Pyruvate Metabolism Guides Definitive Lineage Specification During Hematopoietic Emergence
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ABSTRACT:
SUBMITTER: Dr. Leal Oburoglu
PROVIDER: S-SCDT-EMBOR-2021-54384-T | biostudies-other |
REPOSITORIES: biostudies-other
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Project description:During hematopoietic development, definitive hematopoietic cells are derived from hemogenic endothelial (HE) cells through a process known as endothelial to hematopoietic transition (EHT). During EHT, transitioning cells proliferate and undergo progressive changes in gene expression culminating in the new cell identity with corresponding changes in function, phenotype and morphology. However, the metabolic pathways fueling this transition remain unclear. We show here that glutamine is a crucial regulator of EHT and a rate limiting metabolite in the hematopoietic differentiation of HE cells. Intriguingly, different hematopoietic lineages require distinct derivatives of glutamine. While both derivatives, α-ketoglutarate and nucleotides, are required for early erythroid differentiation of HE during glutamine deprivation, lymphoid differentiation relies on α-ketoglutarate alone. Furthermore, treatment of HE cells with α-ketoglutarate in glutamine-free conditions pushes their differentiation towards lymphoid lineages both in vitro and in vivo, following transplantation into NSG mice. Thus, we report an essential role for glutamine metabolism during EHT, regulating both the emergence and the specification of hematopoietic cells through its various derivatives.
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Project description:Lineage specification during development involves reprogramming of chromatin states, but little is known about how this is regulated in vivo. We previously showed that the chromatin remodeler Chd1 regulates transcriptional output and self-renewal of mouse embryonic stem cells, and is essential for epiblast development. These results raise the question of whether Chd1 regulates the development of other progenitor populations. Here we report that endothelial-specific deletion of Chd1 using Tie2-Cre leads to embryonic lethality by E15.5. Development of the vasculature and of primitive hematopoiesis appears to occur normally in the mutants. However, mutant embryos show signs of anemia as early as E11.5, are depleted of definitive hematopoietic stem /progenitor cells, and display a complete failure of fetal liver erythropoiesis. While mutants at E10.5 appear morphologically normal and can develop hemogenic clusters in the dorsal aorta, the E10.5 mutant endothelium fails to activate a transcriptional program associated with hematopoiesis. This transcriptional program may serve as a resource for the identification of novel markers or regulators of definitive hematopoiesis. Finally, hematopoietic-specific Chd1 deletion using Vav-Cre yields no apparent defects during development or adulthood. These results suggest that Chd1 regulates chromatin-remodeling events critical for a specific developmental window during the transition of endothelial cells to definitive blood progenitors.
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