Pyruvate metabolism guides definitive lineage specification during hematopoietic emergence
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 quiescenc...
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Gespeichert in:
| Autor*in: |
Oburoglu, Leal [verfasserIn] Mansell, Els [verfasserIn] Canals, Isaac [verfasserIn] Sigurdsson, Valgardur [verfasserIn] Guibentif, Carolina [verfasserIn] Soneji, Shamit [verfasserIn] Woods, Niels‐Bjarne [verfasserIn] |
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| Format: |
E-Artikel |
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| Sprache: |
Englisch |
| Erschienen: |
2021 |
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| Schlagwörter: |
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| Anmerkung: |
© The Author(s) 2021 |
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| Übergeordnetes Werk: |
Enthalten in: EMBO Reports - Nature Publishing Group UK, 2023, 23(2021), 2 vom: 16. Dez. |
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| Übergeordnetes Werk: |
volume:23 ; year:2021 ; number:2 ; day:16 ; month:12 |
| Links: |
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| DOI / URN: |
10.15252/embr.202154384 |
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| Katalog-ID: |
SPR058091858 |
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| 245 | 1 | 0 | |a Pyruvate metabolism guides definitive lineage specification during hematopoietic emergence |
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| 520 | |a 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 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. | ||
| 520 | |a Synopsis During EHT, hematopoietic lineage specification is controlled by pyruvate metabolism at the single‐cell level. This commitment is regulated by cholesterol metabolism for definitive hematopoiesis, while primitive erythroid specification relies on epigenetic regulation by LSD1. A metabolic switch with concomitant increases in both glycolysis and oxidative phosphorylation occurs during human endothelial to hematopoietic transition.Metabolic cues involving pyruvate metabolism regulate definitive hematopoietic lineage development in both human in vitro and murine in vivo developmental hematopoiesis models.Single‐cell RNAseq analysis reveals that modulation of pyruvate metabolism in hemogenic endothelial cells affects hematopoietic cell fate decisions at the single‐cell level.Blocking pyruvate flux into mitochondria biases the hematopoietic lineage output toward early arising primitive erythroid cells and this redirection is dependent on epigenetic regulation by Lysine‐Specific Demethylase 1.Conversely, an increase in pyruvate entry into mitochondria leads to a boost in cholesterol metabolism which, in turn, increases Notch1 expression, leading to a biased definitive hematopoietic output. | ||
| 520 | |a Graphical Abstract During EHT, hematopoietic lineage specification is controlled by pyruvate metabolism at the single‐cell level. This commitment is regulated by cholesterol metabolism for definitive hematopoiesis, while primitive erythroid specification relies on epigenetic regulation by LSD1. | ||
| 650 | 4 | |a endothelial‐to‐hematopoietic transition |7 (dpeaa)DE-He213 | |
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| 650 | 4 | |a pyruvate metabolism |7 (dpeaa)DE-He213 | |
| 700 | 1 | |a Mansell, Els |e verfasserin |4 aut | |
| 700 | 1 | |a Canals, Isaac |e verfasserin |0 (orcid)0000-0002-2689-268X |4 aut | |
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| 700 | 1 | |a Guibentif, Carolina |e verfasserin |4 aut | |
| 700 | 1 | |a Soneji, Shamit |e verfasserin |4 aut | |
| 700 | 1 | |a Woods, Niels‐Bjarne |e verfasserin |0 (orcid)0000-0001-6052-922X |4 aut | |
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10.15252/embr.202154384 doi (DE-627)SPR058091858 (SPR)embr.202154384-e DE-627 ger DE-627 rakwb eng Oburoglu, Leal verfasserin (orcid)0000-0003-0130-6602 aut Pyruvate metabolism guides definitive lineage specification during hematopoietic emergence 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2021 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 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. Synopsis During EHT, hematopoietic lineage specification is controlled by pyruvate metabolism at the single‐cell level. This commitment is regulated by cholesterol metabolism for definitive hematopoiesis, while primitive erythroid specification relies on epigenetic regulation by LSD1. A metabolic switch with concomitant increases in both glycolysis and oxidative phosphorylation occurs during human endothelial to hematopoietic transition.Metabolic cues involving pyruvate metabolism regulate definitive hematopoietic lineage development in both human in vitro and murine in vivo developmental hematopoiesis models.Single‐cell RNAseq analysis reveals that modulation of pyruvate metabolism in hemogenic endothelial cells affects hematopoietic cell fate decisions at the single‐cell level.Blocking pyruvate flux into mitochondria biases the hematopoietic lineage output toward early arising primitive erythroid cells and this redirection is dependent on epigenetic regulation by Lysine‐Specific Demethylase 1.Conversely, an increase in pyruvate entry into mitochondria leads to a boost in cholesterol metabolism which, in turn, increases Notch1 expression, leading to a biased definitive hematopoietic output. Graphical Abstract During EHT, hematopoietic lineage specification is controlled by pyruvate metabolism at the single‐cell level. This commitment is regulated by cholesterol metabolism for definitive hematopoiesis, while primitive erythroid specification relies on epigenetic regulation by LSD1. endothelial‐to‐hematopoietic transition (dpeaa)DE-He213 glycolysis (dpeaa)DE-He213 hematopoiesis (dpeaa)DE-He213 OXPHOS (dpeaa)DE-He213 pyruvate metabolism (dpeaa)DE-He213 Mansell, Els verfasserin aut Canals, Isaac verfasserin (orcid)0000-0002-2689-268X aut Sigurdsson, Valgardur verfasserin aut Guibentif, Carolina verfasserin aut Soneji, Shamit verfasserin aut Woods, Niels‐Bjarne verfasserin (orcid)0000-0001-6052-922X aut Enthalten in EMBO Reports Nature Publishing Group UK, 2023 23(2021), 2 vom: 16. Dez. (DE-627)320645622 (DE-600)2025376-X 1469-3178 nnns volume:23 year:2021 number:2 day:16 month:12 https://dx.doi.org/10.15252/embr.202154384 X:SPRINGER Resolving-System kostenfrei Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_72 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_168 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_211 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_252 GBV_ILN_266 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4029 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4116 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4155 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4311 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4318 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4598 GBV_ILN_4700 AR 23 2021 2 16 12 |
| spelling |
10.15252/embr.202154384 doi (DE-627)SPR058091858 (SPR)embr.202154384-e DE-627 ger DE-627 rakwb eng Oburoglu, Leal verfasserin (orcid)0000-0003-0130-6602 aut Pyruvate metabolism guides definitive lineage specification during hematopoietic emergence 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2021 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 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. Synopsis During EHT, hematopoietic lineage specification is controlled by pyruvate metabolism at the single‐cell level. This commitment is regulated by cholesterol metabolism for definitive hematopoiesis, while primitive erythroid specification relies on epigenetic regulation by LSD1. A metabolic switch with concomitant increases in both glycolysis and oxidative phosphorylation occurs during human endothelial to hematopoietic transition.Metabolic cues involving pyruvate metabolism regulate definitive hematopoietic lineage development in both human in vitro and murine in vivo developmental hematopoiesis models.Single‐cell RNAseq analysis reveals that modulation of pyruvate metabolism in hemogenic endothelial cells affects hematopoietic cell fate decisions at the single‐cell level.Blocking pyruvate flux into mitochondria biases the hematopoietic lineage output toward early arising primitive erythroid cells and this redirection is dependent on epigenetic regulation by Lysine‐Specific Demethylase 1.Conversely, an increase in pyruvate entry into mitochondria leads to a boost in cholesterol metabolism which, in turn, increases Notch1 expression, leading to a biased definitive hematopoietic output. Graphical Abstract During EHT, hematopoietic lineage specification is controlled by pyruvate metabolism at the single‐cell level. This commitment is regulated by cholesterol metabolism for definitive hematopoiesis, while primitive erythroid specification relies on epigenetic regulation by LSD1. endothelial‐to‐hematopoietic transition (dpeaa)DE-He213 glycolysis (dpeaa)DE-He213 hematopoiesis (dpeaa)DE-He213 OXPHOS (dpeaa)DE-He213 pyruvate metabolism (dpeaa)DE-He213 Mansell, Els verfasserin aut Canals, Isaac verfasserin (orcid)0000-0002-2689-268X aut Sigurdsson, Valgardur verfasserin aut Guibentif, Carolina verfasserin aut Soneji, Shamit verfasserin aut Woods, Niels‐Bjarne verfasserin (orcid)0000-0001-6052-922X aut Enthalten in EMBO Reports Nature Publishing Group UK, 2023 23(2021), 2 vom: 16. Dez. (DE-627)320645622 (DE-600)2025376-X 1469-3178 nnns volume:23 year:2021 number:2 day:16 month:12 https://dx.doi.org/10.15252/embr.202154384 X:SPRINGER Resolving-System kostenfrei Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_72 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_168 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_211 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_252 GBV_ILN_266 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4029 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4116 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4155 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4311 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4318 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4598 GBV_ILN_4700 AR 23 2021 2 16 12 |
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10.15252/embr.202154384 doi (DE-627)SPR058091858 (SPR)embr.202154384-e DE-627 ger DE-627 rakwb eng Oburoglu, Leal verfasserin (orcid)0000-0003-0130-6602 aut Pyruvate metabolism guides definitive lineage specification during hematopoietic emergence 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2021 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 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. Synopsis During EHT, hematopoietic lineage specification is controlled by pyruvate metabolism at the single‐cell level. This commitment is regulated by cholesterol metabolism for definitive hematopoiesis, while primitive erythroid specification relies on epigenetic regulation by LSD1. A metabolic switch with concomitant increases in both glycolysis and oxidative phosphorylation occurs during human endothelial to hematopoietic transition.Metabolic cues involving pyruvate metabolism regulate definitive hematopoietic lineage development in both human in vitro and murine in vivo developmental hematopoiesis models.Single‐cell RNAseq analysis reveals that modulation of pyruvate metabolism in hemogenic endothelial cells affects hematopoietic cell fate decisions at the single‐cell level.Blocking pyruvate flux into mitochondria biases the hematopoietic lineage output toward early arising primitive erythroid cells and this redirection is dependent on epigenetic regulation by Lysine‐Specific Demethylase 1.Conversely, an increase in pyruvate entry into mitochondria leads to a boost in cholesterol metabolism which, in turn, increases Notch1 expression, leading to a biased definitive hematopoietic output. Graphical Abstract During EHT, hematopoietic lineage specification is controlled by pyruvate metabolism at the single‐cell level. This commitment is regulated by cholesterol metabolism for definitive hematopoiesis, while primitive erythroid specification relies on epigenetic regulation by LSD1. endothelial‐to‐hematopoietic transition (dpeaa)DE-He213 glycolysis (dpeaa)DE-He213 hematopoiesis (dpeaa)DE-He213 OXPHOS (dpeaa)DE-He213 pyruvate metabolism (dpeaa)DE-He213 Mansell, Els verfasserin aut Canals, Isaac verfasserin (orcid)0000-0002-2689-268X aut Sigurdsson, Valgardur verfasserin aut Guibentif, Carolina verfasserin aut Soneji, Shamit verfasserin aut Woods, Niels‐Bjarne verfasserin (orcid)0000-0001-6052-922X aut Enthalten in EMBO Reports Nature Publishing Group UK, 2023 23(2021), 2 vom: 16. Dez. (DE-627)320645622 (DE-600)2025376-X 1469-3178 nnns volume:23 year:2021 number:2 day:16 month:12 https://dx.doi.org/10.15252/embr.202154384 X:SPRINGER Resolving-System kostenfrei Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_72 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_168 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_211 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_252 GBV_ILN_266 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4029 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4116 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4155 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4311 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4318 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4598 GBV_ILN_4700 AR 23 2021 2 16 12 |
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10.15252/embr.202154384 doi (DE-627)SPR058091858 (SPR)embr.202154384-e DE-627 ger DE-627 rakwb eng Oburoglu, Leal verfasserin (orcid)0000-0003-0130-6602 aut Pyruvate metabolism guides definitive lineage specification during hematopoietic emergence 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2021 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 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. Synopsis During EHT, hematopoietic lineage specification is controlled by pyruvate metabolism at the single‐cell level. This commitment is regulated by cholesterol metabolism for definitive hematopoiesis, while primitive erythroid specification relies on epigenetic regulation by LSD1. A metabolic switch with concomitant increases in both glycolysis and oxidative phosphorylation occurs during human endothelial to hematopoietic transition.Metabolic cues involving pyruvate metabolism regulate definitive hematopoietic lineage development in both human in vitro and murine in vivo developmental hematopoiesis models.Single‐cell RNAseq analysis reveals that modulation of pyruvate metabolism in hemogenic endothelial cells affects hematopoietic cell fate decisions at the single‐cell level.Blocking pyruvate flux into mitochondria biases the hematopoietic lineage output toward early arising primitive erythroid cells and this redirection is dependent on epigenetic regulation by Lysine‐Specific Demethylase 1.Conversely, an increase in pyruvate entry into mitochondria leads to a boost in cholesterol metabolism which, in turn, increases Notch1 expression, leading to a biased definitive hematopoietic output. Graphical Abstract During EHT, hematopoietic lineage specification is controlled by pyruvate metabolism at the single‐cell level. This commitment is regulated by cholesterol metabolism for definitive hematopoiesis, while primitive erythroid specification relies on epigenetic regulation by LSD1. endothelial‐to‐hematopoietic transition (dpeaa)DE-He213 glycolysis (dpeaa)DE-He213 hematopoiesis (dpeaa)DE-He213 OXPHOS (dpeaa)DE-He213 pyruvate metabolism (dpeaa)DE-He213 Mansell, Els verfasserin aut Canals, Isaac verfasserin (orcid)0000-0002-2689-268X aut Sigurdsson, Valgardur verfasserin aut Guibentif, Carolina verfasserin aut Soneji, Shamit verfasserin aut Woods, Niels‐Bjarne verfasserin (orcid)0000-0001-6052-922X aut Enthalten in EMBO Reports Nature Publishing Group UK, 2023 23(2021), 2 vom: 16. Dez. (DE-627)320645622 (DE-600)2025376-X 1469-3178 nnns volume:23 year:2021 number:2 day:16 month:12 https://dx.doi.org/10.15252/embr.202154384 X:SPRINGER Resolving-System kostenfrei Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_72 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_168 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_211 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_252 GBV_ILN_266 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4029 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4116 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4155 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4311 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4318 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4598 GBV_ILN_4700 AR 23 2021 2 16 12 |
| allfieldsSound |
10.15252/embr.202154384 doi (DE-627)SPR058091858 (SPR)embr.202154384-e DE-627 ger DE-627 rakwb eng Oburoglu, Leal verfasserin (orcid)0000-0003-0130-6602 aut Pyruvate metabolism guides definitive lineage specification during hematopoietic emergence 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2021 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 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. Synopsis During EHT, hematopoietic lineage specification is controlled by pyruvate metabolism at the single‐cell level. This commitment is regulated by cholesterol metabolism for definitive hematopoiesis, while primitive erythroid specification relies on epigenetic regulation by LSD1. A metabolic switch with concomitant increases in both glycolysis and oxidative phosphorylation occurs during human endothelial to hematopoietic transition.Metabolic cues involving pyruvate metabolism regulate definitive hematopoietic lineage development in both human in vitro and murine in vivo developmental hematopoiesis models.Single‐cell RNAseq analysis reveals that modulation of pyruvate metabolism in hemogenic endothelial cells affects hematopoietic cell fate decisions at the single‐cell level.Blocking pyruvate flux into mitochondria biases the hematopoietic lineage output toward early arising primitive erythroid cells and this redirection is dependent on epigenetic regulation by Lysine‐Specific Demethylase 1.Conversely, an increase in pyruvate entry into mitochondria leads to a boost in cholesterol metabolism which, in turn, increases Notch1 expression, leading to a biased definitive hematopoietic output. Graphical Abstract During EHT, hematopoietic lineage specification is controlled by pyruvate metabolism at the single‐cell level. This commitment is regulated by cholesterol metabolism for definitive hematopoiesis, while primitive erythroid specification relies on epigenetic regulation by LSD1. endothelial‐to‐hematopoietic transition (dpeaa)DE-He213 glycolysis (dpeaa)DE-He213 hematopoiesis (dpeaa)DE-He213 OXPHOS (dpeaa)DE-He213 pyruvate metabolism (dpeaa)DE-He213 Mansell, Els verfasserin aut Canals, Isaac verfasserin (orcid)0000-0002-2689-268X aut Sigurdsson, Valgardur verfasserin aut Guibentif, Carolina verfasserin aut Soneji, Shamit verfasserin aut Woods, Niels‐Bjarne verfasserin (orcid)0000-0001-6052-922X aut Enthalten in EMBO Reports Nature Publishing Group UK, 2023 23(2021), 2 vom: 16. Dez. (DE-627)320645622 (DE-600)2025376-X 1469-3178 nnns volume:23 year:2021 number:2 day:16 month:12 https://dx.doi.org/10.15252/embr.202154384 X:SPRINGER Resolving-System kostenfrei Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_72 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_168 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_211 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_252 GBV_ILN_266 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4029 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4116 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4155 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4311 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4318 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4598 GBV_ILN_4700 AR 23 2021 2 16 12 |
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Enthalten in EMBO Reports 23(2021), 2 vom: 16. Dez. volume:23 year:2021 number:2 day:16 month:12 |
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Enthalten in EMBO Reports 23(2021), 2 vom: 16. Dez. volume:23 year:2021 number:2 day:16 month:12 |
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Oburoglu, Leal @@aut@@ Mansell, Els @@aut@@ Canals, Isaac @@aut@@ Sigurdsson, Valgardur @@aut@@ Guibentif, Carolina @@aut@@ Soneji, Shamit @@aut@@ Woods, Niels‐Bjarne @@aut@@ |
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<?xml version="1.0" encoding="UTF-8"?><collection xmlns="http://www.loc.gov/MARC21/slim"><record><leader>01000naa a22002652 4500</leader><controlfield tag="001">SPR058091858</controlfield><controlfield tag="003">DE-627</controlfield><controlfield tag="005">20241025065207.0</controlfield><controlfield tag="007">cr uuu---uuuuu</controlfield><controlfield tag="008">241025s2021 xx |||||o 00| ||eng c</controlfield><datafield tag="024" ind1="7" ind2=" "><subfield code="a">10.15252/embr.202154384</subfield><subfield code="2">doi</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-627)SPR058091858</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(SPR)embr.202154384-e</subfield></datafield><datafield tag="040" ind1=" " ind2=" "><subfield code="a">DE-627</subfield><subfield code="b">ger</subfield><subfield code="c">DE-627</subfield><subfield code="e">rakwb</subfield></datafield><datafield tag="041" ind1=" " ind2=" "><subfield code="a">eng</subfield></datafield><datafield tag="100" ind1="1" ind2=" "><subfield code="a">Oburoglu, Leal</subfield><subfield code="e">verfasserin</subfield><subfield code="0">(orcid)0000-0003-0130-6602</subfield><subfield code="4">aut</subfield></datafield><datafield tag="245" ind1="1" ind2="0"><subfield code="a">Pyruvate metabolism guides definitive lineage specification during hematopoietic emergence</subfield></datafield><datafield tag="264" ind1=" " ind2="1"><subfield code="c">2021</subfield></datafield><datafield tag="336" ind1=" " ind2=" "><subfield code="a">Text</subfield><subfield code="b">txt</subfield><subfield code="2">rdacontent</subfield></datafield><datafield tag="337" ind1=" " ind2=" "><subfield code="a">Computermedien</subfield><subfield code="b">c</subfield><subfield code="2">rdamedia</subfield></datafield><datafield tag="338" ind1=" " ind2=" "><subfield code="a">Online-Ressource</subfield><subfield code="b">cr</subfield><subfield code="2">rdacarrier</subfield></datafield><datafield tag="500" ind1=" " ind2=" "><subfield code="a">© The Author(s) 2021</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">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 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.</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Synopsis During EHT, hematopoietic lineage specification is controlled by pyruvate metabolism at the single‐cell level. This commitment is regulated by cholesterol metabolism for definitive hematopoiesis, while primitive erythroid specification relies on epigenetic regulation by LSD1. A metabolic switch with concomitant increases in both glycolysis and oxidative phosphorylation occurs during human endothelial to hematopoietic transition.Metabolic cues involving pyruvate metabolism regulate definitive hematopoietic lineage development in both human in vitro and murine in vivo developmental hematopoiesis models.Single‐cell RNAseq analysis reveals that modulation of pyruvate metabolism in hemogenic endothelial cells affects hematopoietic cell fate decisions at the single‐cell level.Blocking pyruvate flux into mitochondria biases the hematopoietic lineage output toward early arising primitive erythroid cells and this redirection is dependent on epigenetic regulation by Lysine‐Specific Demethylase 1.Conversely, an increase in pyruvate entry into mitochondria leads to a boost in cholesterol metabolism which, in turn, increases Notch1 expression, leading to a biased definitive hematopoietic output.</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Graphical Abstract During EHT, hematopoietic lineage specification is controlled by pyruvate metabolism at the single‐cell level. 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Oburoglu, Leal |
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Oburoglu, Leal misc endothelial‐to‐hematopoietic transition misc glycolysis misc hematopoiesis misc OXPHOS misc pyruvate metabolism Pyruvate metabolism guides definitive lineage specification during hematopoietic emergence |
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Pyruvate metabolism guides definitive lineage specification during hematopoietic emergence endothelial‐to‐hematopoietic transition (dpeaa)DE-He213 glycolysis (dpeaa)DE-He213 hematopoiesis (dpeaa)DE-He213 OXPHOS (dpeaa)DE-He213 pyruvate metabolism (dpeaa)DE-He213 |
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misc endothelial‐to‐hematopoietic transition misc glycolysis misc hematopoiesis misc OXPHOS misc pyruvate metabolism |
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misc endothelial‐to‐hematopoietic transition misc glycolysis misc hematopoiesis misc OXPHOS misc pyruvate metabolism |
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Pyruvate metabolism guides definitive lineage specification during hematopoietic emergence |
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Oburoglu, Leal Mansell, Els Canals, Isaac Sigurdsson, Valgardur Guibentif, Carolina Soneji, Shamit Woods, Niels‐Bjarne |
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pyruvate metabolism guides definitive lineage specification during hematopoietic emergence |
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Pyruvate metabolism guides definitive lineage specification during hematopoietic emergence |
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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 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. Synopsis During EHT, hematopoietic lineage specification is controlled by pyruvate metabolism at the single‐cell level. This commitment is regulated by cholesterol metabolism for definitive hematopoiesis, while primitive erythroid specification relies on epigenetic regulation by LSD1. A metabolic switch with concomitant increases in both glycolysis and oxidative phosphorylation occurs during human endothelial to hematopoietic transition.Metabolic cues involving pyruvate metabolism regulate definitive hematopoietic lineage development in both human in vitro and murine in vivo developmental hematopoiesis models.Single‐cell RNAseq analysis reveals that modulation of pyruvate metabolism in hemogenic endothelial cells affects hematopoietic cell fate decisions at the single‐cell level.Blocking pyruvate flux into mitochondria biases the hematopoietic lineage output toward early arising primitive erythroid cells and this redirection is dependent on epigenetic regulation by Lysine‐Specific Demethylase 1.Conversely, an increase in pyruvate entry into mitochondria leads to a boost in cholesterol metabolism which, in turn, increases Notch1 expression, leading to a biased definitive hematopoietic output. Graphical Abstract During EHT, hematopoietic lineage specification is controlled by pyruvate metabolism at the single‐cell level. This commitment is regulated by cholesterol metabolism for definitive hematopoiesis, while primitive erythroid specification relies on epigenetic regulation by LSD1. © The Author(s) 2021 |
| abstractGer |
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 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. Synopsis During EHT, hematopoietic lineage specification is controlled by pyruvate metabolism at the single‐cell level. This commitment is regulated by cholesterol metabolism for definitive hematopoiesis, while primitive erythroid specification relies on epigenetic regulation by LSD1. A metabolic switch with concomitant increases in both glycolysis and oxidative phosphorylation occurs during human endothelial to hematopoietic transition.Metabolic cues involving pyruvate metabolism regulate definitive hematopoietic lineage development in both human in vitro and murine in vivo developmental hematopoiesis models.Single‐cell RNAseq analysis reveals that modulation of pyruvate metabolism in hemogenic endothelial cells affects hematopoietic cell fate decisions at the single‐cell level.Blocking pyruvate flux into mitochondria biases the hematopoietic lineage output toward early arising primitive erythroid cells and this redirection is dependent on epigenetic regulation by Lysine‐Specific Demethylase 1.Conversely, an increase in pyruvate entry into mitochondria leads to a boost in cholesterol metabolism which, in turn, increases Notch1 expression, leading to a biased definitive hematopoietic output. Graphical Abstract During EHT, hematopoietic lineage specification is controlled by pyruvate metabolism at the single‐cell level. This commitment is regulated by cholesterol metabolism for definitive hematopoiesis, while primitive erythroid specification relies on epigenetic regulation by LSD1. © The Author(s) 2021 |
| abstract_unstemmed |
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 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. Synopsis During EHT, hematopoietic lineage specification is controlled by pyruvate metabolism at the single‐cell level. This commitment is regulated by cholesterol metabolism for definitive hematopoiesis, while primitive erythroid specification relies on epigenetic regulation by LSD1. A metabolic switch with concomitant increases in both glycolysis and oxidative phosphorylation occurs during human endothelial to hematopoietic transition.Metabolic cues involving pyruvate metabolism regulate definitive hematopoietic lineage development in both human in vitro and murine in vivo developmental hematopoiesis models.Single‐cell RNAseq analysis reveals that modulation of pyruvate metabolism in hemogenic endothelial cells affects hematopoietic cell fate decisions at the single‐cell level.Blocking pyruvate flux into mitochondria biases the hematopoietic lineage output toward early arising primitive erythroid cells and this redirection is dependent on epigenetic regulation by Lysine‐Specific Demethylase 1.Conversely, an increase in pyruvate entry into mitochondria leads to a boost in cholesterol metabolism which, in turn, increases Notch1 expression, leading to a biased definitive hematopoietic output. Graphical Abstract During EHT, hematopoietic lineage specification is controlled by pyruvate metabolism at the single‐cell level. This commitment is regulated by cholesterol metabolism for definitive hematopoiesis, while primitive erythroid specification relies on epigenetic regulation by LSD1. © The Author(s) 2021 |
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| score |
7.400573 |