title: Histone deacetylase inhibitor valproic acid enhances the cytokine-induced expansion of human hematopoietic stem cells.
abstract: Ex vivo amplification of human hematopoietic stem cells (HSC) without loss of their self-renewing potential represents an important target for transplantation, gene and cellular therapies. Valproic acid is a safe and widely used neurologic agent that acts as a potent inhibitor of histone deacetylase activities. Here, we show that valproic acid addition to liquid cultures of human CD34+ cells isolated from cord blood, mobilized peripheral blood, and bone marrow strongly enhances the ex vivo expansion potential of different cytokine cocktails as shown by morphologic, cytochemical, immunophenotypical, clonogenic, and gene expression analyses. Notably, valproic acid highly preserves the CD34 positivity after 1 week (range, 40-89%) or 3 weeks (range, 21-52%) amplification cultures with two (Flt3L + thrombopoietin) or four cytokines (Flt3L + thrombopoietin + stem cell factor + interleukin 3). Moreover, valproic acid treatment increases histone H4 acetylation levels at specific regulatory sites on HOXB4, a transcription factor gene with a key role in the regulation of HSC self-renewal and AC133, a recognized marker gene for stem cell populations. Overall, our results relate the changes induced by valproic acid on chromatin accessibility with the enhancement of the cytokine effect on the maintenance and expansion of a primitive hematopoietic stem cell population. These findings underscore the potentiality of novel epigenetic approaches to modify HSC fate in vitro.
authors.affiliation: Department of Cellular Biotechnology and Hematology, University of Rome La Sapienza, USA. defelice@bce.uniroma1.it
authors.forename: Lidia
authors.initials: L
authors.lastname: De Felice
authors.forename: Caterina
authors.initials: C
authors.lastname: Tatarelli
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Mascolo
authors.forename: Chiara
authors.initials: C
authors.lastname: Gregorj
authors.forename: Francesca
authors.initials: F
authors.lastname: Agostini
authors.forename: Roberto
authors.initials: R
authors.lastname: Fiorini
authors.forename: Vania
authors.initials: V
authors.lastname: Gelmetti
authors.forename: Simona
authors.initials: S
authors.lastname: Pascale
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Padula
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Petrucci
authors.forename: William
authors.initials: W
authors.lastname: Arcese
authors.forename: Clara
authors.initials: C
authors.lastname: Nervi
mesh_terms: D000071916:AC133 Antigen; D000107:Acetylation / Q000187:drug effects; D015703:Antigens, CD; D018952:Antigens, CD34 / Q000096:biosynthesis; D017209:Apoptosis / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects; D002843:Chromatin / Q000378:metabolism; D016207:Cytokines / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006023:Glycoproteins / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology; D056572:Histone Deacetylase Inhibitors; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D010455:Peptides / Q000378:metabolism; D013926:Thrombopoietin / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism; D014635:Valproic Acid / Q000494:pharmacology*
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; D018952:Antigens, CD34; D002843:Chromatin; D016207:Cytokines; D004791:Enzyme Inhibitors; D006023:Glycoproteins; C090460:HOXB4 protein, human; D056572:Histone Deacetylase Inhibitors; D018398:Homeodomain Proteins; C000606023:PROM1 protein, human; D010455:Peptides; D014157:Transcription Factors; D014635:Valproic Acid; D013926:Thrombopoietin