title: Hypoxia alters progression of the erythroid program.
abstract: Hypoxia can induce erythropoiesis through regulated increase of erythropoietin (Epo) production. We investigated the direct influence of oxygen tension (pO(2)) in the physiologic range (2-8%) on erythroid progenitor cell differentiation using cultures of adult human hematopoietic progenitor cells exposed to decreasing (20% to 2%) pO(2) and independent of variation in Epo levels. Decreases in hemoglobin (Hb)-containing cells were observed at the end of the culture period with decreasing pO(2). This is due, in part, to a reduction in cell growth and, at 2% O(2), a marked increase in cell toxicity. Analysis of the kinetics of cell differentiation showed an increase in the proportion of cells with glycophorin-A expression and Hb accumulation at physiologic pO(2). Cells were characterized by an early induction of gamma-globin expression and a delay and reduction in peak levels of beta-globin expression. Overall, fetal Hb and gamma-globin expression were increased at physiologic pO(2), but these increases were reduced at 2% O(2) as cultures become cytotoxic. At reduced pO(2), induction of Epo-receptor (Epo-R) by Epo was decreased and delayed, analogous to the delay in beta-globin induction. The oxygen-dependent reduction of Epo-R can account for the associated cytotoxicity at 2% O(2). Epo induction of erythroid transcription factors, EKLF, GATA-1, and SCL/Tal-1, was also delayed and decreased at reduced pO(2), consistent with lower levels of Epo-R and resultant Epo signaling. These changes in Epo-R and globin gene expression raise the possibility that the early increase of gamma-globin is a consequence of reduced Epo signaling and a delay in induction of erythroid transcription factors.
authors.affiliation: Molecular Medicine Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-1822, USA.
authors.forename: Heather M
authors.initials: HM
authors.lastname: Rogers
authors.forename: Xiaobing
authors.initials: X
authors.lastname: Yu
authors.forename: Jie
authors.initials: J
authors.lastname: Wen
authors.forename: Reginald
authors.initials: R
authors.lastname: Smith
authors.forename: Eitan
authors.initials: E
authors.lastname: Fibach
authors.forename: Constance Tom
authors.initials: CT
authors.lastname: Noguchi
mesh_terms: D000328:Adult; D001798:Blood Proteins / Q000096:biosynthesis / Q000235:genetics; D018955:CD36 Antigens / Q000096:biosynthesis / Q000235:genetics; D015687:Cell Hypoxia / Q000502:physiology*; D002478:Cells, Cultured / Q000166:cytology / Q000187:drug effects; D015672:Erythroid Precursor Cells / Q000166:cytology / Q000187:drug effects*; D004920:Erythropoiesis / Q000502:physiology*; D004921:Erythropoietin / Q000494:pharmacology; D005319:Fetal Hemoglobin / Q000096:biosynthesis / Q000235:genetics; D020869:Gene Expression Profiling; D005914:Globins / Q000096:biosynthesis / Q000235:genetics; D006021:Glycophorins / Q000096:biosynthesis; D006454:Hemoglobins / Q000096:biosynthesis; D006801:Humans; D010100:Oxygen / Q000494:pharmacology*; D010313:Partial Pressure; D012333:RNA, Messenger / Q000096:biosynthesis; D017467:Receptors, Erythropoietin / Q000096:biosynthesis / Q000235:genetics; D011994:Recombinant Proteins; D015398:Signal Transduction; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics
chemical_list: D001798:Blood Proteins; D018955:CD36 Antigens; D006021:Glycophorins; D006454:Hemoglobins; D012333:RNA, Messenger; D017467:Receptors, Erythropoietin; D011994:Recombinant Proteins; D014157:Transcription Factors; D004921:Erythropoietin; D005914:Globins; D005319:Fetal Hemoglobin; D010100:Oxygen