Phenotypic and functional changes induced at the clonal level in hematopoietic stem cells after 5-fluorouracil treatment
Phenotypic and functional changes induced at the clonal level in hematopoietic stem cells after 5-fluorouracil treatment
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DOI：
10.1182/blood.v89.10.3596.3596_3596_3606
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发表时间：
1997-05-15
期刊：
影响因子：
20.3
通讯作者：
Weissman, IL
中科院分区：
文献类型：
--
作者：
Randall, TD;Weissman, IL
相当一部分造血干细胞（hsc）已被证明对细胞毒性药物（如5-氟尿嘧啶（5-FU））的作用具有抗性，这种药物被认为可以消除骨髓中许多快速分裂的、更坚定的祖细胞，并提供相对丰富的最原始的造血祖细胞群。虽然已经描述了富含5-FU的祖细胞群与来自正常骨髓的祖细胞群之间的差异，但尚不清楚这些差异是否反映了5-FU所揭示的最原始干细胞的特征，或者是否存在干细胞群本身的变化。在这里，我们检查了骨中干细胞的一些特性。在5-FU治疗前后，研究人员已经确定了干细胞群中几种与激活相关的变化。我们发现，长期重建干细胞的生长因子受体c-kit的表达减少了10倍，而整合素Mac-1 （CD11b）的表达增加。这些变化最早在5-FU治疗后24小时开始，并在2 - 3天内最为明显。从5-FU治疗小鼠中分离的hsc的活化表型与胎儿肝脏中发现的干细胞表型相似，与正常骨髓中瞬时再生祖细胞的表型相似。我们发现细胞周期是伴随这些物理变化而诱导的。在2天内，多达29%的干细胞群处于细胞周期的S/G(2)/M期。此外，当在克隆水平上进行检查时，我们发现5-FU似乎并没有消除骨髓中许多短暂的、多能的祖细胞，这些祖细胞被发现与长期再生的、活化的干细胞共增殖。这些结果证明了造血系统对其稳态变化的敏感性，并将几种重要表面分子的表达与造血干细胞的激活状态联系起来。(C) 1997年由美国血液病学会出版。
A significant fraction of hematopoietic stem cells (HSCs) have been shown to be resistant to the effects of cytotoxic agents such as 5-fluorouracil (5-FU), which is thought to eliminate many of the rapidly dividing, more committed progenitors in the bone marrow and to provide a relatively enriched population of the most primitive hematopoietic progenitor cells. Although differences between 5-FU-enriched progenitor populations and those from normal bone marrow have been described, it remained unclear if these differences reflected characteristics of the most primitive stem cells that were revealed by 5-FU, or if there were changes in the stem-cell population itself. Here, we have examined some of the properties of the stem cells in the bone. marrow before and after 5-FU treatment and have defined several activation-related changes in the stem-cell population. We found that long-term reconstituting stem cells decrease their expression of the growth factor receptor c-kit by 10-fold and increase their expression of the integrin Mac-1 (CD11b). These changes begin as early as 24 hours after 5-FU treatment and are most pronounced within 2 to 3 days, This activated phenotype of HSCs isolated from 5-FU-treated mice is similar to the phenotype of stem cells found in the fetal liver and to the phenotype of transiently repopulating progenitors in normal bone marrow, We found that cell cycle is induced concomitantly with these physical changes, and within 2 days as many as 29% of the stem-cell population is in the S/G(2)/M phases of the cell cycle, Furthermore, when examined at a clonal level, we found that 5-FU did not appear to eliminate many of the transient, multipotent progenitors from the bone marrow that were found to be copurified with long-term repopulating, activated stem cells, These results demonstrate the sensitivity of the hematopoietic system to changes in its homeostasis and correlate the expression of several important surface molecules with the activation state of HSCs. (C) 1997 by The American Society of Hematology.