FOXO1 regulates pentose phosphate pathway-mediated induction of developmental erythropoiesis
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, w...
| Main Authors: | , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2022-10-01
|
| Series: | Frontiers in Cell and Developmental Biology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fcell.2022.1039636/full |
| _version_ | 1817985743355641856 |
|---|---|
| author | Anuntxi Monsalve Isaac Canals Leal Oburoglu |
| author_facet | Anuntxi Monsalve Isaac Canals Leal Oburoglu |
| author_sort | Anuntxi Monsalve |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-14T00:01:51Z |
| format | Article |
| id | doaj.art-2ae32ebae0e847dc9f0f0270ff5793ff |
| institution | Directory Open Access Journal |
| issn | 2296-634X |
| language | English |
| last_indexed | 2024-04-14T00:01:51Z |
| publishDate | 2022-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cell and Developmental Biology |
| spelling | doaj.art-2ae32ebae0e847dc9f0f0270ff5793ff2022-12-22T02:23:40ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2022-10-011010.3389/fcell.2022.10396361039636FOXO1 regulates pentose phosphate pathway-mediated induction of developmental erythropoiesisAnuntxi Monsalve0Isaac Canals1Leal Oburoglu2Molecular Medicine and Gene Therapy, Lund Stem Cell Center, Lund University, Lund, SwedenNeurology, Lund Stem Cell Center, Lund University, Lund, SwedenMolecular Medicine and Gene Therapy, Lund Stem Cell Center, Lund University, Lund, SwedenPrimitive, 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.https://www.frontiersin.org/articles/10.3389/fcell.2022.1039636/fulldevelopmental hematopoiesispentose phosphate pathwayFOXO1endothelial to hematopoietic transitionerythropoiesis |
| spellingShingle | Anuntxi Monsalve Isaac Canals Leal Oburoglu FOXO1 regulates pentose phosphate pathway-mediated induction of developmental erythropoiesis Frontiers in Cell and Developmental Biology developmental hematopoiesis pentose phosphate pathway FOXO1 endothelial to hematopoietic transition erythropoiesis |
| title | FOXO1 regulates pentose phosphate pathway-mediated induction of developmental erythropoiesis |
| title_full | FOXO1 regulates pentose phosphate pathway-mediated induction of developmental erythropoiesis |
| title_fullStr | FOXO1 regulates pentose phosphate pathway-mediated induction of developmental erythropoiesis |
| title_full_unstemmed | FOXO1 regulates pentose phosphate pathway-mediated induction of developmental erythropoiesis |
| title_short | FOXO1 regulates pentose phosphate pathway-mediated induction of developmental erythropoiesis |
| title_sort | foxo1 regulates pentose phosphate pathway mediated induction of developmental erythropoiesis |
| topic | developmental hematopoiesis pentose phosphate pathway FOXO1 endothelial to hematopoietic transition erythropoiesis |
| url | https://www.frontiersin.org/articles/10.3389/fcell.2022.1039636/full |
| work_keys_str_mv | AT anuntximonsalve foxo1regulatespentosephosphatepathwaymediatedinductionofdevelopmentalerythropoiesis AT isaaccanals foxo1regulatespentosephosphatepathwaymediatedinductionofdevelopmentalerythropoiesis AT lealoburoglu foxo1regulatespentosephosphatepathwaymediatedinductionofdevelopmentalerythropoiesis |