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Decreased “ineffective erythropoiesis” preserves polycythemia in mice under long-term hypoxia

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Abstract

Hypoxia induces innumerable changes in humans and other animals, including an increase in peripheral red blood cells (polycythemia) caused by the activation of erythropoiesis mediated by increased erythropoietin (EPO) production. However, the elevation of EPO is limited and levels return to normal ranges under normoxia within 5–7 days of exposure to hypoxia, whereas polycythemia continues for as long as hypoxia persists. We investigated erythropoiesis in bone marrow and spleens from mouse models of long-term normobaric hypoxia (10 % O2) to clarify the mechanism of prolonged polycythemia in chronic hypoxia. The numbers of erythroid colony-forming units (CFU-E) in the spleen remarkably increased along with elevated serum EPO levels indicating the activation of erythropoiesis during the first 7 days of hypoxia. After 14 days of hypoxia, the numbers of CFU-E returned to normoxic levels, whereas polycythemia persisted for >140 days. Flow cytometry revealed a prolonged increase in the numbers of TER119-positive cells (erythroid cells derived from pro-erythroblasts through mature erythrocyte stages), especially the TER119 (high) CD71 (high) population, in bone marrow. The numbers of annexin-V-positive cells among the TER119-positive cells particularly declined under chronic hypoxia, suggesting that the numbers of apoptotic cells decrease during erythroid cell maturation. Furthermore, RT-PCR analysis showed that the RNA expression of BMP-4 and stem cell factor that reduces apoptotic changes during erythroid cell proliferation and maturation was increased in bone marrow under hypoxia. These findings indicated that decreased apoptosis of erythroid cells during erythropoiesis contributes to polycythemia in mice during chronic exposure to long-term hypoxia.

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Acknowledgments

This study was supported by a grant-in-aid for Scientific Research (C) and grants-in-aid for Young Scientists (B) from the Ministry of Education, Culture, Sports and Science and Technology of Japan and the Japan Society for the Promotion of Science.

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Authors and Affiliations

  1. Department of Functional Morphology, Nihon University School of Medicine, 30-1 Ohyaguchi-kamicho, Itabashi-ku, Tokyo, 173-8610, Japan

    Tomonori Harada, Isao Tsuboi, Yukio Hirabayashi, Kazuhiro Kosaku, Michiko Naito, Hiroyuki Hara, Tohru Inoue & Shin Aizawa

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  1. Tomonori Harada
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  2. Isao Tsuboi
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  3. Yukio Hirabayashi
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  4. Kazuhiro Kosaku
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  5. Michiko Naito
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  6. Hiroyuki Hara
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  7. Tohru Inoue
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  8. Shin Aizawa
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Correspondence to Isao Tsuboi.

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Harada, T., Tsuboi, I., Hirabayashi, Y. et al. Decreased “ineffective erythropoiesis” preserves polycythemia in mice under long-term hypoxia. Clin Exp Med 15, 179–188 (2015). https://doi.org/10.1007/s10238-014-0286-5

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  • DOI: https://doi.org/10.1007/s10238-014-0286-5

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