AbstractRecent findings suggest that Hematopoietic Stem Cells (HSC) and progenitors arise simultaneously and independently of each other already in the embryonic aorta-gonad mesonephros region, but it is still unknown how their different features are established. Here, we uncover IκBα (Nfkbia, the inhibitor of NF-κB) as a critical regulator of HSC proliferation throughout development.

摘要最近的研究结果表明，造血干细胞（HSC）和祖细胞已经在胚胎主动脉-性腺-中肾区域同时独立出现，但尚不清楚它们的不同特征是如何建立的。在这里，我们发现IκBα（Nfkbia，NF-κB的抑制剂）是整个发育过程中HSC增殖的关键调节剂。

IκBα balances retinoic acid signaling levels together with the epigenetic silencer, PRC2, specifically in HSCs. Loss of IκBα decreases proliferation of HSC and induces a dormancy related gene expression signature instead. Also, IκBα deficient HSCs respond with superior activation to in vitro culture and in serial transplantation.

IκBα与表观遗传沉默子PRC2（特别是在HSC中）一起平衡视黄酸信号传导水平。IκBα的缺失会降低HSC的增殖，并诱导与休眠相关的基因表达特征。此外，IκBα缺陷型HSC对体外培养和连续移植具有优异的激活作用。

At the molecular level, chromatin regions harboring binding motifs for retinoic acid signaling are hypo-methylated for the PRC2 dependent H3K27me3 mark in IκBα deficient HSCs. Overall, we show that the proliferation index in the developing HSCs is regulated by a IκBα-PRC2 axis, which controls retinoic acid signaling..

在分子水平上，对于IκBα缺陷型HSC中PRC2依赖性H3K27me3标记，带有视黄酸信号传导结合基序的染色质区域被低甲基化。总体而言，我们显示发育中的HSC中的增殖指数受IκBα-PRC2轴调节，该轴控制视黄酸信号传导。。

IntroductionHSCs can replenish the adult blood system by generating mature blood cells of all lineages through intermediate stages of multipotent progenitors1. Understanding the molecular programming underlying the formation of HSCs during development is critical to improve the feasibility of generating them from Pluripotent Stem cells, or through re-programming of somatic cells to treat blood malignancies2.

引言HSC可以通过多能祖细胞的中间阶段产生所有谱系的成熟血细胞来补充成人血液系统1。了解发育过程中HSC形成的分子编程对于提高从多能干细胞产生HSC的可行性至关重要，或者通过重新编程体细胞来治疗血液恶性肿瘤2。

Blood stem and progenitor cell (HSPC) emerge through trans-differentiation of specialized endothelial-like cells, termed hemogenic endothelium (HE), and the first cells capable to regenerate the hematopoietic system are found in the Aorta-Gonad-Mesonephros (AGM) region between embryonic day (E) 10.25 and 11.5 in the mouse embryo3,4,5 and accumulate as intra-aortic hematopoietic clusters (IAHC) within the ventral wall of the dorsal aorta (vDA, DA)6,7,8.Hemogenic potential in the DA can be readily identified by the expression of transcription factors such as Gata2 and Gfi19,10,11,12 and a few cells in IAHC co-express markers associated with HSC activity.

造血干细胞和祖细胞（HSPC）是通过特殊的内皮样细胞（称为血源性内皮细胞（HE））的转分化而出现的，第一批能够再生造血系统的细胞是在小鼠胚胎的胚胎日（E）10.25和11.5之间的主动脉-性腺-中肾（AGM）区域中发现的3,4,5，并在背主动脉腹壁（vDA，DA）6,7,8内积累为主动脉内造血簇（IAHC）。DA中的造血潜能可以通过转录因子如Gata2和Gfi19,10,11,12的表达以及IAHC co中的一些细胞来容易地鉴定表达与HSC活性相关的标记。

Some of the IAHC that are cKIT and CD41 positive (Pre-HSCs/T1 HSCs), gain HSC-specific markers, including CD45, SCA1, and EPCR (CD201/PROCR) (T2 HSCs)13. From the AGM, the first HSCs migrate to the FL by E12.5 to amplify and acquire an adult HSC phenotype14. There, the hematopoietic hierarchy is first evident, and a pool of long-term HSCs (LT-HSCs, LSKCD48-CD150+) resides at its apex.Recent studies indicate that (LT-) HSC and HPCs fate is already segregated in the AGM and that the fetal liver merely serves as a niche for their amplification as separate populations, with the (LT)-HSCs pool remaining smaller than the extensively proliferating HPC pool15,16,17.

一些cKIT和CD41阳性（前HSC/T1 HSC）的IAHC获得HSC特异性标记，包括CD45，SCA1和EPCR（CD201/PROCR）（T2 HSC）13。从AGM开始，第一批HSC通过E12.5迁移到FL，以扩增并获得成年HSC表型14。在那里，造血系统的层次结构首先显而易见，并且长期HSC（LT-HSC，LSKCD48-CD150+）的库位于其顶点。最近的研究表明，（LT-）HSC和HPC的命运已经在AGM中分离，胎儿肝脏只是作为单独群体扩增的利基，而（LT）-HSC池仍然小于广泛增殖的HPC池15,16,17。

Signals that allow this segregation, and how these LT-HSCs p.

允许这种分离的信号，以及这些LT-HSC如何p。

IκBα KO has reduced cKIT+CD45+SCA1+EPCR+HSC in the AGMSince we had identified a retention of the AGM HSC signature in IκBα KO LT-HSCs of the E14.5 FL (Fig. 3B), and NF-κB activity is already required during AGM hematopoiesis28,29,30 we aimed to study the spatial distribution of IκBα by performing Immunohistochemistry (IHC) on E11.5 AGM sagittal sections.

IκBαKO在AGM中降低了cKIT+CD45+SCA1+EPCR+HSC，因为我们已经确定了E14.5 FL的IκBαKO LT HSC中AGM HSC特征的保留（图3B），并且在AGM造血过程中已经需要NF-κB活性28,29,30我们旨在通过在E11.5 AGM矢状切片上进行免疫组织化学（IHC）来研究IκBα的空间分布。

We used the Gfi1:tomato embryos to enrich for HSC containing IAHC in the AGM11.Besides the expected cytoplasmic staining, we discovered an accumulation of a punctuated and nuclear signal for IκBα mainly in GFI1 positive HE and IAHC (Fig. 3D and Supplementary Fig. S5D). The nuclear localization of IκBα raised the possibility that we were additionally detecting the form of the (nuclear) IκBα that has been previously linked to stem cell function33,34.

我们使用Gfi1：番茄胚胎来富集AGM11中含有HSC的IAHC。除了预期的细胞质染色外，我们还发现IκBα的点状和核信号主要在Gfi1阳性HE和IAHC中积累（图3D和补充图S5D）。IκBα的核定位增加了我们另外检测先前与干细胞功能相关的（核）IκBα形式的可能性33,34。

Phosphorylated, nuclear IκBα is protected from degradation by SUMOylation43, and is predominantly detected as phosphorylated Ser32,36 IκBα with a specific antibody (p-IκBα). Thus, we examined the presence of p-IκBα in cKIT or GFI1 positive cells and detected nuclear p-IκBα staining mainly in IAHC (Fig. 3E and Supplementary Fig. S5E) with a heterogeneous distribution in around 50% cKIT positive cells (Fig. 3F), strongly suggesting this additional function for IκBα already in the IAHC of the AGM.We next assessed the impact of IκBα deletion in E11.5 AGMs and compared IκBα WT and KO by FACS analysis.

磷酸化的核IκBα被SUMO化43保护免于降解，并且主要被特异性抗体（p-IκBα）检测为磷酸化的Ser32,36 IκBα。因此，我们检测了cKIT或GFI1阳性细胞中p-IκBα的存在，并检测到主要在IAHC中的核p-IκBα染色（图3E和补充图S5E），在约50%的cKIT阳性细胞中具有异质分布（图3F），强烈表明AGM的IAHC中已经存在IκBα的这种额外功能。接下来，我们评估了E11.5 AGM中IκBα缺失的影响，并通过FACS分析比较了IκBαWT和KO。

The frequency of the overall CD31+cKIT+/CD45+ (HSPCs) was not altered in IκBα KO embryos when compared with the controls (Fig. 3G(i), Supplementary Fig. S5F). However, when additional markers that restrict this population further to HSCs were included, i.e. by sub-gating for GFI1/EPCR or SCA1/EPCR13,44,45 then we detected a significant decline in the percentage of HSCs in the IκBα KO.

与对照组相比，IκBαKO胚胎中总体CD31+cKIT+/CD45+（HSPC）的频率没有改变（图3G（I），补充图S5F）。然而，当包括将该群体进一步限制为HSC的其他标记时，即通过对GFI1/EPCR或SCA1/EPCR13,44,45进行亚门控，然后我们检测到iκBαKO中HSC的百分比显着下降。

IκBα KO LT-HSC shows a functional dormant phenotype in vivo and in vitroNext, we aimed to investigate the activation capacity of LT-HSCs by measuring the clonogenic activity of individual IκBα WT and KO LT-HSCs in vitro (Supplementary Fig. S9A). LT-HSCs that are in a dormant/slow-cycling state need more time to proliferate than their already activated counterparts18.

IκBαKO LT-HSC在体内和体外均表现出功能性休眠表型，我们旨在通过测量单个IκBαWT和KO LT-HSC的体外克隆形成活性来研究LT-HSC的活化能力（补充图S9A）。处于休眠/缓慢循环状态的LT-HSC比其已经激活的对应物需要更多的时间增殖18。

In fact, dormant HSCs show a paradoxical behavior upon stress stimuli, including transplantation assays or ex vivo culture: the cells become activated with a delay which has been attributed to their need to exit the quiescent state first. However, once activated, dormant cells possess a higher self-renewal and repopulation capacity than their already activated HSC counterparts49, and even outperform their WT equivalent over time18,19.

事实上，休眠的HSC在应激刺激下表现出矛盾的行为，包括移植试验或离体培养：细胞被激活的延迟归因于它们首先需要退出静止状态。然而，一旦激活，休眠细胞比已经激活的HSC对应物具有更高的自我更新和再增殖能力49，并且随着时间的推移甚至优于其WT等效物18,19。

We, therefore, compared the clonogenic potential of IκBα WT and KO LT-HSC in vitro by sorting single LT-HSCs into individual wells and assessing for the cell number of the clonogenic colonies after 10 days. We detected an overall trend towards increased colony numbers from IκBα KO LT-HSC with the small colonies (10–100 cells) showing the highest increase (Supplementary Fig. S9Aii, iii), suggesting that IκBα KO LT-HSC have a delayed response to stress (more small colonies) but greater proliferation potential (higher overall number of colonies) (Supplementary Fig. S9A).Ultimately, we assessed the dormant phenotype in serial transplantation settings (Fig. 6A).

因此，我们通过将单个LT-HSC分选到单个孔中并评估10天后克隆形成集落的细胞数量，比较了IκBαWT和KO LT-HSC在体外的克隆形成潜力。我们检测到IκBαKO LT-HSC菌落数量增加的总体趋势，其中小菌落（10-100个细胞）显示出最高的增加（补充图S9Aii，iii），这表明IκBαKO LT-HSC对压力的反应延迟（菌落越小），但增殖潜力越大（菌落总数越高）（补充图S9A）。最终，我们评估了连续移植环境中的休眠表型（图6A）。

We evaluated the hematopoietic activity of IκBα KO LT-HSCs (200 per recipient) or LSK (1000 cells) in competition with 500.000 lin- depleted bone marrow WT cells, respectively, in transplantation assay (Fig. 6A). Indeed, PB blood analysis 4 weeks after the transplantation showed a significantly lower blood chimerism from Iκ.

我们在移植试验中分别评估了IκBαKO LT HSC（每个受体200个）或LSK（1000个细胞）与500000个lin耗尽的骨髓WT细胞竞争的造血活性（图6A）。实际上，移植后4周的PB血液分析显示Iκ的血液嵌合体明显降低。

Single-cell RNA-seq data from Zhou et al.13 (https://www.nature.com/articles/nature17997) was downloaded from Gene Expression Omnibus (GEO), accession number GSE67120. The downloaded SRR files were converted to Illumina paired-end fastq using the SRA Toolkit (version 3.0.1) using the function “fastq-dump –split-e” with default parameters.

来自Zhou等人的单细胞RNA-seq数据(https://www.nature.com/articles/nature17997)从Gene Expression Omnibus（GEO）下载，登录号为GSE67120。使用SRA工具包（版本3.0.1），使用带有默认参数的函数“fastq dump–split-e”，将下载的SRR文件转换为Illumina配对端fastq。

We subsequently mapped the fastq files with STAR (REF - https://pubmed.ncbi.nlm.nih.gov/23104886/) (version 2.7.9a) using the STARsolo to the mouse reference genome on 10x genomics webpage (https://cf.10xgenomics.com/supp/cell-exp/refdata-gex-mm10-2020-A.tar.gz). The STARsolo mapping and quantification command were with the following parameters; soloUMIdedup Exact, soloStrand Unstranded, soloFeatures Gene GeneFull, soloMultiMappers EM, outSAMtype BAM SortedByCoordinate.

随后，我们用STAR（参考-https://pubmed.ncbi.nlm.nih.gov/23104886/)（版本2.7.9a）在10x genomics网页上使用STARsolo对小鼠参考基因组(https://cf.10xgenomics.com/supp/cell-exp/refdata-gex-mm10-2020-A.tar.gz)。STARsolo映射和量化命令具有以下参数；soloUMIdedup Exact，soloStrand Unstranded，soloFeatures GeneFull，soloMultiMappers EM，outSAMtype BAM SortedByCoordinate。

Following mapping, the output of STARsolo was loaded into R (version 4.1.0) using the DropletUtils package (version 1.12.1). We obtained 262 cells from the public repository and retained cells with <15% mitochondria reads, leaving 261 cells. Cell identify was taken directly from the Zhou et al.13 metadata with the following population numbers.AGM E11.0 Endothelial (n = 16); AGM E11.0 T1-preHSC CD201 negative (n = 42), AGM E11.0 T1-preHSC CD 201 high (n = 28); AGM E11.0 T2-preHSC CD201high (n = 44); AGM E11.0 T2-preHSC (n = 32); Fetal liver E12.0 HSC (n = 21), Fetal liver E14.0 HSC (n = 32), Bone marrow adult HSC (n = 46).The list of gene signatures (Nfkb members, inflammation) and scripts to process Zhou et al.13 data can be found at: https://github.com/zakiF/PublishedPapers/tree/master/Nat_comms_Ikba.

映射之后，使用DropletUtils软件包（版本1.12.1）将STARsolo的输出加载到R（版本4.1.0）中。我们从公共存储库中获得了262个细胞，并保留了线粒体读数小于15%的细胞，剩下261个细胞。细胞鉴定直接来自Zhou等人的元数据，具有以下人口数量。AGM E11.0内皮（n=16）；AGM E11.0 T1 preHSC CD201阴性（n=42），AGM E11.0 T1 preHSC CD 201高（n=28）；AGM E11.0 T2 preHSC CD201high（n=44）；AGM E11.0 T2 preHSC（n=32）；胎肝E12.0 HSC（n=21），胎肝E14.0 HSC（n=32），骨髓成人HSC（n=46）。基因特征（Nfkb成员，炎症）和处理Zhou等人13数据的脚本列表可以在以下网址找到：https://github.com/zakiF/PublishedPapers/tree/master/Nat_comms_Ikba.

Two group comparisons were performed using the t-test comparison using the ggsignif package (version 0.6.4).Genotyping PCRSmall pieces of embryonic tissue or yolk sac wer.

使用ggsignif软件包（版本0.6.4），使用t检验比较进行两组比较。基因分型PCR胚胎组织或卵黄囊的小块。

Data availability

数据可用性

Single-cell RNA-seq, bulk RNA-seq and CUT&Tag data generated in this study have been deposited in NCBI Gene Expression Omnibus (GEO) repository under GEO SuperSeries accession no. GSE188525, composed in respective SubSeries GSE214699 [https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE214699], GSE188523 [https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE188523] and GSE188524 [https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE188524].

本研究中产生的单细胞RNA-seq、大量RNA-seq和CUT&Tag数据已保存在NCBI基因表达综合库（GEO）中，GEO超级系列登录号为GSE188525，由各自的子系列GSE214699组成[https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE214699]，GSE188523[https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE188523]和GSE188524[https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE188524]。

Additionally, single-cell RNA-seq data from Zhou et al.13 was downloaded from GEO with accession number GSE67120. Source data are provided with this paper..

此外，Zhou等人13的单细胞RNA-seq数据已从GEO下载，登录号为GSE67120。本文提供了源数据。。

Code availability

代码可用性

Scripts that have been used to process data published in Zhou et al.13 are deposited in Github repository: https://github.com/zakiF/PublishedPapers/tree/master/Nat_comms_Ikba Scripts that have been used to process the in house bulk RNA-seq and CUT &Tag assay are deposited in Github repository: https://github.com/BigaSpinosaLab/HSC_dormancy_Ikba_via_retinoic_acid..

用于处理Zhou等人13中发布的数据的脚本存放在Github存储库中：https://github.com/zakiF/PublishedPapers/tree/master/Nat_comms_Ikba用于处理内部批量RNA-seq和切割标签分析的脚本存放在Github存储库中：https://github.com/BigaSpinosaLab/HSC_dormancy_Ikba_via_retinoic_acid..

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Korotkevich，G.，Sukhov，V.，Budin，N.，Atryomov，M.N。＆Sergushichev，A。快速基因集富集分析。生物十四https://doi.org/10.1101/060012（2021年）。Thambyrajah，R。等人。通过JAGGED1顺式抑制NOTCH1维持胚胎造血干细胞的命运。国家公社。151604（2024）。下载参考文献致谢我们感谢Espinosa和Bigas实验室的所有成员进行了有益的讨论和技术支持。

We also thank the animal facility, FACS facility, and genomic facility of the PRBB, CRUK Manchester Institute, and the single-cell Unit of the IJC for their technical support. This work was funded by grants from SAF2016-75613-R, PID2019-104695RB-I00, and PDC2021-120817-I00 from Agencia Estatal de Investigación (AEI) and SLT002/16/00299 from Department of Health, Generalitat de Catalunya.

我们还感谢PRBB的动物设施，FACS设施和基因组设施，克鲁克曼彻斯特研究所以及IJC的单细胞部门提供的技术支持。这项工作由SAF2016-75613-R，PID2019-104695RB-I00和PDC2021-120817-I00（AEI）和SLT002/16/00299（加泰罗尼亚卫生部）资助。

The work in G.L. laboratory is supported by Blood Cancer UK (19014) and Cancer Research UK Manchester Institute Core Grant (C5759/A27412). R.T. is a recipient of BP2016(00021) and BP/MSCA 2018(00034) fellowship programs from Generalitat de Catalunya/MSCA. M.M. is a recipient of a grant from the Instituto Carlos III, grant number CA22/00011 (co-funded by the European Social Fund Plus, ESF+, and by the European Union).Author informationAuthor notesNoemi CastelluccioPresent address: Ghent University Hospital, Ghent, BelgiumThese authors jointly supervised this work: Roshana Thambyrajah, Anna Bigas.Authors and AffiliationsProgram in Cancer Research, Hospital del Mar Research Institute, Barcelona, SpainRoshana Thambyrajah, Maria Maqueda, Martin Proffitt, Yolanda Guillén, Patricia Herrero-Molinero, Carla Brujas, Noemi Castelluccio, Jessica González, Arnau Iglesias, Laura Marruecos, Cristina Ruiz-Herguido, Lluis Espinosa & Anna BigasJosep Carreras Le.

G.L.实验室的工作得到了英国血癌研究所（19014）和英国曼彻斯特癌症研究所核心资助（C5759/A27412）的支持。R、 T.是加泰罗尼亚/MSCA Generalitat de Catalunya/MSCA的BP2016（00021）和BP/MSCA 2018（00034）奖学金项目的获得者。M、 M.是卡洛斯三世研究所（Instituto Carlos III）的资助对象，资助号为CA22/00011（由欧洲社会基金会（European Social Fund Plus），ESF+和欧盟共同资助）。作者信息作者注释Noemi Castelluccio目前的地址：比利时根特根特大学医院这些作者共同监督了这项工作：Roshana Thambyrajah，Anna Bigas。作者和附属机构巴塞罗那德尔马研究所医院癌症研究计划，斯宾罗莎娜·桑比拉贾，玛丽亚·马奎达，马丁·普洛菲特，尤兰达·吉兰，帕特丽夏·埃雷罗·莫利内罗，卡拉·布鲁哈斯，诺埃米·卡斯特卢西奥，杰西卡·冈萨雷斯，阿尔诺·伊格莱西亚斯，劳拉·马鲁埃科斯，克里斯蒂娜·鲁伊斯·赫尔圭多，路易丝·埃斯皮诺萨和安娜·比加·斯约塞普·卡雷拉斯·勒。

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PubMed Google ScholarContributionsA.B., R.T., and L.E. conceptualized the study, designed the experiments, and analyzed data. R.T., W.H.N., P.H., C.B., A.I., J.G., N.C., L.M. and C.R.-H. performed experiments and analyzed data. M.M. and M.P. analyzed the CUT&Tag data. M.C.-P.

PubMed谷歌学术贡献。B、 ，R.T.和L.E.将研究概念化，设计实验并分析数据。R、 T.，W.H.N.，P.H.，C.B.，A.I.，J.G.，N.C.，L.M.和C.R.-H.进行了实验并分析了数据。M、 M.和M.P.分析了切割和标记数据。M、 C.-P。

analyzed the L.S.K. scRNAseq under supervision of E.M. and M.E. Y.G., M.Z.F., G.L. analyzed the E11.5 A.G.M. scRNAseq and Y.G. and M.M. analyzed the bulk RNA-sequencing data of L.T.-HSCs. A.B., R.T., M.M., and G.L. wrote the manuscript.Corresponding authorsCorrespondence to.

在E.M.和M.E.Y.G.，M.Z.F.，G.L.的监督下分析了L.S.K.scRNAseq。分析了E11.5 A.G.M.scRNAseq，Y.G.和M.M.分析了L.T.-HSC的大量RNA测序数据。A、 B.，R.T.，M.M。和G.L.撰写了手稿。通讯作者通讯。

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Reprints and permissionsAbout this articleCite this articleThambyrajah, R., Maqueda, M., Fadlullah, M.Z. et al. IκBα controls dormancy in hematopoietic stem cells via retinoic acid during embryonic development.

转载和许可本文引用本文Thambyrajah，R.，Maqueda，M.，Fadlullah，M.Z.等人。IκBα在胚胎发育过程中通过视黄酸控制造血干细胞的休眠。

Nat Commun 15, 4673 (2024). https://doi.org/10.1038/s41467-024-48854-5Download citationReceived: 14 December 2022Accepted: 14 May 2024Published: 01 June 2024DOI: https://doi.org/10.1038/s41467-024-48854-5Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

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