Mantel C, Hendrie P, Broxmeyer H E
Department of Microbiology, Walther Oncology Center, Indiana University School of Medicine, 1044 West Walnut Street, Indianapolis, IN 46202-5121, USA.
Stem Cells. 2001;19(6):483-91. doi: 10.1634/stemcells.19-6-483.
Asymmetric segregation of cell-fate determinants during mitosis (spatial asymmetry) is an essential mechanism by which stem cells are maintained while simultaneously giving rise to differentiated progenitors that ultimately produce all the specialized cells in the hematopoietic system. Temporal cell cycle asymmetry and heterogeneity are attributes of cell proliferation that are also essential for maintaining tissue organization. Hematopoietic stem cells (HSCs) are regulated by a complex network of cytokines, some of which have very specific effects, while others have very broad ranging effects on HSCs. Some cytokines, like steel factor (SLF), are known to synergize with other cytokines to produce rapid expansion of progenitor cells. Using the human growth factor-dependent MO7e cell line as a model for synergistic proliferation, we present evidence that links proliferation asymmetry to SLF synergy with GM-CSF, and suggests that temporal asymmetry and cell cycle heterogeneity can be regulated by SLF in vitro. We also show that CDK-inhibitor and cell cycle regulator, p27kip-1, may be involved in this temporal asymmetry regulation. We propose that SLF/GM-CSF synergy is, in part, due to a shift in proliferation pattern from a heterogeneous and asymmetric one to a more synchronous and symmetric pattern, thus contributing dramatically to the rapid expansion that accompanies SLF synergy observed in MO7e cells. This kinetic model of asymmetry is consistent with recent evidence showing that even though SLF synergy results in a strong proliferative signal, it does not increase primary HSC self-renewal, which is believed to be highly dependent on asymmetric divisions. The factor-dependent MO7e/SCF- synergy/asymmetry model described here may therefore be useful for studies of the effects of various cytokines on cell cycle asymmetry.
有丝分裂期间细胞命运决定因子的不对称分离（空间不对称）是一种重要机制，通过该机制干细胞得以维持，同时产生分化的祖细胞，这些祖细胞最终产生造血系统中的所有特化细胞。细胞周期的时间不对称性和异质性是细胞增殖的特性，对于维持组织的有序性也至关重要。造血干细胞（HSCs）受细胞因子复杂网络的调控，其中一些细胞因子具有非常特定的作用，而另一些对造血干细胞具有广泛的作用。一些细胞因子，如干细胞因子（SLF），已知可与其他细胞因子协同作用，使祖细胞快速扩增。利用依赖人类生长因子的MO7e细胞系作为协同增殖模型，我们提供了证据，将增殖不对称与SLF与GM-CSF的协同作用联系起来，并表明时间不对称和细胞周期异质性在体外可受SLF调控。我们还表明，细胞周期蛋白依赖性激酶抑制剂和细胞周期调节因子p27kip-1可能参与这种时间不对称调节。我们提出，SLF/GM-CSF协同作用部分是由于增殖模式从异质性和不对称性向更同步和对称性模式的转变，从而极大地促进了MO7e细胞中观察到的伴随SLF协同作用的快速扩增。这种不对称动力学模型与最近的证据一致，即尽管SLF协同作用产生强烈的增殖信号，但它不会增加原代造血干细胞的自我更新，而原代造血干细胞的自我更新被认为高度依赖不对称分裂。因此，这里描述的因子依赖性MO7e/SCF协同作用/不对称模型可能有助于研究各种细胞因子对细胞周期不对称性的影响。
