Modification of hematopoietic stem cell fate by 5aza 2′deoxycytidine and trichostatin A
Modification of hematopoietic stem cell fate by 5aza 2′deoxycytidine and trichostatin A
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DOI：
10.1182/blood-2003-07-2431
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发表时间：
2004-06-01
期刊：
影响因子：
20.3
通讯作者：
Hoffman, R
中科院分区：
文献类型：
--
作者：
Milhem, M;Mahmud, N;Hoffman, R
在体外改变人类造血干细胞（hsc）和祖细胞（HPCs）命运的努力取得了有限的成功。我们假设先前在体外条件下使用可能导致维持原始hsc /HPCs所需的基因沉默。DNA甲基化和组蛋白去乙酰化是调控基因表达的表观遗传程序的组成部分。我们在体外使用可能干扰DNA甲基化和组蛋白去乙酰化的药物，试图维持和扩增具有原始hsc /HPCs表型和功能特征的细胞。将人骨髓CD34（+）细胞暴露于与5aza 2'脱氧胞苷（5azaD）和trichostatin a （TSA）结合的有利于分化的细胞因子混合物中，导致CD34（+）细胞亚群的显著扩增，这些细胞亚群具有表型特性以及原始hsc /HpCs的增殖潜力特征。此外，5azaD-和tsa预处理的细胞，而不是单独暴露于细胞因子的CD34（+）细胞，保留了重新填充免疫缺陷小鼠的能力。我们的研究结果表明，5azaD和TSA可以在体外培养过程中改变原始hsc /HPCs的命运。(C) 2004年由美国血液病学会出版
Efforts to change the fate of human hematopoietic stem cells (HSCs) and progenitor cells (HPCs) in vitro have met with limited success. We hypothesized that previously utilized in vitro conditions might result in silencing of genes required for the maintenance of primitive HSCs/HPCs. DNA methylation and histone deacetylation are components of an epigenetic program that regulates gene expression. Using pharmacologic agents in vitro that might possibly interfere with DNA methylation and histone deacetylation, we attempted to maintain and expand cells with phenotypic and functional characteristics of primitive HSCs/HPCs. Human marrow CD34(+) cells were exposed to a cytokine cocktail favoring differentiation in combination with 5aza 2' deoxycytidine (5azaD) and trichostatin A (TSA), resulting in a significant expansion of a subset of CD34(+) cells that possessed phenotypic properties as well as the proliferative potential characteristic of primitive Hscs/HpCs. In addition, 5azaD- and TSA-pretreated cells but not the CD34(+) cells exposed to cytokines alone retained the ability to repopulate immunodeficient mice. Our findings demonstrate that 5azaD and TSA can be used to alter the fate of primitive HSCs/HPCs during in vitro culture. (C) 2004 by The American Society of Hematology