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Glutamine metabolism regulates endothelial to hematopoietic transition and hematopoietic lineage specification

Oburoglu, Leal LU orcid ; Mansell, Els LU and Woods, Niels Bjarne LU (2021) In Scientific Reports 11(1).
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,... (More)

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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type
Contribution to journal
publication status
published
subject
in
Scientific Reports
volume
11
issue
1
article number
17589
publisher
Nature Publishing Group
external identifiers
  • pmid:34475502
  • scopus:85114611226
ISSN
2045-2322
DOI
10.1038/s41598-021-97194-7
language
English
LU publication?
yes
id
eea22317-76a5-4cb1-b695-c7218bc0a838
date added to LUP
2021-10-08 13:37:52
date last changed
2024-06-16 20:16:27
@article{eea22317-76a5-4cb1-b695-c7218bc0a838,
  abstract     = {{<p>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.</p>}},
  author       = {{Oburoglu, Leal and Mansell, Els and Woods, Niels Bjarne}},
  issn         = {{2045-2322}},
  language     = {{eng}},
  number       = {{1}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Scientific Reports}},
  title        = {{Glutamine metabolism regulates endothelial to hematopoietic transition and hematopoietic lineage specification}},
  url          = {{http://dx.doi.org/10.1038/s41598-021-97194-7}},
  doi          = {{10.1038/s41598-021-97194-7}},
  volume       = {{11}},
  year         = {{2021}},
}