title: Differential effects of epigenetic modifiers on the expansion and maintenance of human cord blood stem/progenitor cells.
abstract: Epigenetic therapies, including DNA methyltransferase and histone deacetylase (HDAC) inhibitors, are increasingly being considered to treat hematological malignancies, but their effects on normal hematopoietic stem cells (HSCs) remain largely unexplored. We compared the effects of several HDAC inhibitors, including valproic acid (VPA) and trichostatin A (TSA), alone or in combination with 5-aza-2'-deoxycytidine (5azaD) on the expansion of HSCs. VPA induced the highest expansion of CD34+CD90+ cells and progenitor cells compared with other HDAC inhibitors or the sequential addition of 5azaD/TSA in culture. Xenotransplantation studies demonstrated that VPA prevents HSC loss, whereas 5azaD/TSA treatment leads to a net expansion of HSCs that retain serial transplantation ability. 5azaD/TSA-mediated HSC expansion was associated with increased histone acetylation and transient DNA demethylation, which corresponded with higher gene transcript levels. However, some genes with increased transcript levels lacked changes in methylation. Importantly, a global microarray analysis revealed a set of differentially expressed genes in 5azaD/TSA- and VPA-expanded CD34+ cells that might be involved in the expansion and maintenance of transplantable HSCs, respectively. In summary, our data indicate that treatment of HSCs with different chromatin-modifying agents results in either the expansion or maintenance of HSCs, an observation of potential therapeutic importance.
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois; University of Illinois Cancer Center, Chicago, Illinois. Electronic address: nadim@uic.edu.
authors.forename: Nadim
authors.initials: N
authors.lastname: Mahmud
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Petro
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois.
authors.forename: Sudhakar
authors.initials: S
authors.lastname: Baluchamy
authors.affiliation: Clinical Microarray Core, University of California, Los Angeles (UCLA), Los Angeles, California.
authors.forename: Xinmin
authors.initials: X
authors.lastname: Li
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois.
authors.forename: Simona
authors.initials: S
authors.lastname: Taioli
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois.
authors.forename: Donald
authors.initials: D
authors.lastname: Lavelle
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois; University of Illinois Cancer Center, Chicago, Illinois.
authors.forename: John G
authors.initials: JG
authors.lastname: Quigley
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois.
authors.forename: Montha
authors.initials: M
authors.lastname: Suphangul
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois.
authors.forename: Hiroto
authors.initials: H
authors.lastname: Araki
mesh_terms: D000818:Animals; D018952:Antigens, CD34 / Q000235:genetics / Q000276:immunology; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D019175:DNA Methylation; D000077209:Decitabine; D044127:Epigenesis, Genetic; D005312:Fetal Blood / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D015870:Gene Expression; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006657:Histones / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D018800:Thy-1 Antigens / Q000235:genetics / Q000276:immunology; D014183:Transplantation, Heterologous; D014635:Valproic Acid / Q000494:pharmacology
chemical_list: D018952:Antigens, CD34; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D018800:Thy-1 Antigens; C012589:trichostatin A; D014635:Valproic Acid; D000077209:Decitabine; D001374:Azacitidine
keywords: Epigenetic modification; Ex vivo expansion; Hematopoiesis; Stem and progenitor cells; Transplantation: basic biology; Umbilical cord blood