Research Planning Department, Nissan Chemical Industries, Tokyo, Japan.
PLoS One. 2011;6(9):e24298. doi: 10.1371/journal.pone.0024298. Epub 2011 Sep 12.
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.
METHODOLOGY/PRINCIPAL FINDINGS: 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.
CONCLUSIONS/SIGNIFICANCE: 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.
人类脐带血（hCB）是造血干细胞和祖细胞（HSCs/PCs）移植的主要来源。为了克服 HSCs/PCs 的相对短缺，人们努力开发了体外扩增 HSCs/PCs 的技术。然而，适合临床实践的方法尚未完全建立。
方法/主要发现：在这项研究中，我们筛选了具有生物活性的天然产物，以寻找促进 hCB HSCs/PCs 体外扩增的活性物质，并确定了植物来源的组蛋白乙酰转移酶（HAT）抑制剂 Garcinol 是一种新型 hCB HSC/PC 扩增刺激物。在添加干细胞因子和血小板生成素的 CD34(+)CD38(-)HSCs 7 天培养过程中，Garcinol 将 CD34(+)CD38(-)HSCs/PCs 的数量增加了 4.5 倍以上，其衍生物 Isogarcinol 增加了 7.4 倍。此外，在 CD34(+)HSCs/PCs 的 7 天培养过程中，Garcinol 将 SCID 再殖细胞（SRCs）的数量扩大了 2.5 倍。我们还证明了 Garcinol 及其衍生物扩增 HSCs/PCs 的能力与其对 HAT 的抑制作用密切相关。能够扩增 HSCs/PCs 的 Garcinol 衍生物抑制了 HAT 活性和组蛋白乙酰化，而无活性的衍生物则没有。
结论/意义：我们的发现将 Garcinol 鉴定为第一个作用于 HSCs/PCs 的天然产物，并表明抑制 HAT 可能是一种操纵 HSCs/PCs 的替代方法。
