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FOXO1 regulates pentose phosphate pathway-mediated induction of developmental erythropoiesis

Monsalve, Anuntxi ; Canals, Isaac LU and Oburoglu, Leal LU orcid (2022) In Frontiers in cell and developmental biology 10.
Abstract

Primitive, neonatal and adult erythroid cells have been previously shown to have an active pentose phosphate pathway (PPP) that fuels various processes. However, it is unclear whether the PPP plays a role during the emergence of erythroid progenitors from hemogenic endothelium (HE). In this study, we explored PPP and its genetic regulation in developmental erythropoiesis. We induced hematopoietic differentiation of human induced pluripotent stem cells (hiPSCs) to obtain HE cells. These cells were treated with lentiviral vectors harboring shRNAs against FOXO1, or with inhibitors against the PPP, NRF2 or AKT. Erythroid differentiation, proliferation and frequency were evaluated by flow cytometry. Gene expression was assessed by qPCR or by... (More)

Primitive, neonatal and adult erythroid cells have been previously shown to have an active pentose phosphate pathway (PPP) that fuels various processes. However, it is unclear whether the PPP plays a role during the emergence of erythroid progenitors from hemogenic endothelium (HE). In this study, we explored PPP and its genetic regulation in developmental erythropoiesis. We induced hematopoietic differentiation of human induced pluripotent stem cells (hiPSCs) to obtain HE cells. These cells were treated with lentiviral vectors harboring shRNAs against FOXO1, or with inhibitors against the PPP, NRF2 or AKT. Erythroid differentiation, proliferation and frequency were evaluated by flow cytometry. Gene expression was assessed by qPCR or by analysis of available RNAseq data. We found that PPP is indispensable for the erythroid differentiation of HE cells and it partially fuels nucleotide biosynthesis. Moreover, we showed that NRF2 and AKT are essential, while FOXO1 is detrimental, for HE-derived erythroid differentiation. In contrast, blocking FOXO1 expression did not affect erythroid differentiation of cord-blood HSPCs. Mechanistically, FOXO1 inhibition in HE cells led to an increase in the non-oxidative branch of the PPP. During developmental erythropoiesis, the gradual decrease in FOXO1 activates the PPP and fuels nucleotide biosynthesis and cell proliferation.

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organization
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type
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publication status
published
subject
keywords
developmental hematopoiesis, endothelial to hematopoietic transition, erythropoiesis, FOXO1, pentose phosphate pathway
in
Frontiers in cell and developmental biology
volume
10
article number
1039636
publisher
Frontiers Media S. A.
external identifiers
  • pmid:36313554
  • scopus:85140616902
ISSN
2296-634X
DOI
10.3389/fcell.2022.1039636
language
English
LU publication?
yes
id
254cc7ef-8cd6-4746-9f92-2f45b46f6bb8
date added to LUP
2022-12-13 14:50:01
date last changed
2024-04-18 16:27:02
@article{254cc7ef-8cd6-4746-9f92-2f45b46f6bb8,
  abstract     = {{<p>Primitive, neonatal and adult erythroid cells have been previously shown to have an active pentose phosphate pathway (PPP) that fuels various processes. However, it is unclear whether the PPP plays a role during the emergence of erythroid progenitors from hemogenic endothelium (HE). In this study, we explored PPP and its genetic regulation in developmental erythropoiesis. We induced hematopoietic differentiation of human induced pluripotent stem cells (hiPSCs) to obtain HE cells. These cells were treated with lentiviral vectors harboring shRNAs against FOXO1, or with inhibitors against the PPP, NRF2 or AKT. Erythroid differentiation, proliferation and frequency were evaluated by flow cytometry. Gene expression was assessed by qPCR or by analysis of available RNAseq data. We found that PPP is indispensable for the erythroid differentiation of HE cells and it partially fuels nucleotide biosynthesis. Moreover, we showed that NRF2 and AKT are essential, while FOXO1 is detrimental, for HE-derived erythroid differentiation. In contrast, blocking FOXO1 expression did not affect erythroid differentiation of cord-blood HSPCs. Mechanistically, FOXO1 inhibition in HE cells led to an increase in the non-oxidative branch of the PPP. During developmental erythropoiesis, the gradual decrease in FOXO1 activates the PPP and fuels nucleotide biosynthesis and cell proliferation.</p>}},
  author       = {{Monsalve, Anuntxi and Canals, Isaac and Oburoglu, Leal}},
  issn         = {{2296-634X}},
  keywords     = {{developmental hematopoiesis; endothelial to hematopoietic transition; erythropoiesis; FOXO1; pentose phosphate pathway}},
  language     = {{eng}},
  publisher    = {{Frontiers Media S. A.}},
  series       = {{Frontiers in cell and developmental biology}},
  title        = {{FOXO1 regulates pentose phosphate pathway-mediated induction of developmental erythropoiesis}},
  url          = {{http://dx.doi.org/10.3389/fcell.2022.1039636}},
  doi          = {{10.3389/fcell.2022.1039636}},
  volume       = {{10}},
  year         = {{2022}},
}