Quantitative insight into proliferation and differentiation of oligodendrocyte type 2 astrocyte progenitor cells in vitro

Abstract

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.Developing a quantitative analysis of the process(s) through which precursor cells generate appropriate numbers of differentiated progeny represents a major challenge in theoretical biology. This challenge has multiple components and includes both cellular biological and mathematical elements. Although the narrative description of biological events is required to generate hypotheses, the tools of quantitative analysis are indispensable for testing alternative descriptive hypotheses. Mathematical analyses have proven of great benefit to our understanding of such diverse topics as prey-predator interactions, population genetics, DNA sequence analysis, and kinetics of cell proliferation in normal and neoplastic tissues. Although there have been several attempts to analyze temporally regulated differentiation of cells, there remains a lack of models that have been tested quantitatively against experimental data. Moreover, there are relatively few cellular systems for which the analysis of differentiation has been carried out in such a detailed manner as to support extensive efforts to develop quantitative insights into the underlying processes.One of the problems in developing a quantitative analysis of differentiation is that although most analyses of this process are carried out at the level of populations, actual differentiation events occur at the level of individual cells that frequently share a clonal relationship with each other. T...

Redox Regulation of Precursor Cell Function: Insights and Paradoxes

“…A number of features of this clock have been identified (see, e.g., 11,12,26,35,81,82,85,87), but we still do not have a satisfactory understanding of how such remarkable biological time-keeping occurs. Distinct from the cell-intrinsic clock that regulates the initiation of oligodendrocyte generation is a second and distinct mechanism that controls the balance between self-renewal and differentiation in dividing precursor cells once oligodendrocyte generation has begun (35).…”

Regulation of DM-20 mRNA expression and intracellular translocation of glutathione-S-transferase pi isoform during oligodendrocyte differentiation in the adult rat spinal cord

“…3b), suggesting asymmetric division of OPCs generating a new OPC and a daughter immature oligodendrocyte (Fig. 6), which is the principal mechanism for oligodendrocyte generation in the adult CNS (Wren et al 1992;Yakovlev et al 1998;Zhu et al 2011). Asymmetric division of OPCs has been known to be effective for maintaining the OPC population in the adult CNS (Zhu et al 2011) by generating a daughter NG2-positive OPC, which inherits the epidermal growth factor receptor from its mother OPC in vitro (Sugiarto et al 2011) along with the production of a new immature oligodendrocyte.…”

Implications for CNS Repair of Redox Modulation of Cell Survival, Division and Differentiation

“…A number of features of this clock have been identified (see, e.g., [10,[17][18][19][20][21][22][23]) but we still do not have a satisfactory understanding of how such remarkable biological timekeeping occurs.…”