Yakovlev A Y, Boucher K, Mayer-Proschel M, Noble M
Huntsman Cancer Institute, Department of Oncological Sciences, University of Utah, 546 Chipeta Way, Suite 1100, Salt Lake City, UT 84108, USA.
Proc Natl Acad Sci U S A. 1998 Nov 24;95(24):14164-7. doi: 10.1073/pnas.95.24.14164.
As part of our attempts at understanding fundamental principles that underlie the generation of nondividing terminally differentiated progeny from dividing precursor cells, we have developed approaches to a quantitative analysis of proliferation and differentiation of oligodendrocyte type 2 astrocyte (O-2A) progenitor cells at the clonal level. Owing to extensive previous studies of clonal differentiation in this lineage, O-2A progenitor cells represent an excellent system for such an analysis. Previous studies have resulted in two competing hypotheses; one of them suggests that progenitor cell differentiation is symmetric, the other hypothesis introduces an asymmetric process of differentiation. We propose a general model that incorporates both such extreme hypotheses as special cases. Our analysis of experimental data has shown, however, that neither of these extreme cases completely explains the observed kinetics of O-2A progenitor cell proliferation and oligodendrocyte generation in vitro. Instead, our results indicate that O-2A progenitor cells become competent for differentiation after they complete a certain number of critical mitotic cycles that represent a period of symmetric development. This number varies from clone to clone and may be thought of as a random variable; its probability distribution was estimated from experimental data. Those O-2A cells that have undergone the critical divisions then may differentiate into an oligodendrocyte in each of the subsequent mitotic cycles with a certain probability, thereby exhibiting the asymmetric type of differentiation.
作为我们尝试理解从分裂的前体细胞产生不分裂的终末分化后代所依据的基本原理的一部分，我们已开发出在克隆水平上对少突胶质细胞2型星形胶质细胞（O-2A）祖细胞的增殖和分化进行定量分析的方法。由于此前对该谱系中克隆分化的广泛研究，O-2A祖细胞是进行此类分析的极佳系统。先前的研究产生了两种相互竞争的假说；其中一种认为祖细胞分化是对称的，另一种假说则引入了不对称的分化过程。我们提出了一个通用模型，该模型将这两种极端假说都作为特殊情况纳入其中。然而，我们对实验数据的分析表明，这两种极端情况都不能完全解释体外观察到的O-2A祖细胞增殖和少突胶质细胞生成的动力学。相反，我们的结果表明，O-2A祖细胞在完成一定数量代表对称发育阶段的关键有丝分裂周期后才具备分化能力。这个数量因克隆而异，可被视为一个随机变量；其概率分布是根据实验数据估计的。那些经历了关键分裂的O-2A细胞随后可能在每个后续有丝分裂周期中以一定概率分化为少突胶质细胞，从而表现出不对称的分化类型。
