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
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发表时间：
1997-05
期刊：
影响因子：
20.3
通讯作者：
T. Randall;I. Weissman
中科院分区：
文献类型：
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作者：
T. Randall;I. Weissman
已经显示造血干细胞（HSC）的显著部分对细胞毒性剂如5-氟尿嘧啶（5-FU）的作用具有抗性，认为细胞毒性剂消除骨髓中许多快速分裂的、更定型的祖细胞，并提供相对富集的最原始的造血祖细胞群。虽然5-FU富集的祖细胞群体和正常骨髓的祖细胞群体之间的差异已经被描述，但仍不清楚这些差异是否反映了5-FU揭示的最原始干细胞的特征，或者干细胞群体本身是否存在变化。在这里，我们检查了5-FU治疗前后骨髓中干细胞的一些特性，并确定了干细胞群中几种活化相关的变化。我们发现，长期重建的干细胞减少其表达的生长因子受体c-kit的10倍，并增加其表达的整合素Mac-1（CD 11b）。这些变化早在5-FU治疗后24小时就开始开始，在2 - 3天内最明显。从5-FU处理的小鼠中分离的HSC的这种活化表型类似于在胎儿肝脏中发现的干细胞的表型和在正常骨髓中瞬时再生祖细胞的表型。我们发现，细胞周期诱导伴随着这些物理变化，并在2天内多达29%的干细胞群体是在S/G2/M期的细胞周期。此外，当在克隆水平检查时，我们发现5-FU似乎没有消除许多来自骨髓的瞬时多能祖细胞，这些祖细胞被发现与长期再生的活化干细胞共纯化。这些结果表明造血系统的敏感性，在其稳态的变化和相关的几个重要的表面分子的表达与HSC的活化状态。
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/G2/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.