Quantitative insight into proliferation and differentiation of oligodendrocyte type 2 astrocytes progenitor cells

Huntsman Cancer Institute, Department of Oncological Sciences, University of Utah, 546 Chipeta Way, Suite 1100, Salt Lake City, UT 84108, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 12/1998; 95(24):14164-7. DOI: 10.1073/pnas.95.24.14164
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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.

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    • "Several methods have been proposed to analyze clonal data (Nedelman et al., 1985; Yakovlev et al., 1998a, 1998b, 2000; Boucher et al., 1999, 2001; von Collani et al., 1999 Zorin et al., 2000; Hyrien et al., 2005a, 2005b; Hyrien, 2007). All these publications resorted to branching processes to model clonal expansion. "
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    ABSTRACT: This article proposes saddlepoint approximations to the expectation and variance-covariance function of multitype age-dependent branching processes. The proposed approximations are found accurate, easy to implement, and much faster to compute than by simulating the process. Multiple applications are presented, including the analyses of clonal data on the generation of oligodendrocytes from their immediate progenitor cells, and on the proliferation of Hela cells. New estimators are also constructed to analyze clonal data. The proposed methods are finally used to approximate the distribution of the generation, which has recently found several applications in cell biology.
    Biometrics 07/2009; 66(2):567-77. DOI:10.1111/j.1541-0420.2009.01281.x · 1.57 Impact Factor
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    • "The model structure was defined following a set of assumptions that specified it as a special case of the Bellman–Harris branching process with two types of cells similar to that studied by Jagers [15]. Further studies [12] [13] [23] [24] proved this model to be overly simplistic, suggesting a number of refinements that have made it much more difficult to handle analytically and numerically. In parallel , estimation techniques have been developed to fit improved versions of the model to various experimental data. "
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    ABSTRACT: This paper considers the relative frequencies of distinct types of individuals in multitype branching processes. We prove that the frequencies are asymptotically multivariate normal when the initial number of ancestors is large and the time of observation is fixed. The result is valid for any branching process with a finite number of types; the only assumption required is that of independent individual evolutions. The problem under consideration is motivated by applications in the area of cell biology. Specifically, the reported limiting results are of advantage in cell kinetics studies where the relative frequencies but not the absolute cell counts are accessible to measurement. Relevant statistical applications are discussed in the context of asymptotic maximum likelihood inference for multitype branching processes.
    The Annals of Applied Probability 03/2009; 19(1). DOI:10.1214/08-AAP539 · 1.45 Impact Factor
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    • "It gives rise to data frequently referred to as colony sizes or clonal data. For a few examples of such experiments see Nedelman et al. (1985), Yakovlev et al. (1998a, b, 2000), Boucher et al. (1999) (2001), von Collani et al. (1999), Zorin et al. (2000) or Hyrien et al. (2005a, b). "
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    ABSTRACT: This paper presents a method for parametric estimation in the class of multitype Bellman-Harris branching processes when the data consist of cell counts collected on several colonies observed at discrete time points. This sampling scheme arises frequently in biology to analyze cell proliferation in tissue culture. We investigate the use of a pseudo-likelihood approach in this context. It is defined from the mean vectors and variance-covariance matrices of the numbers of cells. The proposed estimator is strongly consistent and asymptotically normal as the number of observed colonies goes to infinity. In situations where these two moments have no closed-form expressions their values can be replaced by simulation-based approximations. The resulting simulated pseudo-maximum likelihood estimator is asymptotically equivalent to the pseudo-maximum likelihood estimator as the number of simulation increases. We illustrate the proposed method via two examples, and evaluate its finite sample properties through simulations.
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