title: Valproic acid affects the engraftment of TPO-expanded cord blood cells in NOD/SCID mice.
abstract: Hematopoietic stem and progenitor cells (HSPC) can improve the long-term outcome of transplanted individuals and reduce the relapse rate. Valproic acid (VPA), an inhibitor of histone deacetylase, when combined with different cytokine cocktails, induces the expansion of CD34+ cell populations derived from cord blood (CB) and other sources. We evaluated the effect of VPA, in combination with thrombopoietin (TPO), on the viability and expansion of CB-HSPCs and on short- and long-term engraftability in the NOD/SCID mouse model. In vitro, VPA+TPO inhibited HSPC differentiation and preserved the CD34+ cell fraction; the self-renewal of the CD34+ TPO+VPA-treated cells was suggested by the increased replating efficiency. In vivo, short- and long-term engraftment was determined after 6 and 20 weeks. After 6 weeks, the median chimerism percentage was 13.0% in mice transplanted with TPO-treated cells and only 1.4% in those transplanted with TPO+VPA-treated cells. By contrast, after 20 weeks, the engraftment induced by the TPO+VPA-treated cells was three times more effective than that induced by TPO alone, and over ten times more effective compared to the short-term engraftment induced by the TPO+VPA-treated cells. The in vivo results are consistent with the higher secondary plating efficiency of the TPO+VPA-treated cells in vitro.
authors.affiliation: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, 00161 Rome, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Vulcano
authors.forename: Luisa
authors.initials: L
authors.lastname: Milazzo
authors.forename: Carmela
authors.initials: C
authors.lastname: Ciccarelli
authors.forename: Alessandra
authors.initials: A
authors.lastname: Barca
authors.forename: Francesca
authors.initials: F
authors.lastname: Agostini
authors.forename: Ilaria
authors.initials: I
authors.lastname: Altieri
authors.forename: Giampiero
authors.initials: G
authors.lastname: Macioce
authors.forename: Antonio
authors.initials: A
authors.lastname: Di Virgilio
authors.forename: Maria
authors.initials: M
authors.lastname: Screnci
authors.forename: Lidia
authors.initials: L
authors.lastname: De Felice
authors.forename: Adele
authors.initials: A
authors.lastname: Giampaolo
authors.forename: Hamisa Jane
authors.initials: HJ
authors.lastname: Hassan
mesh_terms: D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D036101:Cord Blood Stem Cell Transplantation / Q000379:methods*; D004357:Drug Synergism; D005312:Fetal Blood / Q000166:cytology* / Q000187:drug effects*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007231:Infant, Newborn; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D061251:Primary Cell Culture / Q000379:methods; D013926:Thrombopoietin / Q000494:pharmacology*; D013997:Time Factors; D016896:Treatment Outcome; D014635:Valproic Acid / Q000494:pharmacology*
chemical_list: D018952:Antigens, CD34; D014635:Valproic Acid; D013926:Thrombopoietin