title: Glucocorticoid hormone-induced chromatin remodeling enhances human hematopoietic stem cell homing and engraftment.
abstract: Efficient hematopoietic stem cell (HSC) homing is important for hematopoietic cell transplantation (HCT), especially when HSC numbers are limited, as in the use of cord blood (CB). In a screen of small-molecule compounds, we identified glucocorticoid (GC) hormone signaling as an activator of CXCR4 expression in human CB HSCs and hematopoietic progenitor cells (HPCs). Short-term GC pretreatment of human CB HSCs and HPCs promoted SDF-1-CXCR4-axis-mediated chemotaxis, homing, and long-term engraftment when these cells were transplanted into primary- and secondary-recipient NSG mice. Mechanistically, activated glucocorticoid receptor binds directly to a glucocorticoid response element in the CXCR4 promoter and recruits the SRC-1-p300 complex to promote H4K5 and H4K16 histone acetylation, facilitating transcription of CXCR4. These results suggest a new and readily available means to enhance the clinical efficacy of CB HCT.
authors.affiliation: Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Guo
authors.affiliation: Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Xinxin
authors.initials: X
authors.lastname: Huang
authors.affiliation: Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Cooper
authors.affiliation: Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Hal E
authors.initials: HE
authors.lastname: Broxmeyer
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D015153:Blotting, Western; D002633:Chemotaxis / Q000187:drug effects*; D042002:Chromatin Assembly and Disassembly / Q000187:drug effects*; D047369:Chromatin Immunoprecipitation; D050881:E1A-Associated p300 Protein / Q000187:drug effects / Q000378:metabolism; D005312:Fetal Blood / Q000166:cytology; D005434:Flow Cytometry; D005938:Glucocorticoids / Q000494:pharmacology*; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000187:drug effects*; D042421:Histone Code / Q000187:drug effects; D006801:Humans; D051379:Mice; D018613:Microscopy, Confocal; D051958:Nuclear Receptor Coactivator 2 / Q000187:drug effects / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D019718:Receptors, CXCR4 / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D020218:Response Elements
chemical_list: C527276:CXCR4 protein, human; D005938:Glucocorticoids; D051958:Nuclear Receptor Coactivator 2; D012333:RNA, Messenger; D019718:Receptors, CXCR4; D050881:E1A-Associated p300 Protein