Nod1-dependent NF-kB activation initiates hematopoietic stem cell specification in response to small Rho GTPases.
Nod1-dependent NF-kB activation initiates hematopoietic stem cell specification in response to small Rho GTPases.
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DOI：
10.1038/s41467-023-43349-1
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发表时间：
2023-11-23
影响因子：
16.6
通讯作者：
Espin-Palazon, Raquel
中科院分区：
文献类型：
--
作者：
Cheng, Xiaoyi;Barakat, Radwa;Pavani, Giulia;Usha, Masuma Khatun;Calderon, Rodolfo;Snella, Elizabeth;Gorden, Abigail;Zhang, Yudi;Gadue, Paul;French, Deborah L.;Dorman, Karin S.;Fidanza, Antonella;Campbell, Clyde A.;Espin-Palazon, Raquel
揭示调控造血特化的机制不仅将克服目前与造血干细胞和祖细胞（HSPC）移植相关的限制，而且将推进细胞免疫治疗。然而，产生功能性人诱导多能干细胞（hiPSC）衍生的HSPC及其衍生物一直是难以捉摸的，需要更好地理解触发HSPC特化的发育机制。在这里，我们揭示了内皮细胞（EC）中Nod 1-Ripk 2-NF-kB炎症通路的早期激活使其将命运转向永久性生血内皮，这是指定HSPC的先决条件。我们的遗传和化学胚胎模型表明，HSPCs未能指定在没有Nod 1及其下游激酶Ripk 2由于造血内皮（HE）编程失败，和小Rho GTP酶协调激活这一途径。在人类造血分化系统中对NOD 1的操纵表明其功能保守。这项工作建立了RAC 1-NOD 1-RIPK 2-NF-kB轴作为一个关键的内在电感器，在HE命运切换和HSPC规范之前启动EC。该途径的操作可以帮助获得适合于指定功能性患者特异性HSPC及其衍生物用于治疗血液疾病的有能力的HE。使内皮细胞转变为造血细胞以产生造血干细胞的信号知之甚少。在这里，作者将病原体的细胞内传感器确定为引发这种开关的诱导性发育线索。
Uncovering the mechanisms regulating hematopoietic specification not only would overcome current limitations related to hematopoietic stem and progenitor cell (HSPC) transplantation, but also advance cellular immunotherapies. However, generating functional human induced pluripotent stem cell (hiPSC)-derived HSPCs and their derivatives has been elusive, necessitating a better understanding of the developmental mechanisms that trigger HSPC specification. Here, we reveal that early activation of the Nod1-Ripk2-NF-kB inflammatory pathway in endothelial cells (ECs) primes them to switch fate towards definitive hemogenic endothelium, a pre-requisite to specify HSPCs. Our genetic and chemical embryonic models show that HSPCs fail to specify in the absence of Nod1 and its downstream kinase Ripk2 due to a failure on hemogenic endothelial (HE) programming, and that small Rho GTPases coordinate the activation of this pathway. Manipulation of NOD1 in a human system of definitive hematopoietic differentiation indicates functional conservation. This work establishes the RAC1-NOD1-RIPK2-NF-kB axis as a critical intrinsic inductor that primes ECs prior to HE fate switch and HSPC specification. Manipulation of this pathway could help derive a competent HE amenable to specify functional patient specific HSPCs and their derivatives for the treatment of blood disorders. The signals that enable endothelial cells to switch to hemogenic to generate hematopoietic stem cells are poorly understood. Here, the authors identify an intracellular sensor of pathogens as an inductive developmental cue that primes this switch.
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影响因子：
2
作者：
Barakat, Radwa;Campbell, Clyde A.;Espin-Palazon, Raquel
通讯作者：
Espin-Palazon, Raquel
影响因子：
--
作者：
Correa RG;Khan PM;Askari N;Zhai D;Gerlic M;Brown B;Magnuson G;Spreafico R;Albani S;Sergienko E;Diaz PW;Roth GP;Reed JC
通讯作者：
Reed JC
影响因子：
30.3
作者：
Burberry A;Zeng MY;Ding L;Wicks I;Inohara N;Morrison SJ;Núñez G
通讯作者：
Núñez G
影响因子：
9.8
作者：
Bernales S;McDonald KL;Walter P
通讯作者：
Walter P
影响因子：
20.3
作者：
Bennett, CM;Kanki, JP;Look, AT
通讯作者：
Look, AT