title: Ex vivo expansion of human hematopoietic stem cells by garcinol, a potent inhibitor of histone acetyltransferase.
abstract: BACKGROUND
  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.
  
  
  RESULTS
  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
  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.
authors.affiliation: Research Planning Department, Nissan Chemical Industries, Tokyo, Japan.
authors.forename: Taito
authors.initials: T
authors.lastname: Nishino
authors.forename: Changshan
authors.initials: C
authors.lastname: Wang
authors.forename: Makiko
authors.initials: M
authors.lastname: Mochizuki-Kashio
authors.forename: Mitsujiro
authors.initials: M
authors.lastname: Osawa
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Nakauchi
authors.forename: Atsushi
authors.initials: A
authors.lastname: Iwama
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000378:metabolism; D000107:Acetylation / Q000187:drug effects; D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D001688:Biological Products / Q000737:chemistry / Q000494:pharmacology; D002452:Cell Count; D049109:Cell Proliferation / Q000187:drug effects; D003114:Colony-Forming Units Assay; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D051548:Histone Acetyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D013729:Terpenes / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D018952:Antigens, CD34; D001688:Biological Products; D004791:Enzyme Inhibitors; D013729:Terpenes; D051548:Histone Acetyltransferases; D051997:ADP-ribosyl Cyclase 1; C054597:garcinol