of the EHT process in an unbiased manner. Single-cell RNA and chromatin accessibility multi-omics will enable detailed mapping of the dynamic molecular regulation of EHT, revealing gene regulatory networks (GRNs) that drive the activation of distinct cell fates. Additionally, (phospho)proteomics will provide the first insights into the dynamics of protein expression and signalling pathways underlying EHT. The resulting data will serve as a comprehensive resource for researchers studying blood development. This research will also inform future strategies to manipulate haematopoietic lineage choices, offering a comparative basis for future enhancements of generation of therapeutically relevant blood lineages. Developing similar human HE (hHE) cell lines would be a transformative step in the field, enabling scalable platforms for producing blood cells for therapeutic applications. The work outlined here will serve as a blueprint for the development, characterization, and utilization of novel human HE cell lines. The long-term impact of this research will be the creation of robust human platforms capable of generating modified cells for transplantation, transfusion, and cellular (immuno-) therapies, ultimately paving the way for innovative therapeutic interventions.
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