Chang Hannah H, Oh Philmo Y, Ingber Donald E, Huang Sui
Vascular Biology Program, Department of Pathology and Surgery, Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
BMC Cell Biol. 2006 Feb 28;7:11. doi: 10.1186/1471-2121-7-11.
Cell differentiation has long been theorized to represent a switch in a bistable system, and recent experimental work in micro-organisms has revealed bistable dynamics in small gene regulatory circuits. However, the dynamics of mammalian cell differentiation has not been analyzed with respect to bistability.
Here we studied how HL60 promyelocytic precursor cells transition to the neutrophil cell lineage after stimulation with the differentiation inducer, dimethyl sulfoxide (DMSO). Single cell analysis of the expression kinetics of the differentiation marker CD11b (Mac-1) revealed all-or-none switch-like behavior, in contrast to the seemingly graduated change of expression when measured as a population average. Progression from the precursor to the differentiated state was detected as a discrete transition between low (CD11bLow) and high (CD11bHigh) expressor subpopulations distinguishable in a bimodal distribution. Hysteresis in the dependence of CD11b expression on DMSO dose suggests that this bimodality may reflect a bistable dynamic. But when an "unswitched" (CD11bLow) subpopulation of cells in the bistable/bimodal regime was isolated and cultured, these cells were found to differ from undifferentiated precursor cells in that they were "primed" to differentiate.
These findings indicate that differentiation of human HL60 cells into neutrophils does not result from a simple state transition of a bistable switch as traditionally modeled. Instead, mammalian differentiation appears to be a multi-step process in a high-dimensional system, a result which is consistent with the high connectivity of the cells' complex underlying gene regulatory network.
长期以来，细胞分化被理论化为代表双稳态系统中的一种转换，并且最近在微生物中的实验工作揭示了小基因调控回路中的双稳态动力学。然而，尚未就双稳态对哺乳动物细胞分化的动力学进行分析。
在此，我们研究了HL60早幼粒细胞前体细胞在用分化诱导剂二甲基亚砜（DMSO）刺激后如何向中性粒细胞谱系转变。对分化标志物CD11b（Mac-1）表达动力学的单细胞分析揭示了全或无的开关样行为，这与以群体平均值测量时看似渐进的表达变化形成对比。从前体细胞到分化状态的进展被检测为在双峰分布中可区分的低（CD11bLow）和高（CD11bHigh）表达亚群之间的离散转变。CD11b表达对DMSO剂量的依赖性中的滞后现象表明这种双峰性可能反映了双稳态动力学。但是，当在双稳态/双峰状态下分离并培养“未转换”（CD11bLow）的细胞亚群时，发现这些细胞与未分化的前体细胞不同，因为它们已被“启动”以进行分化。
这些发现表明，人类HL60细胞向中性粒细胞的分化并非如传统模型中双稳态开关的简单状态转换那样产生。相反，哺乳动物的分化似乎是高维系统中的一个多步骤过程，这一结果与细胞复杂的潜在基因调控网络的高连通性一致。
