title: Histone deacetylase 3 modulates the expansion of human hematopoietic stem cells.
abstract: Epigenetic changes are regarded as emerging major players for hematopoietic stem cell (HSC) biology. Although some histone deacetylase (HDAC) inhibitors, such as valproic acid (VA), induce differentiation and apoptosis in a variety of leukemic cells in vitro, they produce a favorable effect on the expansion of normal HSCs. In this study, we have identified the VA target HDAC3 as a negative regulator of umbilical cord blood HSC expansion. We demonstrate that knockdown of the transcript dramatically improves CD34+ cell expansion, which correlates with a higher potential to generate colony-forming units in functional assays. We show that this effect is mediated at the level of primitive hematopoietic cells and that it is not due to negative effects on specific cell commitment or alterations in the cell cycle. HDAC3 inhibition does not block commitment to the monocytic lineage and the maturation of monocyte precursors, which are the main inhibited pathways in the presence of VA. Therefore, our results identify HDAC3 as a promising target for therapies aiming to expand HSCs.
authors.affiliation: Mesenchymal and Hematopoietic Stem Cell Laboratory, Fundación Inbiomed, Paseo Mikeletegi, San Sebastián, Spain.
authors.forename: Carina
authors.initials: C
authors.lastname: Elizalde
authors.forename: Jon
authors.initials: J
authors.lastname: Fernández-Rueda
authors.forename: Juan Manuel
authors.initials: JM
authors.lastname: Salcedo
authors.forename: Akaitz
authors.initials: A
authors.lastname: Dorronsoro
authors.forename: Izaskun
authors.initials: I
authors.lastname: Ferrin
authors.forename: Emma
authors.initials: E
authors.lastname: Jakobsson
authors.forename: César
authors.initials: C
authors.lastname: Trigueros
mesh_terms: D018952:Antigens, CD34 / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D019070:Cell Lineage; D049109:Cell Proliferation / Q000187:drug effects; D005312:Fetal Blood / Q000166:cytology; D005434:Flow Cytometry; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D034741:RNA, Small Interfering / Q000235:genetics; D014635:Valproic Acid / Q000494:pharmacology; D000099186:Histone Deacetylase 3
chemical_list: D018952:Antigens, CD34; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D034741:RNA, Small Interfering; D014635:Valproic Acid; D000099186:Histone Deacetylase 3