Histone deacetylase inhibitor valproic acid enhances the cytokine-induced expansion of human hematopoietic stem cells

Lidia De Felice, Caterina Tatarelli, Maria Grazia Mascolo, Chiara Gregorj, Francesca Agostini, Roberto Fiorini, Vania Gelmetti, Simona Pascale, Fabrizio Padula, Maria Teresa Petrucci, William Arcese, Clara Nervi

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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.

Original languageEnglish
Pages (from-to)1505-1513
Number of pages9
JournalCancer Research
Volume65
Issue number4
DOIs
Publication statusPublished - Feb 15 2005

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ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

De Felice, L., Tatarelli, C., Mascolo, M. G., Gregorj, C., Agostini, F., Fiorini, R., Gelmetti, V., Pascale, S., Padula, F., Petrucci, M. T., Arcese, W., & Nervi, C. (2005). Histone deacetylase inhibitor valproic acid enhances the cytokine-induced expansion of human hematopoietic stem cells. Cancer Research, 65(4), 1505-1513. https://doi.org/10.1158/0008-5472.CAN-04-3063