Enforced P-glycoprotein pump function in murine bone marrow cells results in expansion of side population stem cells in vitro and repopulating cells in vivo
Enforced P-glycoprotein pump function in murine bone marrow cells results in expansion of side population stem cells in vitro and repopulating cells in vivo
复制标题
DOI：
10.1182/blood.v96.3.902.015k40_902_909
复制
发表时间：
2000-08-01
期刊：
影响因子：
20.3
通讯作者：
Sorrentino, BP
中科院分区：
文献类型：
--
作者：
Bunting, KD;Zhou, S;Sorrentino, BP
人多药耐药1（MDR 1）基因产物P-糖蛋白（P-gp）以其赋予耐药性的能力而闻名;然而，最近的证据表明，P-gp表达对细胞发育具有更广泛的影响。为了支持这一想法，之前的研究表明，逆转录病毒介导的小鼠骨髓细胞中的MDR 1表达会导致培养物中干细胞的扩增以及移植小鼠中骨髓增生综合征的发生。现在报道，MDR 1介导的干细胞扩增与侧群（SP）干细胞的增加相关，通过Hoechst染料染色确定。用MDR 1逆转录病毒载体转导小鼠骨髓细胞，导致几乎2！在培养12天内SP细胞数量的对数增加，而对照培养物中SP细胞的快速损失。干细胞扩增不限于离体扩增培养物，但当MDR 1转导的细胞直接移植到照射小鼠中时也是明显的。在这些情况下，干细胞扩增与干细胞克隆中相对高的载体拷贝数相关。如前所述，一些病例与特征性骨髓增生综合征相关。使用功能失活的MDR 1突变cDNA表明，P-gp泵功能对于表型定义的SP细胞和功能定义的再增殖细胞的扩增都是必需的。这些研究进一步支持ABC转运蛋白功能对造血干细胞发育具有重要影响的概念。(C)2000年，美国血液学会。
The human multidrug resistance-1 (MDR1) gene product, P-glycoprotein (P-gp), is well known for its ability to confer drug resistance; however, recent evidence suggests that P-gp expression can have more general effects on cellular development. In support of this idea, it was previously shown that retroviral-mediated MDR1 expression in murine bone marrow cells resulted in the expansion of stem cells in culture and in the development of a myeloproliferative syndrome in transplanted mice. It is now reported that MDR1-mediated stem cell expansion is associated with an increase in side population (SP) stem cells, defined by Hoechst dye staining. Transduction of murine bone marrow cells with an MDR1 retroviral vector resulted in an almost 2! log increase in SP cell numbers over 12 days in culture, whereas there was a rapid loss of SP cells from control cultures, Stem cell amplification was not limited to ex vivo expansion cultures but Was also evident when MDR1-transduced cells were directly transplanted into irradiated mice. In these cases, stem cell expansion was associated with relatively high vector copy numbers in stem cell clones. As previously reported, some cases were associated with a characteristic myeloproliferative syndrome, A functionally inactive MDR1 mutant cDNA was used to show that P-gp pump function was required both for amplification of phenotypically defined SP cells and functionally defined repopulating cells. These studies further support the concept that ABC transporter function can have important effects on hematopoietic stem cell development. (C) 2000 by The American Society of Hematology.