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A metabolic switch during embryonic hematopoiesis is a major regulator of lineage commitment

UMAP of differentiating iPSC
An optimised iPSC-differentiation protocol allowed the authors to study endothelial cells (purple), transitioning cells (pink), and hematopoietic stem-like cells (blue) using scRNA-seq. A UMAP visualise the cells in the shape of a butterfly.

In a recent study from the SCC group of Niels-Bjarne Woods and collaborators, they have investigated the metabolic changes accompanying the emergence of blood during embryonic development. They discovered a previously unknown metabolic switch during endothelial to hematopoietic transition (EHT), the process by which the first blood cells are formed. This switch showed to be crucial in the determination of blood cell-type upon differentiation.

During embryonic development, hematopoiesis occurs through primitive and definitive waves, giving rise to distinct blood lineages. The hematopoietic stem cells (HSCs), which later in life give rise to all of our blood cells, emerge from hemogenic endothelial (HE) cells through endothelial-to-hematopoietic transition (EHT). However, metabolic processes underlying the generation of HSCs from HE cells have remained unclear until now.

In this study from the group of Niels-Bjarne Woods and collaborators, published in EMBO Reports, they investigated the metabolic changes accompanying EHT during the generation of blood progenitors in embryonic development. Their data revealed that the emergence of blood is regulated by multiple metabolic pathways that induce or modulate the differentiation towards specific hematopoietic lineages during human EHT. Using both in vitro and in vivo settings, they demonstrate that the modulation of pyruvate metabolism can skew hematopoietic lineage commitment. Specifically, steering pyruvate use toward glycolysis or oxidative phosphorylation guided the hematopoietic differentiation of HE cells toward either an erythroid fate with primitive phenotype or a definitive lymphoid fate, respectively, revealing that pyruvate metabolism is a major regulator of primitive versus definitive hematopoietic cell fate choices during EHT.

This novel metabolic link significantly advances our understanding of human hematopoietic cell development and suggests that hematopoietic waves during embryonic development are regulated by the availability of nutrients in the hematopoietic niche. In a more long-term perspective, this study is an important step towards clinical translation, where generation of functional and transplantable hematopoietic stem cells in vitro is strongly sought-after due their potential to treat hematological disorders and malignancies.

Further reading

The full article "Pyruvate metabolism guides definitive lineage specification during hematopoietic emergence", Oburoglu et al., published in EMBO reports.

The homepage of Niels-Bjarne Woods’ group “Hematopoietic Cell Development Laboratory”.