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Hematopoietic cells emerging from hemogenic endothelium exhibit lineage-specific oxidative stress responses

Biezeman, Harmke ; Nubiè, Martina and Oburoglu, Leal LU orcid (2024) In Journal of Biological Chemistry 300(11).
Abstract

During human embryogenesis, distinct waves of hematopoiesis give rise to various blood cell types, originating from hemogenic endothelial (HE) cells. As HE cells reside in hypoxic conditions in the embryo, we investigated the role of hypoxia in human endothelial to hematopoietic transition and subsequent hematopoiesis. Using single-cell RNA sequencing, we describe hypoxia-related transcriptional changes in different HE-derived blood lineages, which reveal that erythroid cells are particularly susceptible to oxidative stress, due to decreased NRF2 activity in hypoxia. In contrast, nonerythroid CD45+ cells exhibit increased proliferative rates in hypoxic conditions and enhanced resilience to oxidative stress. We find that even... (More)

During human embryogenesis, distinct waves of hematopoiesis give rise to various blood cell types, originating from hemogenic endothelial (HE) cells. As HE cells reside in hypoxic conditions in the embryo, we investigated the role of hypoxia in human endothelial to hematopoietic transition and subsequent hematopoiesis. Using single-cell RNA sequencing, we describe hypoxia-related transcriptional changes in different HE-derived blood lineages, which reveal that erythroid cells are particularly susceptible to oxidative stress, due to decreased NRF2 activity in hypoxia. In contrast, nonerythroid CD45+ cells exhibit increased proliferative rates in hypoxic conditions and enhanced resilience to oxidative stress. We find that even in normoxia, erythroid cells present a clear predisposition to oxidative stress, with low glutathione levels and high lipid peroxidation, in contrast to CD45+ cells. Intriguingly, reactive oxygen species are produced at different sites in GPA+ and CD45+ cells, revealing differences in oxidative phosphorylation and the use of canonical versus noncanonical tricarboxylic acid cycle in these lineages. Our findings elucidate how hypoxia and oxidative stress distinctly affect HE-derived hematopoietic lineages, uncovering critical transcriptional and metabolic pathways that influence blood cell development.

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type
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publication status
published
subject
keywords
endothelial to hematopoietic transition, erythropoiesis, glutathione, hematopoiesis, hypoxia, induced pluripotent stem cells, Nrf2, oxidative stress
in
Journal of Biological Chemistry
volume
300
issue
11
article number
107815
publisher
American Society for Biochemistry and Molecular Biology
external identifiers
  • scopus:85206821345
  • pmid:39326495
ISSN
0021-9258
DOI
10.1016/j.jbc.2024.107815
language
English
LU publication?
yes
additional info
Publisher Copyright: © 2024 The Authors
id
d329483b-f7c9-44fd-8062-998881d294de
date added to LUP
2024-12-18 08:57:34
date last changed
2025-07-31 03:26:52
@article{d329483b-f7c9-44fd-8062-998881d294de,
  abstract     = {{<p>During human embryogenesis, distinct waves of hematopoiesis give rise to various blood cell types, originating from hemogenic endothelial (HE) cells. As HE cells reside in hypoxic conditions in the embryo, we investigated the role of hypoxia in human endothelial to hematopoietic transition and subsequent hematopoiesis. Using single-cell RNA sequencing, we describe hypoxia-related transcriptional changes in different HE-derived blood lineages, which reveal that erythroid cells are particularly susceptible to oxidative stress, due to decreased NRF2 activity in hypoxia. In contrast, nonerythroid CD45<sup>+</sup> cells exhibit increased proliferative rates in hypoxic conditions and enhanced resilience to oxidative stress. We find that even in normoxia, erythroid cells present a clear predisposition to oxidative stress, with low glutathione levels and high lipid peroxidation, in contrast to CD45<sup>+</sup> cells. Intriguingly, reactive oxygen species are produced at different sites in GPA<sup>+</sup> and CD45<sup>+</sup> cells, revealing differences in oxidative phosphorylation and the use of canonical versus noncanonical tricarboxylic acid cycle in these lineages. Our findings elucidate how hypoxia and oxidative stress distinctly affect HE-derived hematopoietic lineages, uncovering critical transcriptional and metabolic pathways that influence blood cell development.</p>}},
  author       = {{Biezeman, Harmke and Nubiè, Martina and Oburoglu, Leal}},
  issn         = {{0021-9258}},
  keywords     = {{endothelial to hematopoietic transition; erythropoiesis; glutathione; hematopoiesis; hypoxia; induced pluripotent stem cells; Nrf2; oxidative stress}},
  language     = {{eng}},
  number       = {{11}},
  publisher    = {{American Society for Biochemistry and Molecular Biology}},
  series       = {{Journal of Biological Chemistry}},
  title        = {{Hematopoietic cells emerging from hemogenic endothelium exhibit lineage-specific oxidative stress responses}},
  url          = {{http://dx.doi.org/10.1016/j.jbc.2024.107815}},
  doi          = {{10.1016/j.jbc.2024.107815}},
  volume       = {{300}},
  year         = {{2024}},
}