Quesniaux V F, Graham G J, Pragnell I, Donaldson D, Wolpe S D, Iscove N N, Fagg B
Sandoz Pharma Ltd, Basel, Switzerland.
Blood. 1993 Mar 15;81(6):1497-504.
A macrophage-derived inhibitor of early hematopoietic progenitors (colony-forming unit-spleen, CFU-A) called stem cell inhibitor was found to be identical to macrophage inflammatory protein-1 alpha (MIP-1 alpha). We investigated the effect of MIP-1 alpha on the earliest stem cells that sustain long-term hematopoiesis in vivo in a competitive bone marrow repopulation assay. Because long-term reconstituting (LTR) stem cells are normally quiescent, an in vivo model was first developed in which they are triggered to cycle. A first 5-fluorouracil (5-FU) injection was used to eliminate later progenitors, causing the LTR stem cells, which are normally resistant to 5-FU, to enter the cell cycle and become sensitive to a second 5-FU injection administered 5 days later. Human MIP-1 alpha administered from day 0 to 7 was unable to prevent the depletion of the LTR stem cells by the second 5-FU treatment, as observed on day 7 in this model, suggesting that the LTR stem cells were not prevented from being triggered into cycle despite the MIP-1 alpha treatment. However, the MIP-1 alpha protocol used here did substantially decrease the number of more mature hematopoietic progenitors (granulocyte-macrophage colony-forming cells [CFC], burst-forming unit-erythroid, CFCmulti, and preCFCmulti) recovered in the bone marrow shortly after a single 5-FU injection. In vitro, MIP-1 alpha had no inhibitory effect on the ability of these progenitors to form colonies. This study confirms the in vivo inhibitory effect of MIP-1 alpha on subpopulations of hematopoietic progenitors that are activated in myelodepressed animals. However, MIP-1 alpha had no effect on the long-term reconstituting stem cells in vivo under conditions in which it effectively reduced all later progenitors.
一种由巨噬细胞产生的早期造血祖细胞（脾集落形成单位，CFU-A）抑制剂，称为干细胞抑制剂，被发现与巨噬细胞炎性蛋白-1α（MIP-1α）相同。我们在竞争性骨髓移植试验中研究了MIP-1α对体内维持长期造血的最早干细胞的影响。由于长期重建造血（LTR）干细胞通常处于静止状态，因此首先建立了一个体内模型，在该模型中促使它们进入细胞周期。首次注射5-氟尿嘧啶（5-FU）用于清除较晚期的祖细胞，使通常对5-FU有抗性的LTR干细胞进入细胞周期，并对5天后给予的第二次5-FU注射变得敏感。从第0天到第7天给予人MIP-1α并不能防止第二次5-FU处理导致的LTR干细胞耗竭，如在该模型第7天所观察到的，这表明尽管进行了MIP-1α处理，LTR干细胞仍未被阻止进入细胞周期。然而，此处使用的MIP-1α方案确实显著减少了单次5-FU注射后不久在骨髓中恢复的更成熟造血祖细胞（粒细胞-巨噬细胞集落形成细胞[CFC]、红系爆式集落形成单位、多能CFC和多能前体细胞）的数量。在体外，MIP-1α对这些祖细胞形成集落的能力没有抑制作用。本研究证实了MIP-1α对骨髓抑制动物中被激活的造血祖细胞亚群的体内抑制作用。然而，在有效减少所有较晚期祖细胞的条件下，MIP-1α对体内长期重建造血干细胞没有影响。
