Pyruvate metabolism guides definitive lineage specification during hematopoietic emergence
(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
- Oburoglu, Leal LU ; Mansell, Els LU ; Canals, Isaac LU ; Sigurdsson, Valgardur LU ; Guibentif, Carolina LU ; Soneji, Shamit LU and Woods, Niels Bjarne LU
- organization
-
- Division of Molecular Medicine and Gene Therapy
- StemTherapy: National Initiative on Stem Cells for Regenerative Therapy
- Hematopoietic Stem Cell Development (research group)
- LUCC: Lund University Cancer Centre
- Stem Cells, Aging and Neurodegeneration (research group)
- Neurology, Lund
- Stem Cell Metabolism (research group)
- eSSENCE: The e-Science Collaboration
- Division of Molecular Hematology (DMH)
- publishing date
- 2022
- 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
- 2024-09-08 08:55:17
@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}}, }