脐血扩增。嘧啶吲哚衍生物是人类造血干细胞自我更新的激动剂。
Cord blood expansion. Pyrimidoindole derivatives are agonists of human hematopoietic stem cell self-renewal.
作者信息
Fares Iman, Chagraoui Jalila, Gareau Yves, Gingras Stéphane, Ruel Réjean, Mayotte Nadine, Csaszar Elizabeth, Knapp David J H F, Miller Paul, Ngom Mor, Imren Suzan, Roy Denis-Claude, Watts Kori L, Kiem Hans-Peter, Herrington Robert, Iscove Norman N, Humphries R Keith, Eaves Connie J, Cohen Sandra, Marinier Anne, Zandstra Peter W, Sauvageau Guy
机构信息
Molecular Genetics of Stem Cells Laboratory, Institute of Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, QC, Canada.
Medicinal Chemistry, IRIC, University of Montreal, Montreal, QC, Canada.
出版信息
Science. 2014 Sep 19;345(6203):1509-12. doi: 10.1126/science.1256337.
Abstract
The small number of hematopoietic stem and progenitor cells in cord blood units limits their widespread use in human transplant protocols. We identified a family of chemically related small molecules that stimulates the expansion ex vivo of human cord blood cells capable of reconstituting human hematopoiesis for at least 6 months in immunocompromised mice. The potent activity of these newly identified compounds, UM171 being the prototype, is independent of suppression of the aryl hydrocarbon receptor, which targets cells with more-limited regenerative potential. The properties of UM171 make it a potential candidate for hematopoietic stem cell transplantation and gene therapy.
摘要
脐带血单位中造血干细胞和祖细胞数量较少，限制了它们在人类移植方案中的广泛应用。我们鉴定出了一类化学结构相关的小分子，它们能在体外刺激人类脐带血细胞的扩增，这些细胞能够在免疫缺陷小鼠体内重建人类造血功能至少6个月。这些新鉴定出的化合物（以UM171为原型）的强大活性独立于芳烃受体的抑制作用，芳烃受体靶向具有更有限再生潜力的细胞。UM171的特性使其成为造血干细胞移植和基因治疗的潜在候选物。
相似文献
1
Cord blood expansion. Pyrimidoindole derivatives are agonists of human hematopoietic stem cell self-renewal.脐血扩增。嘧啶吲哚衍生物是人类造血干细胞自我更新的激动剂。
Science. 2014 Sep 19;345(6203):1509-12. doi: 10.1126/science.1256337.
2
Small molecule regulation of normal and leukemic stem cells.小分子对正常干细胞和白血病干细胞的调控
Curr Opin Hematol. 2015 Jul;22(4):309-16. doi: 10.1097/MOH.0000000000000151.
3
Hematopoietic stem cell transplantation using single UM171-expanded cord blood: a single-arm, phase 1-2 safety and feasibility study.使用单一UM171扩增脐血的造血干细胞移植：一项单臂1-2期安全性和可行性研究。
Lancet Haematol. 2020 Feb;7(2):e134-e145. doi: 10.1016/S2352-3026(19)30202-9. Epub 2019 Nov 6.
4
Effects of Eupalinilide E and UM171, alone and in combination on cytokine stimulated ex-vivo expansion of human cord blood hematopoietic stem cells.Eupalinilide E 和 UM171 单独及联合对细胞因子刺激的人脐血造血干祖细胞体外扩增的影响。
Blood Cells Mol Dis. 2020 Sep;84:102457. doi: 10.1016/j.bcmd.2020.102457. Epub 2020 Jun 1.
5
Synthesis and evaluation of pyrimidoindole analogs in umbilical cord blood ex vivo expansion.在脐血体外扩增中嘧啶并吲哚类似物的合成与评价。
Eur J Med Chem. 2019 Jul 15;174:181-197. doi: 10.1016/j.ejmech.2019.04.042. Epub 2019 Apr 22.
6
EPCR expression marks UM171-expanded CD34 cord blood stem cells.EPCR 表达标志着 UM171 扩增的 CD34 脐血干细胞。
Blood. 2017 Jun 22;129(25):3344-3351. doi: 10.1182/blood-2016-11-750729. Epub 2017 Apr 13.
7
Medicine. The blood stem cell Holy Grail?医学。血液干细胞是圣杯吗？
Science. 2010 Sep 10;329(5997):1291-2. doi: 10.1126/science.1195173.
8
Pyrimidoindole derivative UM171 enhances derivation of hematopoietic progenitor cells from human pluripotent stem cells.嘧啶并吲哚衍生物UM171可增强人多能干细胞向造血祖细胞的分化。
Stem Cell Res. 2017 May;21:32-39. doi: 10.1016/j.scr.2017.03.014. Epub 2017 Mar 21.
9
Comparison of Different Cytokine Conditions Reveals Resveratrol as a New Molecule for Ex Vivo Cultivation of Cord Blood-Derived Hematopoietic Stem Cells.不同细胞因子条件的比较揭示白藜芦醇是用于脐血来源造血干细胞体外培养的新分子。
Stem Cells Transl Med. 2015 Sep;4(9):1064-72. doi: 10.5966/sctm.2014-0284. Epub 2015 Jul 9.
10
Ex Vivo Expansion of CD34 CD90 CD49f Hematopoietic Stem and Progenitor Cells from Non-Enriched Umbilical Cord Blood with Azole Compounds.利用唑类化合物对非富集脐血中的CD34 CD90 CD49f造血干细胞和祖细胞进行体外扩增。
Stem Cells Transl Med. 2018 May;7(5):376-393. doi: 10.1002/sctm.17-0251. Epub 2018 Feb 2.
引用本文的文献
1
Decreased non-neurogenic acetylcholine in bone marrow triggers age-related defective stem/progenitor cell homing.骨髓中非神经源性乙酰胆碱减少引发与年龄相关的干/祖细胞归巢缺陷。
Nat Commun. 2025 Jul 1;16(1):5475. doi: 10.1038/s41467-025-60515-9.
2
CoREST in pieces: Dismantling the CoREST complex for cancer therapy and beyond.CoREST分解：为癌症治疗及其他领域拆解CoREST复合物
Sci Adv. 2025 Jun 6;11(23):eads6556. doi: 10.1126/sciadv.ads6556.
3
Structural mimicry of UM171 and neomorphic cancer mutants co-opts E3 ligase KBTBD4 for HDAC1/2 recruitment.UM171与新形态癌症突变体的结构模拟利用E3连接酶KBTBD4招募HDAC1/2。
Nat Commun. 2025 Apr 2;16(1):3144. doi: 10.1038/s41467-025-58350-z.
4
Regulation of HSC development and function by Lin28b.Lin28b对造血干细胞发育和功能的调控
Front Cell Dev Biol. 2025 Mar 12;13:1555877. doi: 10.3389/fcell.2025.1555877. eCollection 2025.
5
Very small embryonic-like stem cells (VSELs) on the way for potential applications in regenerative medicine.非常小的胚胎样干细胞（VSELs）有望应用于再生医学。
Front Bioeng Biotechnol. 2025 Mar 7;13:1564964. doi: 10.3389/fbioe.2025.1564964. eCollection 2025.
6
DNA-PK inhibition enhances gene editing efficiency in HSPCs for CRISPR-based treatment of X-linked hyper IgM syndrome.DNA依赖性蛋白激酶（DNA-PK）抑制可提高造血干细胞（HSPCs）中的基因编辑效率，用于基于CRISPR的X连锁高免疫球蛋白M综合征治疗。
Mol Ther Methods Clin Dev. 2024 Jul 27;32(3):101297. doi: 10.1016/j.omtm.2024.101297. eCollection 2024 Sep 12.
7
Molecular glue unexpectedly mimics the effect of cancer mutations.分子胶意外地模拟了癌症突变的效果。
Nature. 2025 Mar;639(8053):42-43. doi: 10.1038/d41586-025-00090-7.
8
Converging mechanism of UM171 and KBTBD4 neomorphic cancer mutations.UM171与KBTBD4新形态癌症突变的汇聚机制
Nature. 2025 Mar;639(8053):241-249. doi: 10.1038/s41586-024-08533-3. Epub 2025 Feb 12.
9
UM171 glues asymmetric CRL3-HDAC1/2 assembly to degrade CoREST corepressors.UM171 结合不对称的CRL3-HDAC1/2 组装体以降解 CoREST 共抑制因子。
Nature. 2025 Mar;639(8053):232-240. doi: 10.1038/s41586-024-08532-4. Epub 2025 Feb 12.
10
Protocol for the generation of HLF+ HOXA+ human hematopoietic progenitor cells from pluripotent stem cells.从多能干细胞生成HLF+HOXA+人类造血祖细胞的方案。
STAR Protoc. 2025 Mar 21;6(1):103592. doi: 10.1016/j.xpro.2024.103592. Epub 2025 Jan 24.
本文引用的文献
1
HLA match likelihoods for hematopoietic stem-cell grafts in the U.S. registry.美国注册中心造血干细胞移植供者 HLA 配型概率。
N Engl J Med. 2014 Jul 24;371(4):339-48. doi: 10.1056/NEJMsa1311707.
2
Analysis of the clonal growth and differentiation dynamics of primitive barcoded human cord blood cells in NSG mice.分析原始条码化人脐血细胞在 NSG 小鼠中的克隆生长和分化动力学。
Blood. 2013 Oct 31;122(18):3129-37. doi: 10.1182/blood-2013-06-508432. Epub 2013 Sep 12.
3
Genotypic and functional diversity of phenotypically defined primitive hematopoietic cells in patients with chronic myeloid leukemia.慢性髓性白血病患者表型定义的原始造血细胞的基因型和功能多样性。
Exp Hematol. 2013 Oct;41(10):837-47. doi: 10.1016/j.exphem.2013.07.001. Epub 2013 Jul 11.
4
Heterogeneity in hematopoietic stem cell populations: implications for transplantation.造血干细胞群体的异质性：对移植的影响。
Curr Opin Hematol. 2013 Jul;20(4):257-64. doi: 10.1097/MOH.0b013e328360aaf6.
5
Umbilical cord blood graft enhancement strategies: has the time come to move these into the clinic?脐带血移植物增强策略：是否到了将这些策略推向临床应用的时机？
Bone Marrow Transplant. 2013 Jul;48(7):884-9. doi: 10.1038/bmt.2012.163. Epub 2012 Sep 3.
6
Hematopoietic stem cell subtypes expand differentially during development and display distinct lymphopoietic programs.造血干细胞亚型在发育过程中会以不同的方式扩增，并表现出不同的淋巴造血程序。
Cell Stem Cell. 2012 Mar 2;10(3):273-83. doi: 10.1016/j.stem.2012.02.007.
7
Rapid expansion of human hematopoietic stem cells by automated control of inhibitory feedback signaling.自动化控制抑制反馈信号促进人类造血干细胞的快速扩增。
Cell Stem Cell. 2012 Feb 3;10(2):218-29. doi: 10.1016/j.stem.2012.01.003.
8
Small-molecule regulators of human stem cell self-renewal.人类干细胞自我更新的小分子调节剂
Chembiochem. 2011 Apr 11;12(6):854-7. doi: 10.1002/cbic.201000734. Epub 2011 Mar 4.
9
Aryl hydrocarbon receptor antagonists promote the expansion of human hematopoietic stem cells.芳基烃受体拮抗剂促进人类造血干细胞的扩增。
Science. 2010 Sep 10;329(5997):1345-8. doi: 10.1126/science.1191536. Epub 2010 Aug 5.
10
Allogeneic hematopoietic cell transplantation for hematologic malignancy: relative risks and benefits of double umbilical cord blood.异基因造血细胞移植治疗血液系统恶性肿瘤：双脐血的相对风险和获益。
Blood. 2010 Nov 25;116(22):4693-9. doi: 10.1182/blood-2010-05-285304. Epub 2010 Aug 4.
Zotero 插件