title: Chromatin-modifying agents promote the ex vivo production of functional human erythroid progenitor cells.
abstract: Presently, blood transfusion products (TPs) are composed of terminally differentiated cells with a finite life span. We have developed an ex vivo-generated TP composed of erythroid progenitor cells (EPCs) and precursors cells. Several histone deacetylase inhibitors (HDACIs) were used in vitro to promote the preferential differentiation of cord blood (CB) CD34(+) cells to EPCs. A combination of cytokines and valproic acid (VPA): (1) promoted the greatest degree of EPC expansion, (2) led to the generation of EPCs which were capable of differentiating into the various stages of erythroid development, (3) led to epigenetic modifications (increased H3 acetylation) of promoters for erythroid-specific genes, which resulted in the acquisition of a gene expression pattern characteristic of primitive erythroid cells, and (4) promoted the generation of a TP that when infused into NOD/SCID mice produced mature RBCs containing both human adult and fetal globins as well Rh blood group Ag which persisted for 3 weeks and the retention of human EPCs and erythroid precursor cells within the BM of recipient mice. This ex vivo-generated EPC-TP likely represents a paradigm shift in transfusion medicine because of its potential to continue to generate additional RBCs after its infusion.
authors.affiliation: Division of Hematology/Medical Oncology, Department of Medicine, Tisch Cancer Institute, Mount Sinai School of Medicine, New York, NY, USA. pratima.chaurasia@mssm.edu
authors.forename: Pratima
authors.initials: P
authors.lastname: Chaurasia
authors.forename: Dmitriy
authors.initials: D
authors.lastname: Berenzon
authors.forename: Ronald
authors.initials: R
authors.lastname: Hoffman
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D002843:Chromatin / Q000187:drug effects*; D036101:Cord Blood Stem Cell Transplantation / Q000379:methods*; D041905:Erythroid Cells / Q000166:cytology*; D005312:Fetal Blood / Q000166:cytology; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D010641:Phenotype; D011401:Promoter Regions, Genetic / Q000502:physiology; D014635:Valproic Acid / Q000494:pharmacology
chemical_list: D018952:Antigens, CD34; D002843:Chromatin; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; C012589:trichostatin A; D014635:Valproic Acid