MYCT1控制人类造血干细胞的环境传感-动脉网

MYCT1 controls environmental sensing in human haematopoietic stem cells

Nature 等信源发布 2024-06-05 22:58

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AbstractThe processes that govern human haematopoietic stem cell (HSC) self-renewal and engraftment are poorly understood and challenging to recapitulate in culture to reliably expand functional HSCs1,2,3. Here we identify MYC target 1 (MYCT1; also known as MTLC) as a crucial human HSC regulator that moderates endocytosis and environmental sensing in HSCs.

摘要控制人类造血干细胞（HSC）自我更新和植入的过程知之甚少，并且难以在培养中重现以可靠地扩增功能性HSC 1,2,3。在这里，我们确定MYC靶标1（MYCT1；也称为MTLC）是一种关键的人类HSC调节剂，可调节HSC的内吞作用和环境感应。

MYCT1 is selectively expressed in undifferentiated human haematopoietic stem and progenitor cells (HSPCs) and endothelial cells but becomes markedly downregulated during HSC culture. Lentivirus-mediated knockdown of MYCT1 prevented human fetal liver and cord blood (CB) HSPC expansion and engraftment.

MYCT1在未分化的人类造血干细胞和祖细胞（HSPC）和内皮细胞中选择性表达，但在HSC培养过程中显着下调。慢病毒介导的MYCT1敲低阻止了人胎肝和脐带血（CB）HSPC的扩增和植入。

By contrast, restoring MYCT1 expression improved the expansion and engraftment of cultured CB HSPCs. Single-cell RNA sequencing of human CB HSPCs in which MYCT1 was knocked down or overexpressed revealed that MYCT1 governs important regulatory programmes and cellular properties essential for HSC stemness, such as ETS factor expression and low mitochondrial activity.

相比之下，恢复MYCT1表达改善了培养的CB HSPC的扩增和植入。其中MYCT1被敲低或过表达的人CB HSPC的单细胞RNA测序显示MYCT1控制HSC干性所必需的重要调节程序和细胞特性，例如ETS因子表达和低线粒体活性。

MYCT1 is localized in the endosomal membrane in HSPCs and interacts with vesicle trafficking regulators and signalling machinery. MYCT1 loss in HSPCs led to excessive endocytosis and hyperactive signalling responses, whereas restoring MYCT1 expression balanced culture-induced endocytosis and dysregulated signalling.

MYCT1位于HSPC的内体膜中，并与囊泡运输调节剂和信号传导机制相互作用。HSPC中MYCT1的丢失导致过度的内吞作用和过度活跃的信号传导反应，而恢复MYCT1表达平衡培养诱导的内吞作用和信号失调。

Moreover, sorting cultured CB HSPCs on the basis of lowest endocytosis rate identified HSPCs with preserved MYCT1 expression and MYCT1-regulated HSC stemness programmes. Our work identifies MYCT1-moderated endocytosis and environmental sensing as essential regulatory mechanisms required to preserve human HSC stemness.

此外，根据最低的内吞率分选培养的CB HSPC，鉴定出具有保留的MYCT1表达和MYCT1调节的HSC干性程序的HSPC。我们的工作将MYCT1介导的内吞作用和环境感应确定为保护人类HSC干性所需的基本调节机制。

Our data also pinpoint silencing of MYCT1 as a cell-culture-induced vulnerability that compromises human HSC expansion..

我们的数据还指出，沉默MYCT1是一种细胞培养诱导的脆弱性，会损害人类HSC的扩增。。

MainHSCs sustain blood formation throughout life owing to their ability to respond to microenvironmental cues to balance self-renewal and differentiation. HSCs can provide life-saving therapy for patients with haematological malignancies and patients with inherited blood disorders. But access to HSC transplantation is limited by the difficulty in finding immune-compatible bone marrow (BM) donors and the low quantity of HSCs in cord blood (CB)1,2,3.

MainHSC在整个生命过程中维持血液形成，因为它们能够响应微环境线索以平衡自我更新和分化。造血干细胞可以为血液系统恶性肿瘤患者和遗传性血液疾病患者提供挽救生命的治疗。但是，由于难以找到免疫相容的骨髓（BM）供体以及脐带血（CB）1,2,3中HSC的含量低，HSC移植的途径受到限制。

Thus, it has been a long-standing goal to optimize the cell culture environment to expand human HSCs ex vivo4,5. However, transfer of human HSCs from their niche to culture results in extensive changes in transcriptome, epigenome, signalling, metabolism, proteostasis and other cellular functions that severely compromise HSC function4,6,7,8,9,10,11.The diverse approaches available to recapitulate human HSC self-renewal ex vivo include co-culture with niche cells such as BM mesenchymal stromal cells9,12 or endothelial cells (ECs)13, and 3D cultures within a hydrophilic matrix11.

因此，优化细胞培养环境以体外扩增人类HSC一直是一个长期目标4,5。然而，将人类HSC从其生态位转移到培养物中会导致转录组，表观基因组，信号传导，代谢，蛋白质稳态和其他细胞功能的广泛变化，从而严重损害HSC功能4,6,7,8,9,10,11。可用于概括人类HSC离体自我更新的多种方法包括与生态位细胞（如BM间充质基质细胞9,12或内皮细胞（EC）13）和亲水基质中的3D培养物11共培养。

Other methods include supplementation of HSC cytokines with HSC-supportive small molecules such as SR1 (ref. 14) or UM171 (ref. 15), and albumin-free conditions that replace cytokines with chemical agonists16. Moreover, transcriptional regulators that can promote human HSC expansion in culture, such as MLLT3 (ref.

其他方法包括用HSC支持性小分子如SR1（参考文献14）或UM171（参考文献15）补充HSC细胞因子，以及用化学激动剂替代细胞因子的无白蛋白条件16。此外，可以促进人类HSC在培养物中扩增的转录调节因子，如MLLT3（参考文献）。

10) and MSI2 (ref. 17), have been discovered and functionally validated following transplantation. Another goal is to identify molecular markers that indicate the preservation of HSC properties. Recent advances include more specific surface markers for cultured human HSCs, such as EPCR18, ITGA3 (ref.

10）和MSI2（参考文献17）已在移植后被发现并进行了功能验证。另一个目标是鉴定表明HSC特性保存的分子标记。最近的进展包括培养的人HSC的更具特异性的表面标记，如EPCR18，ITGA3（参考文献）。

19) and RET20, and signature genes in the HSC transcriptome (for example, MLLT3 (ref. 10), HLF21,22 and MECOM23). Desirable cellular characterist.

19）和RET20，以及HSC转录组中的特征基因（例如MLLT3（参考文献10），HLF21,22和MECOM23）。理想的细胞特征。

Data availability

数据可用性

The RNA-seq and scRNA-seq datasets generated during the current study are available at the GEO under the accession codes GSE233478 (bulk RNA-seq for human haematopoietic populations), GSE232360 (bulk RNA-seq for KG1 and E4EC), GSE232361 (scRNA-seq of MYCT1 OE and KD) and GSE254857 (scRNA-seq of endocytosis fractions).

本研究期间产生的RNA-seq和scRNA-seq数据集可在GEO获得，登录号为GSE233478（人类造血群体的大量RNA-seq），GSE232360（KG1和E4EC的大量RNA-seq），GSE232361（MYCT1 OE和KD的scRNA-seq）和GSE254857（内吞作用部分的scRNA-seq）。

The MS and phospho MS datasets are available at PRIDE under the accession code PXD042257. There are no restrictions on data availability. Published data from ref. 41 are available under GSE175400. Published data are available in table S1 of ref. 28, table S3 of ref. 19 and table S3 of ref. 9. Published data from ref.

MS和phospho-MS数据集可在PRIDE获得，登录号为PXD042257。数据可用性没有限制。参考文献41中公布的数据可在GSE175400下获得。公布的数据可在参考文献28的表S1，参考文献19的表S3和参考文献9的表S3中获得。参考文献中发布的数据。

10 are available at the GEO under accession GSE111483. Source data are provided with this paper..

10可在GEO获得，登录号为GSE111483。本文提供了源数据。。

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Download referencesAcknowledgementsWe thank the staff at the BSCRC flow cytometry and microscopy cores, the Jonsson Comprehensive Cancer Center Flow Cytometry Shared Resource, and the Technology Center for Genomics & Bioinformatics sequencing cores (supported by P30CA016042 from NCI) at UCLA; the Next Generation Sequencing Core Facility at the Salk Institute for Biological Studies; the CryoCell team at Cedars-Sinai for their help with CB collection; and S. Rafii for providing the E4EC cell line.

下载参考文献致谢我们感谢加州大学洛杉矶分校BSCRC流式细胞术和显微镜核心，Jonsson综合癌症中心流式细胞术共享资源以及基因组学和生物信息学测序核心技术中心（由NCI的P30CA016042支持）的工作人员；索尔克生物研究所的下一代测序核心设施；Cedars Sinai的CryoCell团队帮助收集CB；和S.Rafii提供E4EC细胞系。

Schematics depicting experimental outlines in Figs. 3a and 4e and Extended Data Figs. 2c, 4a, 11c and 12a,d,h,l were created with BioRender (https://www.biorender.com). This work was supported by 5R01DK100959, 1R01HL162408, 1RO1DK125097 and 1R01DK121557 (to H.K.A.M); the Swiss National Science Foundation (P2ZHP3_178113), European Molecular Biology Organization (ALTF 433-2019) (to J.A.-G.); BSCRC post-doctoral fellowships (to J.A.-G., I.F.

图3a和4e中描绘实验轮廓的示意图以及扩展数据图2c，4a，11c和12a，d，h，l是用BioRender创建的(https://www.biorender.com)。这项工作得到了5R01DK100959、1R01HL162408、1RO1DK125097和1R01DK121557（致H.K.A.M）的支持；瑞士国家科学基金会（P2ZHP3\U 178113），欧洲分子生物学组织（ALTF 433-2019）（致J.A.-G.）；BSCRC博士后奖学金（授予J.A.-G.，I.F。

and V.C.); Jonsson Comprehensive Cancer Center fellowship (to J.A.-G.); Sir Henry Dale Fellowship (jointly funded by Wellcome and the Royal Society, 221978/Z/20/Z, to V.C.), T32 HL-086345-13 Developmental Haematology fellowship (to I.F.); funds from the Board of Governors Regenerative Medicine Institute at Cedars-Sinai Medical Center (to H.S.G); NIH GM153408 (to J.W); NIH P30AI152501 (to the UCLA CFAR Humanized Mouse and Gene Therapy Core); and the UCLA AIDS Institute, the James B.

和V.C.）；琼森综合癌症中心奖学金（致J.A.-G.）；亨利·戴尔爵士奖学金（由惠康和皇家学会联合资助，221978/Z/20/Z，授予V.C.），T32 HL-086345-13发育血液学奖学金（授予I.F.）；雪松西奈医学中心理事会再生医学研究所（H.S.G）的资金；NIH GM153408（致J.W）；NIH P30AI152501（至加州大学洛杉矶分校CFAR人源化小鼠和基因治疗核心）；和加州大学洛杉矶分校艾滋病研究所，詹姆斯B。

Pendleton Charitable Trust, and the McCarthy Family Foundation. This research was made possible by a grant to GMC from the California Institute of Regenerative Medicine (GC1R-06673-B [CRP]). The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of CIRM or any other agency of t.

彭德尔顿慈善信托基金会和麦卡锡家族基金会。这项研究是由加州再生医学研究所（GC1R-06673-B[CRP]）向GMC提供的资助实现的。本出版物的内容仅由作者负责，不一定代表CIRM或t的任何其他机构的官方观点。

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PubMed Google ScholarContributionsJ.A.-G. and H.K.A.M. designed experiments and interpreted data. J.A.-G. performed and/or supervised all experiments and related data analyses. Y.J.-A. performed MS and phospho MS assays and processed the raw data. J.A.W. assisted with design and data interpretation of MS experiments.

PubMed谷歌学术贡献。A、 -G.和H.K.A.M.设计了实验并解释了数据。J、 A.-G.执行和/或监督所有实验和相关数据分析。Y、 J.-A.进行了MS和磷酸化MS分析，并处理了原始数据。J、 A.W.协助MS实验的设计和数据解释。

V.C. and M.M. generated MYCT1 KD and OE vectors. V.C. was responsible for the RNA-seq analysis of the human embryonic, fetal and post-natal haematopoietic tissues, which was overseen by G.M.C. and H.K.A.M. V.C. also assisted with data interpretation and contextualization. I.F. performed IP for MS. M.K.

五、 C.和M.M.产生了MYCT1 KD和OE载体。五、 C.负责人类胚胎，胎儿和产后造血组织的RNA-seq分析，由G.M.C.和H.K.A.M.V.C.监督，还协助数据解释和背景分析。一、 F.为M.K.女士执行IP。

and H.J. assisted in wet laboratory experiments. V.R. and Y.W. contributed to the transplantation experiments in NSG and NBSGW mice. F.M. assisted with the bioinformatics analysis of scRNA-seq data. J.E.S., K.J.N. and H.S.G. coordinated CB collection and procurement, and Y.W. performed CB purifications.

和H.J.协助湿实验室实验。五、 R.和Y.W.为NSG和NBSGW小鼠的移植实验做出了贡献。F、 M.协助scRNA-seq数据的生物信息学分析。J、 E.S.，K.J.N.和H.S.G.协调CB收集和采购，Y.W.进行CB纯化。

S.L. and K.S.-L. coordinated the collection and procurement of human developmental tissues. J.A.-G. and H.K.A.M wrote the manuscript, which all of the authors read and approved.Corresponding authorsCorrespondence to.

S、 L.和K.S.-L.协调人类发育组织的收集和采购。J、 A.-G.和H.K.A.M撰写了手稿，所有作者都阅读并批准了手稿。通讯作者通讯。

Júlia Aguadé-Gorgorió or Hanna K. A. Mikkola.Ethics declarations

Júlia Aguadé-Gorgorióor Hanna K.A.Mikkola。道德宣言

Competing interests

相互竞争的利益

The authors declare the following competing interests: H.K.A.M is a scientific advisory board member for Notch therapeutics and a consultant for MaroBio. H.K.A.M. and J.A.-G. have submitted a provisional patent application based on the work presented here (“Methods and compositions for haematopoietic stem cell enhancement”; PCT patent application submitted; institution: UCLA; inventors: H.K.A.M.

作者声明了以下相互竞争的利益：H.K.A.M是Notch therapeutics的科学顾问委员会成员和MaroBio的顾问。H.K.A.M.和J.A.-G.根据此处介绍的工作提交了临时专利申请（“造血干细胞增强的方法和组成”；提交的PCT专利申请；机构：加州大学洛杉矶分校；发明人：H.K.A.M。

and J.A.-G.), covering increasing expression and/or activity of MYCT1 and controlling endocytosis in cultured HSCs to improve transplantability and/or provide better in vitro models for pluripotent stem cell-derived haematopoiesis. All other authors declare no competing interests..

和J.A.-G.），涵盖增加MYCT1的表达和/或活性以及控制培养的HSC中的内吞作用，以提高移植性和/或为多能干细胞衍生的造血提供更好的体外模型。所有其他作者声明没有利益冲突。。

Peer review

同行评审

Peer review information

同行评审信息

Nature thanks David Kent and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

《自然》杂志感谢大卫·肯特和另一位匿名审稿人为这项工作的同行评审做出的贡献。

Additional informationPublisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.Extended data figures and tablesExtended Data Fig. 1 Silencing of MYCT1 expression in cultured human HSPCs.a MYCT1 expression in human sorted hematopoietic populations from the DMAP dataset29,31.

Additional informationPublisher的注释Springer Nature在已发布的地图和机构隶属关系中的管辖权主张方面保持中立。扩展数据图和表扩展数据图1培养的人HSPC中MYCT1表达的沉默。来自DMAP数据集的人类分选造血群体中的MYCT1表达29,31。

b Myct1 expression in mouse hematopoietic populations from Bloodspot31. c-g Relative expression of MYCT1 and other HSC regulatory genes in sorted FL or CB HSPCs that were isolated freshly and after culture in different conditions. c Microarray analysis of CD34+CD38−CD90+FL HSPCs co-cultured with OP9 stroma supplemented with cytokines as indicated9.

b Myct1在来自Bloodspot31的小鼠造血群体中的表达。在新鲜分离和在不同条件下培养后分离的分选的FL或CB HSPC中MYCT1和其他HSC调节基因的c-g相对表达。c如所示，与补充有细胞因子的OP9基质共培养的CD34+CD38-CD90+FL HSPC的微阵列分析9。

Mean±s.e.m. of all available microarray probes for MYCT1 (2), MECOM (5), and RUNX1 (10) from n = 3 (uncultured and week 2) or n = 2 (week 5) independent experiments. d RNAseq analysis of CD34+CD38−CD90+CD45RA-CD49f+ CB LT-HSPC cultured without stroma as indicated28. e RT-qPCR of CD34+CD38−CD90+ CB HSPCs co-cultured with E4EC13 as indicated.

来自n=3（未培养和第2周）或n=2（第5周）独立实验的MYCT1（2），MECOM（5）和RUNX1（10）的所有可用微阵列探针的平均值±标准差。d如所示，在没有基质的情况下培养的CD34+CD38-CD90+CD45RA-CD49f+CB LT-HSPC的RNAseq分析28。如所示，与E4EC13共培养的CD34+CD38-CD90+CB HSPC的RT-qPCR。

n = 2 experiments, mean and individual data points. f,g Gene expression (RNAseq) and UCSC genome browser tracks of MYCT1 and MECOM genomic regions showing RNA seq and Chip-seq of histone marks in CD34+CD38−CD90+ FL HSPCs isolated freshly or co-cultured with OP9 stroma as indicated10. Gene expression is from n = 3 (uncultured) or n = 2 (week 4) experiments, mean with individual data points.Source DataExtended Data Fig.

n=2个实验，平均值和单个数据点。f、 g基因表达（RNAseq）和UCSC基因组浏览器跟踪MYCT1和MECOM基因组区域，显示新鲜分离或与OP9基质共培养的CD34+CD38-CD90+FL HSPC中组蛋白标记的RNA-seq和Chip-seq。基因表达来自n=3（未培养）或n=2（第4周）实验，平均值为单个数据点。源数据扩展数据图。

2 Validation of MYCT1 knockdown and its effects in cord blood HSPCs.a,b Validating MYCT1 knockdown. a Relative MYCT1 expression by RT-qPCR in control or MYCT1 knockdown (KD) sorted CB HSPCs (CD34+CD38−CD90+) 72 h post-transduction. Mean±s.e.m, two-tailed paired t-test, n = 3 (KD1) or mean, n = 2 (KD2) independent experiments.

2验证MYCT1敲低及其在脐带血HSPC中的作用。a，b验证MYCT1敲低。转导后72小时，通过RT-qPCR在对照或MYCT1敲低（KD）分选的CB HSPC（CD34+CD38-CD90+）中相对MYCT1表达。平均值±s.e.m，双尾配对t检验，n=3（KD1）或平均值，n=2（KD2）独立实验。

b W.

b W。

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Reprints and permissionsAbout this articleCite this articleAguadé-Gorgorió, J., Jami-Alahmadi, Y., Calvanese, V. et al. MYCT1 controls environmental sensing in human haematopoietic stem cells.

转载和许可本文引用本文Aguadé-Gorgorió，J.，Jami Alahmadi，Y.，Calvanese，V。等人。MYCT1控制人类造血干细胞中的环境感应。

Nature (2024). https://doi.org/10.1038/s41586-024-07478-xDownload citationReceived: 30 May 2023Accepted: 26 April 2024Published: 05 June 2024DOI: https://doi.org/10.1038/s41586-024-07478-xShare 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.

《自然》（2024）。https://doi.org/10.1038/s41586-024-07478-xDownload引文接收日期：2023年5月30日接收日期：2024年4月26日发布日期：2024年6月5日OI：https://doi.org/10.1038/s41586-024-07478-xShare本文与您共享以下链接的任何人都可以阅读此内容：获取可共享链接对不起，本文目前没有可共享的链接。复制到剪贴板。

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