Hoxb4-deficient mice undergo normal hematopoietic development but exhibit a mild proliferation defect in hematopoietic stem cells
Hoxb4-deficient mice undergo normal hematopoietic development but exhibit a mild proliferation defect in hematopoietic stem cells
复制标题
DOI：
10.1182/blood-2003-10-3557
复制
发表时间：
2004-06-01
期刊：
影响因子：
20.3
通讯作者：
Karlsson, S
中科院分区：
文献类型：
--
作者：
Brun, ACM;Björnsson, JM;Karlsson, S
Hoxb 4的强制表达显著增加了移植后小鼠造血干细胞（HSC）的再生，并增强了人严重联合免疫缺陷（SCID）再增殖细胞的再增殖能力。因此，我们想知道Hoxb 4在造血中的生理作用。一种缺乏完整Hoxb 4基因的新型小鼠模型表现出脾脏和骨髓（BM）中细胞结构的显著减少以及红细胞计数和血红蛋白值的轻微降低。在成人骨髓和胎肝中观察到原始祖细胞和干细胞数量轻度减少，而谱系分布正常。虽然在内源性造血过程中原始祖细胞的细胞周期动力学是正常的，但在骨髓和胎肝HSC移植后，在培养和体内观察到BM Lin（-）Sca 1（+）c-kit（+）干细胞和祖细胞的增殖反应缺陷。从胎肝mRNA的定量分析表明，缺乏Hoxb 4单独改变了其他几个Hox基因和参与细胞周期调控的基因的表达水平。总之，Hoxb 4的缺乏导致造血器官中细胞减少和增殖能力受损。然而，Hoxb 4对于HSC的产生或稳态造血的维持不是必需的。
Enforced expression of Hoxb4 dramatically increases the regeneration of murine hematopoletic stem cells (HSCs) after transplantation and enhances the repopulation ability of human severe combined immunodeficiency (SCID) repopulating cells. Therefore, we asked what physiologic role Hoxb4 has in hematopoiesis. A novel mouse model lacking the entire Hoxb4 gene exhibits significantly reduced cellularity in spleen and bone marrow (BM) and a subtle reduction in red blood cell counts and hemoglobin values. A mild reduction was observed in the numbers of primitive progenitors and stem cells in adult BM and fetal liver, whereas lineage distribution was normal. Although the cell cycle kinetics of primitive progenitors was normal during endogenous hematopoiesis, defects in proliferative responses of BM Lin(-) Sca1(+) c-kit(+) stem and progenitor cells were observed in culture and in vivo after the transplantation of BM and fetal liver HSCs. Quantitative analysis of mRNA from fetal liver revealed that a deficiency of Hoxb4 alone changed the expression levels of several other Hox genes and of genes involved in cell cycle regulation. In summary, the deficiency of Hoxb4 leads to hypocellularity in hematopoietic organs and impaired proliferative capacity. However, Hoxb4 is not required for the generation of HSCs or the maintenance of steady state hematopoiesis.