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Pyruvate metabolism guides definitive lineage specification during hematopoietic emergence

Oburoglu, Leal LU orcid ; Mansell, Els LU ; Canals, Isaac LU ; Sigurdsson, Valgardur LU ; Guibentif, Carolina LU ; Soneji, Shamit LU and Woods, Niels Bjarne LU (2022) In EMBO Reports 23(2).
Abstract

During embryonic development, hematopoiesis occurs through primitive and definitive waves, giving rise to distinct blood lineages. Hematopoietic stem cells (HSCs) emerge from hemogenic endothelial (HE) cells, through endothelial-to-hematopoietic transition (EHT). In the adult, HSC quiescence, maintenance, and differentiation are closely linked to changes in metabolism. However, metabolic processes underlying the emergence of HSCs from HE cells remain unclear. Here, we show that the emergence of blood is regulated by multiple metabolic pathways that induce or modulate the differentiation toward specific hematopoietic lineages during human EHT. In both in vitro and in vivo settings, steering pyruvate use toward glycolysis or OXPHOS... (More)

During embryonic development, hematopoiesis occurs through primitive and definitive waves, giving rise to distinct blood lineages. Hematopoietic stem cells (HSCs) emerge from hemogenic endothelial (HE) cells, through endothelial-to-hematopoietic transition (EHT). In the adult, HSC quiescence, maintenance, and differentiation are closely linked to changes in metabolism. However, metabolic processes underlying the emergence of HSCs from HE cells remain unclear. Here, we show that the emergence of blood is regulated by multiple metabolic pathways that induce or modulate the differentiation toward specific hematopoietic lineages during human EHT. In both in vitro and in vivo settings, steering pyruvate use toward glycolysis or OXPHOS differentially skews the hematopoietic output of HE cells toward either an erythroid fate with primitive phenotype, or a definitive lymphoid fate, respectively. We demonstrate that glycolysis-mediated differentiation of HE toward primitive erythroid hematopoiesis is dependent on the epigenetic regulator LSD1. In contrast, OXPHOS-mediated differentiation of HE toward definitive hematopoiesis is dependent on cholesterol metabolism. Our findings reveal that during EHT, metabolism is a major regulator of primitive versus definitive hematopoietic differentiation.

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author
; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
endothelial-to-hematopoietic transition, glycolysis, hematopoiesis, OXPHOS, pyruvate metabolism
in
EMBO Reports
volume
23
issue
2
publisher
Nature Publishing Group
external identifiers
  • pmid:34914165
  • scopus:85121365030
ISSN
1469-221X
DOI
10.15252/embr.202154384
language
English
LU publication?
yes
id
17bf80fd-62b8-4b06-857b-435647a6e62c
date added to LUP
2022-01-31 12:13:17
date last changed
2024-06-17 03:32:37
@article{17bf80fd-62b8-4b06-857b-435647a6e62c,
  abstract     = {{<p>During embryonic development, hematopoiesis occurs through primitive and definitive waves, giving rise to distinct blood lineages. Hematopoietic stem cells (HSCs) emerge from hemogenic endothelial (HE) cells, through endothelial-to-hematopoietic transition (EHT). In the adult, HSC quiescence, maintenance, and differentiation are closely linked to changes in metabolism. However, metabolic processes underlying the emergence of HSCs from HE cells remain unclear. Here, we show that the emergence of blood is regulated by multiple metabolic pathways that induce or modulate the differentiation toward specific hematopoietic lineages during human EHT. In both in vitro and in vivo settings, steering pyruvate use toward glycolysis or OXPHOS differentially skews the hematopoietic output of HE cells toward either an erythroid fate with primitive phenotype, or a definitive lymphoid fate, respectively. We demonstrate that glycolysis-mediated differentiation of HE toward primitive erythroid hematopoiesis is dependent on the epigenetic regulator LSD1. In contrast, OXPHOS-mediated differentiation of HE toward definitive hematopoiesis is dependent on cholesterol metabolism. Our findings reveal that during EHT, metabolism is a major regulator of primitive versus definitive hematopoietic differentiation.</p>}},
  author       = {{Oburoglu, Leal and Mansell, Els and Canals, Isaac and Sigurdsson, Valgardur and Guibentif, Carolina and Soneji, Shamit and Woods, Niels Bjarne}},
  issn         = {{1469-221X}},
  keywords     = {{endothelial-to-hematopoietic transition; glycolysis; hematopoiesis; OXPHOS; pyruvate metabolism}},
  language     = {{eng}},
  number       = {{2}},
  publisher    = {{Nature Publishing Group}},
  series       = {{EMBO Reports}},
  title        = {{Pyruvate metabolism guides definitive lineage specification during hematopoietic emergence}},
  url          = {{http://dx.doi.org/10.15252/embr.202154384}},
  doi          = {{10.15252/embr.202154384}},
  volume       = {{23}},
  year         = {{2022}},
}