Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, 00161 Rome, Italy.
Exp Cell Res. 2012 Feb 15;318(4):400-7. doi: 10.1016/j.yexcr.2011.11.012. Epub 2011 Dec 6.
Hematopoietic stem and progenitor cells (HSPC) can improve the long-term outcome of transplanted individuals and reduce the relapse rate. Valproic acid (VPA), an inhibitor of histone deacetylase, when combined with different cytokine cocktails, induces the expansion of CD34+ cell populations derived from cord blood (CB) and other sources. We evaluated the effect of VPA, in combination with thrombopoietin (TPO), on the viability and expansion of CB-HSPCs and on short- and long-term engraftability in the NOD/SCID mouse model. In vitro, VPA+TPO inhibited HSPC differentiation and preserved the CD34+ cell fraction; the self-renewal of the CD34+ TPO+VPA-treated cells was suggested by the increased replating efficiency. In vivo, short- and long-term engraftment was determined after 6 and 20 weeks. After 6 weeks, the median chimerism percentage was 13.0% in mice transplanted with TPO-treated cells and only 1.4% in those transplanted with TPO+VPA-treated cells. By contrast, after 20 weeks, the engraftment induced by the TPO+VPA-treated cells was three times more effective than that induced by TPO alone, and over ten times more effective compared to the short-term engraftment induced by the TPO+VPA-treated cells. The in vivo results are consistent with the higher secondary plating efficiency of the TPO+VPA-treated cells in vitro.
造血干细胞和祖细胞 (HSPC) 可以改善移植个体的长期预后，降低复发率。组蛋白去乙酰化酶抑制剂丙戊酸 (VPA) 与不同细胞因子鸡尾酒联合使用时，可诱导脐血 (CB) 和其他来源的 CD34+细胞群体扩增。我们评估了 VPA 与血小板生成素 (TPO) 联合使用对 CB-HSPC 活力和扩增的影响，以及在 NOD/SCID 小鼠模型中的短期和长期植入能力。在体外，VPA+TPO 抑制 HSPC 分化并保留 CD34+细胞群；TPO+VPA 处理细胞的自我更新能力通过增加 replating 效率得到证实。在体内，在 6 和 20 周后确定短期和长期植入情况。6 周后，TPO 处理组的嵌合百分比中位数为 13.0%，而 TPO+VPA 处理组仅为 1.4%。相比之下，20 周后，TPO+VPA 处理组诱导的植入效果是 TPO 单独诱导的三倍，是 TPO+VPA 处理组短期诱导的植入效果的十倍以上。体内结果与体外 TPO+VPA 处理组更高的二次培养效率一致。
