Decreased "ineffective erythropoiesis" preserves polycythemia in mice under long-term hypoxia
Decreased "ineffective erythropoiesis" preserves polycythemia in mice under long-term hypoxia
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DOI：
10.1007/s10238-014-0286-5
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发表时间：
2015-05-01
影响因子：
4.6
通讯作者：
Aizawa, Shin
中科院分区：
文献类型：
--
作者：
Harada, Tomonori;Tsuboi, Isao;Aizawa, Shin
缺氧在人类和其他动物中引起无数的变化，包括由促红细胞生成素（EPO）产生增加介导的红细胞生成激活引起的外周血红细胞（红细胞增多症）的增加。然而，EPO的升高是有限的，在低氧条件下，EPO水平在5-7天内恢复到正常范围，而红细胞增多症只要缺氧持续就会持续。我们研究了长期常压缺氧（10% O-2）小鼠模型的骨髓和脾脏的红细胞生成情况，以阐明慢性缺氧下延长红细胞增多症的机制。脾脏中红细胞集落形成单位（CFU-E）的数量随着血清EPO水平的升高而显著增加，表明在缺氧的前7天红细胞生成被激活。缺氧14天后，CFU-E的数量恢复到正常水平，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（红细胞来源于成熟红细胞阶段的原红细胞）的数量持续增加，特别是TER119（高）CD71（高）群体。ter119阳性细胞中膜联蛋白v阳性细胞的数量在慢性缺氧下明显减少，提示红细胞成熟过程中凋亡细胞数量减少。此外，RT-PCR分析显示，缺氧条件下骨髓中减少红细胞增殖和成熟过程中凋亡变化的BMP-4和干细胞因子的RNA表达增加。这些发现表明，在长期慢性缺氧条件下，红细胞生成过程中红细胞凋亡的减少有助于小鼠红细胞增多症的发生。
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 % O-2) 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.