Keller J R, Jacobsen S E, Sill K T, Ellingsworth L R, Ruscetti F W
Biological Carcinogenesis and Development Program, Program Resources, Inc., Frederick, MD.
Proc Natl Acad Sci U S A. 1991 Aug 15;88(16):7190-4. doi: 10.1073/pnas.88.16.7190.
Transforming growth factor beta 1 (TGF-beta 1) is known to inhibit the growth of immature hematopoietic progenitor cells, whereas more mature, lineage-restricted progenitors are not inhibited. In contrast, in the presence of saturating concentrations of granulocyte/macrophage-colony-stimulating factor (GM-CSF), TGF-beta promoted a 3- to 5-fold increase in the number and size (greater than 0.5 mm) of bone marrow colonies in a dose-dependent manner with an ED50 of 10-20 pM; TGF-beta 1 alone had no effect. Morphological examination showed an increase in granulocyte colonies. In suspension cultures, TGF-beta 1 and GM-CSF stimulated an increase in total viable cells with markedly enhanced neutrophilic differentiation and a concomitant decrease in the number of monocytes/macrophages by day 6 in culture. Limiting dilution analysis demonstrated a 2- to 5-fold increase in the frequency of progenitor cells that responded to GM-CSF plus TGF-beta 1 vs. GM-CSF alone. Bone marrow progenitors obtained from mice 3 days after treatment with 5-fluorouracil responded to a combination of GM-CSF and TGF-beta 1, whereas either factor alone had no effect. A single-cell assay identified a progenitor cell that directly responded to TGF-beta and GM-CSF. TGF-beta increased the number of GM-CSF receptors on bone marrow cells. Thus, TGF-beta 1 can act as a bifunctional mediator of hematopoietic cell growth, and TGF-beta 1 and GM-CSF act together to stimulate granulopoiesis as measured by large granulocyte colony formation; the progenitor cell is tentatively designated granulocyte burst-forming unit.
已知转化生长因子β1（TGF-β1）可抑制未成熟造血祖细胞的生长，而对更成熟的、谱系受限的祖细胞则无抑制作用。相反，在存在饱和浓度的粒细胞/巨噬细胞集落刺激因子（GM-CSF）的情况下，TGF-β以剂量依赖方式促进骨髓集落数量增加3至5倍，集落大小（大于0.5毫米）也增加，半数有效剂量（ED50）为10 - 20皮摩尔；单独使用TGF-β1则无作用。形态学检查显示粒细胞集落增加。在悬浮培养中，TGF-β1和GM-CSF刺激总活细胞数量增加，到培养第6天，嗜中性粒细胞分化明显增强，单核细胞/巨噬细胞数量随之减少。极限稀释分析表明，与单独使用GM-CSF相比，对GM-CSF加TGF-β1有反应的祖细胞频率增加了2至5倍。在用5-氟尿嘧啶治疗3天后从小鼠获得的骨髓祖细胞对GM-CSF和TGF-β1的组合有反应，而单独使用任何一种因子均无作用。单细胞分析鉴定出一种直接对TGF-β和GM-CSF有反应的祖细胞。TGF-β增加了骨髓细胞上GM-CSF受体的数量。因此，TGF-β1可作为造血细胞生长的双功能介质，并且TGF-β1和GM-CSF共同作用以刺激粒细胞生成，这通过大粒细胞集落形成来衡量；该祖细胞暂定为粒细胞爆式形成单位。
