Blanc Lionel, Papoin Julien, Debnath Gargi, Vidal Michel, Amson Robert, Telerman Adam, An Xiuli, Mohandas Narla
Red Cell Physiology Lab, New York Blood Center, New York, New York.
Am J Hematol. 2015 Mar;90(3):235-41. doi: 10.1002/ajh.23920.
Genetic ablation of the ferrireductase STEAP3, also known as TSAP6, leads to severe microcytic and hypochromic red cells with moderate anemia in the mouse. However, the mechanism leading to anemia is poorly understood. Previous results indicate that TSAP6/Steap3 is a regulator of exosome secretion. Using TSAP6/Steap3 knockout mice, we first undertook a comprehensive hematologic characterization of the red cell compartment, and confirmed a dramatic decrease in the volume and hemoglobin content of these erythrocytes. We observed marked anisocytosis as well as the presence of fragmenting erythrocytes. Consistent with these observations, we found by ektacytometry decreased membrane mechanical stability of knockout red cells. However, we were unable to document significant changes in the expression levels of the major skeletal and transmembrane proteins to account for this decrease in the membrane stability. Furthermore, there were no differences in red cell survival between wild type and knockout animals. However, when we monitored erythropoiesis, we found a decreased number of proerythroblasts in the bone marrow of TSAP6/Steap3(-/-) animals. In addition, progression from the proerythroblastic to the orthochromatic stage was affected, with accumulation of cells at the polychromatic stage. Altogether, our findings demonstrate that abnormal erythroid maturation is the main cause of anemia in these mice.
铁还原酶STEAP3（也称为TSAP6）的基因消融会导致小鼠出现严重的小细胞低色素性红细胞，并伴有中度贫血。然而，导致贫血的机制尚不清楚。先前的结果表明，TSAP6/Steap3是外泌体分泌的调节因子。我们使用TSAP6/Steap3基因敲除小鼠，首先对红细胞区室进行了全面的血液学特征分析，并证实这些红细胞的体积和血红蛋白含量显著降低。我们观察到明显的红细胞大小不均以及破碎红细胞的存在。与这些观察结果一致，我们通过激光衍射法发现基因敲除红细胞的膜机械稳定性降低。然而，我们无法证明主要骨架蛋白和跨膜蛋白的表达水平有显著变化来解释膜稳定性的降低。此外，野生型和基因敲除动物之间的红细胞存活率没有差异。然而，当我们监测红细胞生成时，我们发现TSAP6/Steap3(-/-)动物骨髓中的早幼红细胞数量减少。此外，从早幼红细胞阶段到正染红细胞阶段的进程受到影响，细胞在多染红细胞阶段积累。总之，我们的研究结果表明，异常的红细胞成熟是这些小鼠贫血的主要原因。
