Harada Tomonori, Tsuboi Isao, Hirabayashi Yukio, Kosaku Kazuhiro, Naito Michiko, Hara Hiroyuki, Inoue Tohru, Aizawa Shin
Department of Functional Morphology, Nihon University School of Medicine, 30-1 Ohyaguchi-kamicho, Itabashi-ku, Tokyo, 173-8610, Japan.
Clin Exp Med. 2015 May;15(2):179-88. doi: 10.1007/s10238-014-0286-5. Epub 2014 Jun 13.
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.
缺氧会在人类和其他动物身上引发无数变化，包括由于促红细胞生成素（EPO）产量增加介导的红细胞生成激活导致外周红细胞增多（红细胞增多症）。然而，EPO的升高是有限的，在缺氧暴露5 - 7天内，在常氧条件下其水平会恢复到正常范围，而红细胞增多症会持续到缺氧持续的时间。我们研究了长期常压缺氧（10% O₂）小鼠模型骨髓和脾脏中的红细胞生成，以阐明慢性缺氧时红细胞增多症持续存在的机制。在缺氧的前7天，脾脏中红系集落形成单位（CFU - E）的数量随着血清EPO水平的升高而显著增加，表明红细胞生成被激活。缺氧14天后，CFU - E的数量恢复到常氧水平，而红细胞增多症持续了>140天。流式细胞术显示骨髓中TER119阳性细胞（从早幼红细胞到成熟红细胞阶段的红系细胞）数量持续增加，尤其是TER119（高）CD71（高）群体。在慢性缺氧条件下，TER119阳性细胞中膜联蛋白 - V阳性细胞的数量尤其减少，这表明在红系细胞成熟过程中凋亡细胞的数量减少。此外，RT - PCR分析表明，在缺氧条件下，骨髓中BMP - 4和干细胞因子的RNA表达增加，这些因子在红系细胞增殖和成熟过程中可减少凋亡变化。这些发现表明，在慢性长期缺氧期间，红系细胞生成过程中凋亡减少有助于小鼠红细胞增多症的发生。
