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Glutamine metabolism regulates endothelial to hematopoietic transition and hematopoietic lineage specification.

ABSTRACT: 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.

SUBMITTER: Oburoglu L

PROVIDER: S-EPMC8413451 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundHematopoietic stem cells are able to self-renew and differentiate into all blood cell lineages. Hematopoietic stem cell transplantation is a mainstay of life-saving therapy for hematopoietic malignancies and hypoproliferative disorders. In vitro hematopoietic differentiation of human pluripotent stem cells (hPSCs) is a promising approach for modeling hematopoietic development and cell replacement therapies. Although using hPSCs to derive hematopoietic progenitor cells has achieved some successes in the past, differentiation from hPSCs to produce all hematopoietic cells which can provide robust long-term multilineage engraftment is still very difficult. Here, we reported a novel culture system for hematopoietic differentiation from human embryonic stem cells (hESCs) with optimal cytokines combinations under hypoxia condition.MethodsIn vitro production of T lineage hematopoietic stem/progenitor cells from hESCs by using hypoxia differentiation system, the effects and the potential mechanism of hypoxia promoting T lineage hematopoiesis were investigated by RT-qPCR validation, cell cycle assay and flow cytometry analysis.ResultsUsing our differentiation system, almost 80% CD45+ cells generated from hESCs were hematopoietic cells and particularly could be further induced into CD3+TCRαβ+ T cells in vitro. We detected more CD34+CD144+ hematopoietic endothelial progenitors (HEPs) induced from hESCs than those in normoxia conditions, and the early HEPs-related gene DLL4 was upregulated by enhancing the hypoxia signaling via potential HIF-1α/NOTCH1/DLL4 axis to enhance arterial feature, thus drove T lineage during the hematopoiesis. Strikingly, hematopoietic cells generated in our system exhibited the potential for all multilineage reconstruction including lymphoid, myeloid and erythroid lineages in vivo by transplantation assay.ConclusionOur results demonstrated that hypoxia plays an important role in T lineage hematopoiesis by promoting the expression of arterial endothelial gene DLL4 and upregulation of NOTCH1 through the activation of the HIF-1α signaling pathway. These results provide a significant approach for in vitro and in vivo production of fully functional hematopoietic stem/progenitor cells from hESCs.

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Glutamine metabolism regulates endothelial to hematopoietic transition and hematopoietic lineage specification.

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