Valproic Acid Increases CXCR4 Expression in Hematopoietic Stem/Progenitor Cells by Chromatin Remodeling
Valproic Acid Increases CXCR4 Expression in Hematopoietic Stem/Progenitor Cells by Chromatin Remodeling
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DOI：
10.1089/scd.2008.0235
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发表时间：
2009-07-01
影响因子：
4
通讯作者：
Janowska-Wieczorek, Anna
中科院分区：
文献类型：
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作者：
Gul, Hilal;Marquez-Curtis, Leah A.;Janowska-Wieczorek, Anna
脐带血（CB）造血干/祖细胞（HSPC）移植在成人患者中的一个主要限制是可用的细胞剂量低，这与移植延迟或失败有关。这促使深入研究开发新的策略来改善HSPC植入和重建。趋化因子受体CXCR 4及其配体基质细胞衍生因子（SDF）-1 α在HSPC的归巢和再增殖能力中起着至关重要的作用。我们假设在HSPC中，CXCR 4受体通过组蛋白脱乙酰酶抑制剂（HDIs）如丙戊酸（VPA）通过染色质重塑进行调节。使用CB CD 34（+）细胞和表达CD 34抗原的未成熟造血细胞模型，即白血病细胞系KG-1a和KG-1，我们发现VPA增加了这些细胞中表面和mRNA CXCR 4水平，从而增强了它们向SDF-1 α梯度的迁移。我们还发现VPA对CXCR 4基因转录的调节与CB CD 34（+）和KG-1细胞中组蛋白H4的乙酰化状态相关。因此，我们认为在CB移植中，用VPA引发HSPCs可以改善归巢和植入。
A major limitation of cord blood (CB) hematopoietic stem/progenitor cell (HSPC) transplantation in adult patients is the low cell dose available, which is associated with delayed or failed engraftment. This has prompted intensive research to develop novel strategies to improve HSPC engraftment and reconstitution. The chemokine receptor CXCR4 and its ligand stromal cell-derived factor (SDF)-1 alpha play a crucial role in the homing and repopulation capacity of HSPCs. We hypothesized that in HSPCs the CXCR4 receptor is regulated through chromatin remodeling by histone deacetylase inhibitors (HDIs) such as valproic acid (VPA). Using CB CD34(+) cells and the models of immature hematopoietic cells expressing CD34 antigen, namely the leukemic cell lines KG-1a and KG-1, we found that VPA increases surface and mRNA CXCR4 levels in these cells, thereby enhancing their migration toward an SDF-1 alpha gradient. We also found that modulation of CXCR4 gene transcription by VPA correlates with the acetylation status of histone H4 in CB CD34(+) and KG-1 cells. Hence we suggest that in CB transplantation priming of HSPCs with VPA could improve homing and engraftment.