The onset of circulation triggers a metabolic switch required for endothelial to hematopoietic transition.
The onset of circulation triggers a metabolic switch required for endothelial to hematopoietic transition.
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DOI：
10.1016/j.celrep.2021.110103
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发表时间：
2021-12-14
期刊：
影响因子：
8.8
通讯作者：
de Bruijn MFTR
中科院分区：
文献类型：
--
作者：
Azzoni E;Frontera V;Anselmi G;Rode C;James C;Deltcheva EM;Demian AS;Brown J;Barone C;Patelli A;Harman JR;Nicholls M;Conway SJ;Morrissey E;Jacobsen SEW;Sparrow DB;Harris AL;Enver T;de Bruijn MFTR
造血干细胞(HSCs)在发育过程中从胚胎主要动脉的血管壁中分化出来。循环的开始触发了几个过程，这些过程为HSC的产生提供了关键的外部因素。然而，循环的开始如何以及何时影响HSC的出现尚不完全清楚。在这里，我们表明，在Ncx1HSC小鼠胚胎中，缺乏循环的−/−谱系一直发育到表型前-HSC阶段。然而，这些细胞居住在异常的微环境中，无法激活RUNX1下游的造血程序，功能受损。单细胞转录组研究表明，在从内皮细胞到造血细胞的转变过程中，野生型细胞中的Ncx1−/−细胞没有经历糖酵解到氧化磷酸化代谢的转换。有趣的是，糖酵解的实验性激活会导致胚胎内造血减少。我们的结果表明，循环的开始触发了代谢变化，从而使HSC的生成得以进行。在缺乏循环的Ncx1−/−胚胎中出现了血源性内皮(HE)和前-HSCs，NCx1-−/−前-HSCs在转录和功能上受到损害，HE向前HSC的转变涉及糖酵解到OxPhos代谢转变。有报道称，在没有循环的情况下，造血干细胞前体(ProHSC)仍然会出现，但功能受损，不能激活造血程序。单细胞转录学表明，循环的开始诱导了造血发育所需的代谢开关。
Hematopoietic stem cells (HSCs) emerge during development from the vascular wall of the main embryonic arteries. The onset of circulation triggers several processes that provide critical external factors for HSC generation. Nevertheless, it is not fully understood how and when the onset of circulation affects HSC emergence. Here we show that in Ncx1−/− mouse embryos devoid of circulation the HSC lineage develops until the phenotypic pro-HSC stage. However, these cells reside in an abnormal microenvironment, fail to activate the hematopoietic program downstream of Runx1, and are functionally impaired. Single-cell transcriptomics shows that during the endothelial-to-hematopoietic transition, Ncx1−/− cells fail to undergo a glycolysis to oxidative phosphorylation metabolic switch present in wild-type cells. Interestingly, experimental activation of glycolysis results in decreased intraembryonic hematopoiesis. Our results suggest that the onset of circulation triggers metabolic changes that allow HSC generation to proceed. Hemogenic endothelium (HE) and pro-HSCs emerge in Ncx1−/− embryos lacking circulation Ncx1−/− pro-HSCs are transcriptionally and functionally impaired The HE to pro-HSC transition involves a glycolysis to OxPhos metabolic shift Activation of glycolysis reduces hematopoietic output of E9.5 intraembryonic precursors Azzoni et al. report that hematopoietic stem cell precursors (pro-HSC) still emerge in the absence of circulation, but are functionally impaired and do not activate the hematopoietic program. Single-cell transcriptomics indicate that the onset of circulation induces a metabolic switch that is required for hematopoietic development.
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影响因子：
46.9
作者：
Becht, Etienne;McInnes, Leland;Newell, Evan W.
通讯作者：
Newell, Evan W.
影响因子：
7.7
作者：
Azzoni E;Frontera V;McGrath KE;Harman J;Carrelha J;Nerlov C;Palis J;Jacobsen SEW;de Bruijn MF
通讯作者：
de Bruijn MF
DOI：
10.1084/jem.20142235
发表时间：
2015-05-04
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Diaz MF;Li N;Lee HJ;Adamo L;Evans SM;Willey HE;Arora N;Torisawa YS;Vickers DA;Morris SA;Naveiras O;Murthy SK;Ingber DE;Daley GQ;García-Cardeña G;Wenzel PL
通讯作者：
Wenzel PL
影响因子：
16.6
作者：
Gama-Norton L;Ferrando E;Ruiz-Herguido C;Liu Z;Guiu J;Islam AB;Lee SU;Yan M;Guidos CJ;López-Bigas N;Maeda T;Espinosa L;Kopan R;Bigas A
通讯作者：
Bigas A
影响因子：
5.9
作者：
Batsivari A;Rybtsov S;Souilhol C;Binagui-Casas A;Hills D;Zhao S;Travers P;Medvinsky A
通讯作者：
Medvinsky A