Abstract
BackgroundHuman 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 FindingsIn 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/SignificanceOur 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.
Highlights
Hematopoietic stem cells (HSCs) have been applied to the treatment of a wide variety of blood disorders through HSC transplantations and gene therapy [1,2,3]
We found that Garcinol, a benzophenone derivative originally isolated from Garcinia indica [20,21], expands HSCs/PCs through an inhibitory effect on histone acetyltransferase (HAT)
GAR, ISO, and MMI facilitated the expansion of CD34+CD38– cells compared with the DMSO control (Figure 2A), but little affected the total cell numbers at their effective concentrations (10 mM of GAR: 109.7610.3%, 5 mM of ISO: 71.56 23.7%, 2 mM of MMI: 91.16 2.5%, 0.5 mM of DMI: 93.064.1% relative to the blank control)
Summary
Hematopoietic stem cells (HSCs) have been applied to the treatment of a wide variety of blood disorders through HSC transplantations and gene therapy [1,2,3]. Additional clinical studies will be required to confirm the enhanced kinetics of engraftment in humans, and identification of the cell signaling that governs the self-renewal of HSCs is needed to improve existing methods of hCB HSC expansion ex vivo. In a search for biologically active natural products that may activate signals required for HSC expansion, we screened natural products for effects on hCB CD34+CD38– cells, which are reported to be primitive hematopoietic stem and progenitor cells (HSCs/PCs) [18,19]. We found that Garcinol, a benzophenone derivative originally isolated from Garcinia indica [20,21], expands HSCs/PCs through an inhibitory effect on HAT. This is the first report of a small-molecule HAT inhibitor promoting HSC expansion ex vivo
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