Metabolic Regulation of Inflammasome Activity Controls Embryonic Hematopoietic Stem and Progenitor Cell Production.
Metabolic Regulation of Inflammasome Activity Controls Embryonic Hematopoietic Stem and Progenitor Cell Production.
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DOI：
10.1016/j.devcel.2020.07.015
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发表时间：
2020-10-26
影响因子：
11.8
通讯作者：
North TE
中科院分区：
文献类型：
--
作者：
Frame JM;Kubaczka C;Long TL;Esain V;Soto RA;Hachimi M;Jing R;Shwartz A;Goessling W;Daley GQ;North TE
胚胎造血干细胞和祖细胞（HSPC）在体内稳健地增殖，同时保持多谱系潜能;然而，对支配其生成的时空线索的不完全理解阻碍了体外人类诱导多能干细胞（iPSC）的稳健生产。使用斑马鱼模型，我们证明了NLRP 3炎性小体介导的白细胞介素-1-β（IL 1 β）信号转导驱动HSPC产生以响应代谢活动。通过runx 1/cmyb原位杂交和流式细胞术评估，活性IL 1 β的遗传诱导或药理学炎性体刺激增加了HSPC数量。炎性小体成分（包括il 1b）的缺失减少了CD 41 + HSPC，并阻止了它们响应代谢线索的扩增。细胞消融研究表明，巨噬细胞是必不可少的初始炎性体刺激IL 1 rl 1 + HSPCs。值得注意的是，在人iPSC衍生的造血前体中，瞬时炎性小体刺激增加了多谱系造血集落形成单位和T细胞祖细胞。这项工作建立了炎性小体作为保守的代谢传感器，在体内和体外扩大HSPC的生产。Frame等人鉴定了炎性小体在刺激斑马鱼和人造血干细胞和祖细胞（HSPC）的从头产生中的不可或缺的作用。炎性小体相关的IL 1 β信号传导在体内由发育代谢线索诱导，并从原始巨噬细胞传递到生血内皮，以促进胚胎HSPC形成。
Embryonic hematopoietic stem and progenitor cells (HSPCs) robustly proliferate while maintaining multilineage potential in vivo; however, an incomplete understanding of spatiotemporal cues governing their generation has impeded robust production from human induced pluripotent stem cells (iPSCs) in vitro. Using the zebrafish model, we demonstrate that NLRP3 inflammasome-mediated interleukin-1-beta (IL1β) signaling drives HSPC production in response to metabolic activity. Genetic induction of active IL1β or pharmacologic inflammasome stimulation increased HSPC number as assessed by in situ hybridization for runx1/cmyb and flow cytometry. Loss of inflammasome components, including il1b, reduced CD41+ HSPCs, and prevented their expansion in response to metabolic cues. Cell ablation studies indicated that macrophages were essential for initial inflammasome stimulation of Il1rl1+ HSPCs. Significantly, in human iPSC-derived hemogenic precursors, transient inflammasome stimulation increased multilineage hematopoietic colony-forming units and T-cell progenitors. This work establishes the inflammasome as a conserved metabolic sensor that expands HSPC production in vivo and in vitro. Frame et al. identify an integral role for the inflammasome in stimulating de novo production of zebrafish and human hematopoietic stem and progenitor cells (HSPCs). Inflammasome-associated IL1β signaling is induced in vivo by developmental metabolic cues and relayed from primitive macrophages to hemogenic endothelium to promote embryonic HSPC formation.
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影响因子：
8.8
作者：
Cortes M;Chen MJ;Stachura DL;Liu SY;Kwan W;Wright F;Vo LT;Theodore LN;Esain V;Frost IM;Schlaeger TM;Goessling W;Daley GQ;North TE
通讯作者：
North TE
影响因子：
21.3
作者：
Ditadi A;Sturgeon CM;Tober J;Awong G;Kennedy M;Yzaguirre AD;Azzola L;Ng ES;Stanley EG;French DL;Cheng X;Gadue P;Speck NA;Elefanty AG;Keller G
通讯作者：
Keller G
影响因子：
7.8
作者：
Camell C;Goldberg E;Dixit VD
通讯作者：
Dixit VD
DOI：
10.4049/jimmunol.0901363
发表时间：
2009-07-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Bauernfeind FG;Horvath G;Stutz A;Alnemri ES;MacDonald K;Speert D;Fernandes-Alnemri T;Wu J;Monks BG;Fitzgerald KA;Hornung V;Latz E
通讯作者：
Latz E
影响因子：
64.5
作者：
Espín-Palazón R;Stachura DL;Campbell CA;García-Moreno D;Del Cid N;Kim AD;Candel S;Meseguer J;Mulero V;Traver D
通讯作者：
Traver D