Differential effects of epigenetic modifiers on the expansion and maintenance of human cord blood stem/progenitor cells.
Differential effects of epigenetic modifiers on the expansion and maintenance of human cord blood stem/progenitor cells.
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DOI：
10.1016/j.bbmt.2013.12.562
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发表时间：
2014-04
期刊：
影响因子：
--
通讯作者：
Araki H
中科院分区：
文献类型：
--
作者：
Mahmud N;Petro B;Baluchamy S;Li X;Taioli S;Lavelle D;Quigley JG;Suphangul M;Araki H
表观遗传疗法，包括DNA甲基转移酶和组蛋白脱乙酰酶（HDAC）抑制剂，越来越多地被认为是治疗血液恶性肿瘤，但它们对正常造血干细胞（HSC）的影响仍然在很大程度上未被探索。我们比较了几种HDAC抑制剂，包括丙戊酸（VPA）和阿司他丁A（TSA），单独使用或与5-氮杂-2 ′-脱氧胞苷（5azaD）联合使用对HSC扩增的影响。与其他HDAC抑制剂或在培养物中顺序添加5azaD/TSA相比，VPA诱导了最高的CD 34 + CD 90+细胞和祖细胞扩增。异种移植研究表明，VPA防止HSC损失，而5azaD/TSA处理导致保留连续移植能力的HSC净扩增。5azaD/TSA介导的HSC扩增与组蛋白乙酰化和瞬时DNA去甲基化增加相关，这与较高的基因转录水平相对应。然而，一些转录水平增加的基因缺乏甲基化的变化。重要的是，全球微阵列分析揭示了5azaD/TSA和VPA扩增的CD 34+细胞中的一组差异表达基因，这些基因可能分别参与可移植HSC的扩增和维持。总之，我们的数据表明，用不同的染色质修饰剂处理HSC导致HSC的扩增或维持，这是具有潜在治疗重要性的观察结果。
Epigenetic therapies, including DNA methyltransferase and histone deacetylase (HDAC) inhibitors, are increasingly being considered to treat hematological malignancies, but their effects on normal hematopoietic stem cells (HSCs) remain largely unexplored. We compared the effects of several HDAC inhibitors, including valproic acid (VPA) and trichostatin A (TSA), alone or in combination with 5-aza-2′-deoxycytidine (5azaD) on the expansion of HSCs. VPA induced the highest expansion of CD34+CD90+ cells and progenitor cells compared with other HDAC inhibitors or the sequential addition of 5azaD/TSA in culture. Xenotransplantation studies demonstrated that VPA prevents HSC loss, whereas 5azaD/TSA treatment leads to a net expansion of HSCs that retain serial transplantation ability. 5azaD/TSA-mediated HSC expansion was associated with increased histone acetylation and transient DNA demethylation, which corresponded with higher gene transcript levels. However, some genes with increased transcript levels lacked changes in methylation. Importantly, a global microarray analysis revealed a set of differentially expressed genes in 5azaD/TSA- and VPA-expanded CD34+ cells that might be involved in the expansion and maintenance of transplantable HSCs, respectively. In summary, our data indicate that treatment of HSCs with different chromatin-modifying agents results in either the expansion or maintenance of HSCs, an observation of potential therapeutic importance.
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影响因子：
20.3
作者：
Milhem, M;Mahmud, N;Hoffman, R
通讯作者：
Hoffman, R
影响因子：
3.8
作者：
Reeves ME;Baldwin SW;Baldwin ML;Chen ST;Moretz JM;Aragon RJ;Li X;Strong DD;Mohan S;Amaar YG
通讯作者：
Amaar YG
影响因子：
2.6
作者：
Araki H;Baluchamy S;Yoshinaga K;Petro B;Petiwala S;Parajuli R;Milhem M;Lavelle D;DeSimone J;Mahmud N
通讯作者：
Mahmud N
DOI：
10.1073/pnas.1116110108
发表时间：
2011-12-13
影响因子：
11.1
作者：
Pang, Wendy W.;Price, Elizabeth A.;Weissman, Irving L.
通讯作者：
Weissman, Irving L.
影响因子：
11.2
作者：
De Felice, LD;Tatarelli, C;Nervi, C
通讯作者：
Nervi, C