Kaur Kiranpreet, Mirlashari Mohammad Reza, Kvalheim Gunnar, Kjeldsen-Kragh Jens
Stem Cell Res Ther. 2013 May 24;4(3):60. doi: 10.1186/scrt208.
Human hematopoietic stem cells (HSCs) have been clinically used for transplantation and gene and cellular therapy for more than 4 decades. However, this use is limited because of the challenges in the ex vivo culturing of HSCs. The major hurdle is to amplify these cells without losing their self-renewing property.
In our study, we tested 3',4'-dimethoxyflavone (3'4'-DMF) and valproic acid (VPA) on the ex vivo expansion of HSCs under both normoxic (20% O2) and hypoxic (1% O2) conditions. 3'4'-DMF is a widely used anticancer drug that acts as a competitive antagonist of the aryl hydrocarbon receptor. VPA is a potent inhibitor of histone deacetylase and is used in the treatment of neurologic disorders.
Culturing HSCs (from mobilized peripheral blood) under normoxia, with 3'4'-DMF and VPA, highly preserved the CD34 positivity (3'4'-DMF, 22.1%, VPA, 20.3%) after 1 week and strongly enhanced the CD34(+) cells (3'4'-DMF, 27.8 fold; VPA, 34.1 fold) compared with the control cultures (11.6% and 14.4 fold). Addition of 3'4'-DMF and VPA also resulted in more primary colonies and replating efficiency compared with control cultures. Although no significant effect was observed on the enhancement of CD34(+) cells under hypoxia, the number of primary colonies was significantly higher than the control cultures.
Based on these findings, this study presents, for the first time, in vitro evidence for a new and relevant effect of 3'4'-DMF on human HSCs. In addition, the results suggest a potential clinical use of 3'4'-DMF and VPA in HSC therapy.
人类造血干细胞（HSCs）已在临床上用于移植以及基因和细胞治疗超过40年。然而，由于造血干细胞体外培养面临的挑战，这种应用受到限制。主要障碍是在扩增这些细胞的同时不丧失其自我更新特性。
在我们的研究中，我们在常氧（20%氧气）和低氧（1%氧气）条件下，测试了3'，4'-二甲氧基黄酮（3'4'-DMF）和丙戊酸（VPA）对造血干细胞体外扩增的影响。3'4'-DMF是一种广泛使用的抗癌药物，作为芳烃受体的竞争性拮抗剂发挥作用。VPA是一种有效的组蛋白脱乙酰酶抑制剂，用于治疗神经系统疾病。
在常氧条件下，用3'4'-DMF和VPA培养动员外周血来源的造血干细胞，1周后高度保留了CD34阳性率（3'4'-DMF为22.1%，VPA为20.3%），与对照培养物（11.6%）相比，显著增强了CD34(+)细胞数量（3'4'-DMF为27.8倍；VPA为34.1倍）。与对照培养物相比，添加3'4'-DMF和VPA还导致更多的原始集落和再接种效率。虽然在低氧条件下对CD34(+)细胞的增强未观察到显著影响，但原始集落数量显著高于对照培养物。
基于这些发现，本研究首次提供了体外证据，证明3'4'-DMF对人类造血干细胞有新的相关作用。此外，结果表明3'4'-DMF和VPA在造血干细胞治疗中具有潜在的临床应用价值。
