Valproic acid increases CXCR4 expression in hematopoietic stem/progenitor cells by chromatin remodeling.
A major limitation of cord blood (CB) hematopoietic stem/progenitor cell (HSPC) transplantation in adult patients is the low cell dose available, which is associated with delayed or failed engraftment. This has prompted intensive research to develop novel strategies to improve HSPC engraftment and reconstitution. The chemokine receptor CXCR4 and its ligand stromal cell-derived factor (SDF)-1alpha play a crucial role in the homing and repopulation capacity of HSPCs. We hypothesized that in HSPCs the CXCR4 receptor is regulated through chromatin remodeling by histone deacetylase inhibitors (HDIs) such as valproic acid (VPA). Using CB CD34(+) cells and the models of immature hematopoietic cells expressing CD34 antigen, namely the leukemic cell lines KG-1a and KG-1, we found that VPA increases surface and mRNA CXCR4 levels in these cells, thereby enhancing their migration toward an SDF-1alpha gradient. We also found that modulation of CXCR4 gene transcription by VPA correlates with the acetylation status of histone H4 in CB CD34(+) and KG-1 cells. Hence we suggest that in CB transplantation priming of HSPCs with VPA could improve homing and engraftment.
Canadian Blood Services R&D, University of Alberta, Edmonton, Alberta, Canada. , Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.
Hilal
H
Gul
Leah A
LA
Marquez-Curtis
Nadia
N
Jahroudi
Jennifer
J
Lo
A Robert
AR
Turner
Anna
A
Janowska-Wieczorek
D000107:Acetylation / Q000187:drug effects; D018952:Antigens, CD34 / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D054377:Chemokine CXCL12 / Q000494:pharmacology; D042002:Chromatin Assembly and Disassembly / Q000187:drug effects*; D006412:Hematopoietic Stem Cells / Q000187:drug effects* / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D011401:Promoter Regions, Genetic / Q000235:genetics; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects*; D014635:Valproic Acid / Q000494:pharmacology*
D018952:Antigens, CD34; D054377:Chemokine CXCL12; D006657:Histones; D019718:Receptors, CXCR4; D014635:Valproic Acid