Hypoxia Regulates BMP4 Expression in the Murine Spleen during the Recovery from Acute Anemia

BACKGROUND: Bone marrow erythropoiesis is primarily homeostatic, producing new erythrocytes at a constant rate. However at times of acute anemia, new erythrocytes must be rapidly produced much faster than bone marrow steady state erythropoiesis. At these times stress erythropoiesis predominates. Stress erythropoiesis occurs in the fetal liver during embryogenesis and in the adult spleen and liver. In adult mice, stress erythropoiesis utilizes a specialized population of stress erythroid progenitors that are resident in the spleen. In response to acute anemia, these progenitors rapidly expand and differentiate in response to three signals, BMP4, SCF and hypoxia. In absence of acute anemic stress, two of these signals, BMP4 and hypoxia, are not present and the pathway is not active. The initiating event in the activation of this pathway is the up-regulation of BMP4 expression in the spleen. METHODOLOGY/PRINCIPAL FINDINGS: In this paper we analyze the regulation of BMP4 expression in the spleen by hypoxia. Using stromal cell lines, we establish a role for hypoxia transcription factor HIFs (Hypoxia Inducible Factors) in the transcription of BMP4. We identified putative Hypoxia Responsive Elements (HREs) in the BMP4 gene using bioinformatics. Analysis of these elements showed that in vivo, Hif2α binds two cis regulatory sites in the BMP4 gene, which regulate BMP4 expression during the recovery from acute anemia. CONCLUSIONS AND SIGNIFICANCE: These data show that hypoxia plays a key role in initiating the BMP4 dependent stress erythropoiesis pathway by regulating BMP4 expression.