LINEAGE COMMITMENT IN HUMAN HEMATOPOIESIS INVOLVES ASYMMETRIC CELL-DIVISION OF MULTIPOTENT PROGENITORS AND DOES NOT APPEAR TO BE INFLUENCED BY CYTOKINES
LINEAGE COMMITMENT IN HUMAN HEMATOPOIESIS INVOLVES ASYMMETRIC CELL-DIVISION OF MULTIPOTENT PROGENITORS AND DOES NOT APPEAR TO BE INFLUENCED BY CYTOKINES
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DOI：
10.1002/jcp.1041570318
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发表时间：
1993-12-01
影响因子：
5.6
通讯作者：
LANSDORP, PM
中科院分区：
文献类型：
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作者：
MAYANI, H;DRAGOWSKA, W;LANSDORP, PM
已经提出了不同的模型来解释造血过程中的谱系定向。一些人认为谱系定型以随机方式发生，不受细胞外因素的直接影响；其他人假设细胞因子决定多能细胞是否会成为红系祖细胞或粒细胞/巨噬细胞祖细胞。在本研究中，在补充有不同细胞因子组合的无血清培养系统中分析了单独分选的人脐带血来源的原始造血细胞（高度富集多能祖细胞）的增殖和分化模式。在第一组实验中，比较了单个细胞对不同细胞因子组合的反应，而在第二组实验中，允许单个细胞进行一次分裂，然后将两个子细胞物理分离并在相同或不同的细胞因子组合中培养。祖细胞的增殖绝对依赖于细胞因子，肥大细胞生长因子加白细胞介素6的组合足以诱导有丝分裂。当将有利于红细胞生成和/或骨髓生成的细胞因子组合添加到培养物中时，观察到分选的原始祖细胞更剧烈的增殖反应。有趣的是，无论使用何种细胞因子组合，粒细胞/巨噬细胞、红细胞和多能祖细胞的相对比例或多或少保持相同，这表明细胞因子在造血分化中发挥许可作用，而不是指导作用。在我们的实验条件下，在能够形成集落的祖细胞中观察到了 3-17% 的不对称细胞分裂，定义为产生两个具有不同功能特性的子细胞的分裂。在其余部分，观察到涉及多能和谱系定向祖细胞的对称分裂。这项研究的结果表明，在多能祖细胞水平的造血早期阶段发生的不对称细胞分裂不能通过添加特定的细胞因子组合来扭曲。这些发现支持这样的假设：造血过程中的谱系定型以随机方式通过仍有待阐明的机制发生。 (C) 1993 Wiley-Liss, Inc.
Different models have been proposed to explain lineage commitment in hemopoiesis. Some suggest that lineage commitment occurs in a stochastic manner without the direct influence of extracellular factors; others postulate that cytokines determine whether multipotent cells will become erythroid or granulocyte/macrophage progenitors. In the present study, the patterns of proliferation and differentiation of individually sorted human cord blood-derived primitive hemopoietic cells (highly enriched for multipotent progenitors) were analyzed in a serum-free culture system supplemented with different cytokine combinations. In a first set of experiments, the response of individual cells to different cytokine combinations was compared, whereas in a second set of experiments, single cells were allowed to undergo one division after which the two daughter cells were physically separated and cultured in either the same or different cytokine combinations. Proliferation of progenitor cells was absolutely dependent on cytokines, and the combination of mast cell growth factor plus interleukin 6 was sufficient to induce mitosis. When cytokine combinations favoring erythropoiesis and/or myelopoiesis were added to the cultures, a more vigorous proliferative response of the sorted primitive progenitors was observed. Interestingly, the relative proportions of granulocyte/macrophage, erythroid, and multipotent progenitors remained more or less the same regardless of the cytokine combination used, indicating a permissive rather than an instructive role for cytokines in hemopoietic differentiation. Asymmetric cell divisions, defined as a division that yields two daughter cells with distinct functional properties, were observed in 3-17% of the progenitor cells capable of forming colonies under our experimental conditions. In the rest, symmetric divisions involving multipotent and lineage-committed progenitors were observed. The results of this study demonstrate that the asymmetric cell divisions that occur in the early stages of hemopoiesis at the level of multipotent progenitors cannot be skewed by the addition of specific cytokine combinations. These findings support the hypothesis that lineage commitment in hemopoiesis occurs in a stochastic manner by mechanisms that remain to be elucidated. (C) 1993 Wiley-Liss, Inc.