Ex vivo expansion of human hematopoietic stem cells by garcinol, a potent inhibitor of histone acetyltransferase.
Ex vivo expansion of human hematopoietic stem cells by garcinol, a potent inhibitor of histone acetyltransferase.
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DOI：
10.1371/journal.pone.0024298
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Iwama A
中科院分区：
文献类型：
--
作者：
Nishino T;Wang C;Mochizuki-Kashio M;Osawa M;Nakauchi H;Iwama A
人脐带血（Human cord blood，hCB）是造血干/祖细胞（hematopoietic stem and progenitor cells，HSCs/PCs）的主要来源。克服HSC/PC的相对短缺的努力已经导致了离体扩增HSC/PC的技术。然而，适用于临床实践的方法尚未完全建立。在这项研究中，我们筛选了具有生物活性的天然产物，以促进hCB HSC/PC的体外扩增，并确定Garcinol，一种植物来源的组蛋白乙酰转移酶（HAT）抑制剂，作为hCB HSC/PC扩增的新刺激剂。在补充有干细胞因子和血小板生成素的CD 34 + CD 38-HSC的7天培养期间，Garcinol使CD 34 + CD 38-HSC/PC的数量增加了4.5倍以上，Garcinol的衍生物Isogarcinol增加了7.4倍。此外，在CD 34 + HSC/PC的7天培养期间，Garcinol使SCID重建细胞（SRC）的数量增加了2.5倍。我们还证明了Garcinol及其衍生物扩增HSC/PC的能力与其对HAT的抑制作用密切相关。Garcinol衍生物能抑制HAT活性和组蛋白乙酰化，而非活性衍生物则不能。我们的研究结果确定Garcinol作为第一个作用于HSC/PC的天然产物，并建议抑制HAT是操纵HSC/PC的另一种方法。
Human cord blood (hCB) is the main source of hematopoietic stem and progenitor cells (HSCs/PCs) for transplantation. Efforts to overcome relative shortages of HSCs/PCs have led to technologies to expand HSCs/PCs ex vivo. However, methods suitable for clinical practice have yet to be fully established. In this study, we screened biologically active natural products for activity to promote expansion of hCB HSCs/PCs ex vivo, and identified Garcinol, a plant-derived histone acetyltransferase (HAT) inhibitor, as a novel stimulator of hCB HSC/PC expansion. During a 7-day culture of CD34+CD38– HSCs supplemented with stem cell factor and thrombopoietin, Garcinol increased numbers of CD34+CD38– HSCs/PCs more than 4.5-fold and Isogarcinol, a derivative of Garcinol, 7.4-fold. Furthermore, during a 7-day culture of CD34+ HSCs/PCs, Garcinol expanded the number of SCID-repopulating cells (SRCs) 2.5-fold. We also demonstrated that the capacity of Garcinol and its derivatives to expand HSCs/PCs was closely correlated with their inhibitory effect on HAT. The Garcinol derivatives which expanded HSCs/PCs inhibited the HAT activity and acetylation of histones, while inactive derivatives did not. Our findings identify Garcinol as the first natural product acting on HSCs/PCs and suggest the inhibition of HAT to be an alternative approach for manipulating HSCs/PCs.
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