NOTCH-mediated ex vivo expansion of human hematopoietic stem and progenitor cells by culture under hypoxia.
NOTCH-mediated ex vivo expansion of human hematopoietic stem and progenitor cells by culture under hypoxia.
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缺氧法体外扩增人造血干/祖细胞。
DOI：
10.1016/j.stemcr.2021.08.001
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发表时间：
2021-09-14
影响因子：
5.9
通讯作者：
Larochelle A
中科院分区：
文献类型：
--
作者：
Araki D;Fu JF;Huntsman H;Cordes S;Seifuddin F;Alvarado LJ;Cheruku PS;Cash A;Traba J;Li Y;Pirooznia M;Smith RH;Larochelle A
Activation of NOTCH signaling in human hematopoietic stem/progenitor cells (HSPCs) by treatment with an engineered Delta-like ligand (DELTA1ext-IgG [DXI]) has enabled ex vivo expansion of short-term HSPCs, but the effect on long-term repopulating hematopoietic stem cells (LTR-HSCs) remains uncertain. Here, we demonstrate that ex vivo culture of human adult HSPCs with DXI under low oxygen tension limits ER stress in LTR-HSCs and lineage-committed progenitors compared with normoxic cultures. A distinct HSC gene signature was upregulated in cells cultured with DXI in hypoxia and, after 21 days of culture, the frequency of LTR-HSCs increased 4.9-fold relative to uncultured cells and 4.2-fold compared with the normoxia + DXI group. NOTCH and hypoxia pathways intersected to maintain undifferentiated phenotypes in cultured HSPCs. Our work underscores the importance of mitigating ER stress perturbations to preserve functional LTR-HSCs in extended cultures and offers a clinically feasible platform for the expansion of human HSPCs. Superior NOTCH-mediated expansion of human HSPCs in hypoxic cultures Culture under hypoxia mitigates ER stress in human HSPCs Hypoxia potentiates NOTCH intracellular signaling in cultured human HSPCs Larochelle and colleagues concurrently activate NOTCH and hypoxic pathways in ex vivo cultures of human adult HSPCs to enable a clinically relevant expansion of cells with long-term repopulating potential after transplantation. They characterize the molecular intersection between the two signaling pathways and demonstrate the important role of low oxygen tension in mitigating ER stress during NOTCH-mediated expansion of human HSPCs.
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影响因子：
5.2
作者：
Giuntoli, Serena;Rovida, Elisabetta;Dello Sbarba, Persio
通讯作者：
Dello Sbarba, Persio
影响因子：
30.5
作者：
Laurenti E;Doulatov S;Zandi S;Plumb I;Chen J;April C;Fan JB;Dick JE
通讯作者：
Dick JE
影响因子：
4.6
作者：
Bigarella, Carolina L.;Liang, Raymond;Ghaffari, Saghi
通讯作者：
Ghaffari, Saghi
影响因子：
82.9
作者：
Eppert, Kolja;Takenaka, Katsuto;Dick, John E.
通讯作者：
Dick, John E.
通过减轻氧休克来增强造血干细胞移植功效。
影响因子：
64.5
作者：
Mantel CR;O'Leary HA;Chitteti BR;Huang X;Cooper S;Hangoc G;Brustovetsky N;Srour EF;Lee MR;Messina-Graham S;Haas DM;Falah N;Kapur R;Pelus LM;Bardeesy N;Fitamant J;Ivan M;Kim KS;Broxmeyer HE
通讯作者：
Broxmeyer HE