Hypoxia alters progression of the erythroid program.
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.
Rogers
Heather M
HM
Molecular Medicine Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-1822, USA.
Yu
Xiaobing
X
Wen
Jie
J
Smith
Reginald
R
Fibach
Eitan
E
Noguchi
Constance Tom
CT
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
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