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  • Title: Low oxygen concentration as a general physiologic regulator of erythropoiesis beyond the EPO-related downstream tuning and a tool for the optimization of red blood cell production ex vivo.
    Author: Vlaski M, Lafarge X, Chevaleyre J, Duchez P, Boiron JM, Ivanovic Z.
    Journal: Exp Hematol; 2009 May; 37(5):573-84. PubMed ID: 19375648.
    Abstract:
    OBJECTIVE: The control of mature erythroid progenitors and precursors' production via erythropoietin (EPO) is the major systemic regulatory mechanism in erythropoiesis. However, hypoxia seems to influence erythropoiesis beyond this well-known mechanism. The aim of our study is to test this hypothesis adapting the oxygenation level to each stage of erythropoiesis. MATERIALS AND METHODS: We exploited the newly developed ex vivo three-phase protocol for red blood cell (RBC) production starting from the steady-state peripheral blood and cord blood CD34(+) cells exposed to adapted O(2) concentrations. Differentiation and maturation were followed by functional tests, morphology, immunophenotype, and analysis of molecular markers' expression. RESULTS: We report here an enhancement of total RBC production if low O(2) concentrations (1.5-5%) were applied, instead of 20% O(2), during the first phase of culture. This results from a comprehensive action of low-O(2) concentration on: 1) amplification of erythroid progenitors, 2) acceleration of their proliferation, 3) differentiation, and 4) maturation of erythroid precursors. In addition, arterial blood O(2) concentration (13%) is critical for stromal cells to fully sustain the differentiation of erythroid precursors. These effects were associated with upregulation of erythroid 5-aminolevulinate synthase and gamma-globin gene expression. CONCLUSION: These results imply that integral regulation of erythropoiesis is operated by low O(2) concentrations, beyond the EPO/EPO-responsive cells loop and provide a tool to optimize the technology for ex vivo production of RBC.
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