Growth Rate Of Cell Population Research Articles

Modeling the impact of single-cell stochasticity and size control on the population growth rate in asymmetrically dividing cells.

Microbial populations show striking diversity in cell growth morphology and lifecycle; however, our understanding of how these factors influence the growth rate of cell populations remains limited. We use theory and simulations to predict the impact of asymmetric cell division, cell size regulation and single-cell stochasticity on the population growth rate. Our model predicts that coarse-grained noise in the single-cell growth rate λ decreases the population growth rate, as previously seen for symmetrically dividing cells. However, for a given noise in λ we find that dividing asymmetrically can enhance the population growth rate for cells with strong size control (between a "sizer" and an "adder"). To reconcile this finding with the abundance of symmetrically dividing organisms in nature, we propose that additional constraints on cell growth and division must be present which are not included in our model, and we explore the effects of selected extensions thereof. Further, we find that within our model, epigenetically inherited generation times may arise due to size control in asymmetrically dividing cells, providing a possible explanation for recent experimental observations in budding yeast. Taken together, our findings provide insight into the complex effects generated by non-canonical growth morphologies.

Coarse-grained modeling of cell division in 3D: influence of density, medium viscosity, and inter-membrane friction on cell growth and nearest neighbor distribution

ABSTRACT Considerable experimental and theoretical research has been dedicated to understanding the connection between the biochemical activity of cells and their mechanical environment. This is exemplified by the common structures of developing epithelial cells between various species and the decay of cell population growth rate over time. We study these two phenomena in a system of simulated cells with identical mechanical properties, and growth factors in both epithelial and 3D configurations embedded in viscous fluid. We demonstrate that the increase in the density of cellular systems and the consequential crowding of cells by their neighbors are crucial factors in causing the decay of tissue growth rate. We also show that tissue structure can be reproduced by a purely mechanical model with a more faithful treatment of inter-membrane interactions. Finally, we also show that, assuming all other factors constant, growth, and final structure depends on inter-membrane and medium friction coefficients. Of these two, the latter has a stronger influence on slowing down growth and disrupting structure.

Effects of telomerase activity and apoptosis on ex vivo expansion of cord blood CD34+ cells

Ex vivo expansion of CD34(+) cells has become critically important in order to obtain sufficient haematopoietic stem cells for clinical application. Among major regulators involved in ex vivo expansion, telomerase activity and apoptosis have been revealed to be closely linked to cell cycle progression. However, all exact roles remain to be elucidated. Here, change in telomerase activity and level of apoptosis in cord blood (CB) CD34(+) cells were evaluated together with specific cell population growth rate during ex vivo culture. CD34(+) cells isolated from human CB were expanded ex vivo over a 28-day period. Besides monitoring cell proliferation kinetics of the CD34(+) cells, changes in telomerase activity and apoptotic levels were investigated. Several relevant genes were quantified by qRT-PCR during the culture period. Significant elevation of telomerase activity had close relationship to activation of CB CD34(+) cell expansion. Peak apoptotic level was accompanied by a remarkable decline in cell-specific growth rate, and apoptotic level of differentiated CD34(-) population was significantly higher than that of the CD34(+) population. Although telomerase activity was activated during the culture, expansion of CB CD34(+) cells seemed to be more susceptible to apoptotic suppression when cultured ex vivo, which implied that apoptosis may serve as a rate-limiting factor involved in controlling expansion efficiency.

Mapping the Environmental Fitness Landscape of a Synthetic Gene Circuit

Gene expression actualizes the organismal phenotypes encoded within the genome in an environment-dependent manner. Among all encoded phenotypes, cell population growth rate (fitness) is perhaps the most important, since it determines how well-adapted a genotype is in various environments. Traditional biological measurement techniques have revealed the connection between the environment and fitness based on the gene expression mean. Yet, recently it became clear that cells with identical genomes exposed to the same environment can differ dramatically from the population average in their gene expression and division rate (individual fitness). For cell populations with bimodal gene expression, this difference is particularly pronounced, and may involve stochastic transitions between two cellular states that form distinct sub-populations. Currently it remains unclear how a cell population's growth rate and its subpopulation fractions emerge from the molecular-level kinetics of gene networks and the division rates of single cells. To address this question we developed and quantitatively characterized an inducible, bistable synthetic gene circuit controlling the expression of a bifunctional antibiotic resistance gene in Saccharomyces cerevisiae. Following fitness and fluorescence measurements in two distinct environments (inducer alone and antibiotic alone), we applied a computational approach to predict cell population fitness and subpopulation fractions in the combination of these environments based on stochastic cellular movement in gene expression space and fitness space. We found that knowing the fitness and nongenetic (cellular) memory associated with specific gene expression states were necessary for predicting the overall fitness of cell populations in combined environments. We validated these predictions experimentally and identified environmental conditions that defined a “sweet spot” of drug resistance. These findings may provide a roadmap for connecting the molecular-level kinetics of gene networks to cell population fitness in well-defined environments, and may have important implications for phenotypic variability of drug resistance in natural settings.

LONG-RANGE PREDICTABILITY IN MODELS OF CELL POPULATIONS SUBJECTED TO PHASE-SPECIFIC DRUGS: GROWTH-RATE APPROXIMATION USING PROPERTIES OF POSITIVE COMPACT OPERATORS

The aim of the present work is twofold: to develop numerical procedures for a priori determining whether a given cell population, having a distributed cell-cycle duration, will grow or decay when subjected to prescribed chemotherapy; to evaluate the cumulative error in the long-term predictions for such populations. We show that cell population dynamics under drug treatment can be modelled by iterative application of a compact operator on the initial cell age-distribution. We further show that this model can be approximated by iterative application of matrices on some finite-dimensional vector, containing initial conditions. Moreover, we develop a method for estimating the growth rate of cell population and show that in fully periodic treatments the estimated error does not grow as time tends to infinity. From the biomedical viewpoint this means that only fully periodic (strictly periodic) schedules can be considered for successfully predicting the long-term effect of chemotherapy. Thus, cyclic drug treatment is shown to be advantageous, not only in increasing selectivity of chemotherapy, as has been previously demonstrated, but also in increasing long-term predictability of specific treatment schedules.

Sporulation at minimum specific growth rate in Aspergillus nidulans chemostat culture predicted using protein synthesis efficiency estimations.

Ribosomal efficiency (RE) estimates provide a quantitative descriptor of intrinsic growth rate of cell populations using readily-obtainable experimental data. In Aspergillus nidulans chemostat cultures, RE increased linearly with growth rate over the range 25-60% of maximum growth rate (mu max), consistent with increasing ribosomal usage with increased growth rate. Above 60%, RE did not increase significantly, suggesting that all ribosomes were functional at 60% of mu max, further increases in growth rate, presumably resulting from increased polypeptide chain elongation rate. Extrapolating the linear part of the RE/growth rate curve predicted zero RE at a growth rate of 0.04 h-1. Chemostat steady state cultures at 0.04 h-1 contained spores (conidia), apparently undergoing a continuous sporulation/germination cycle. We propose that the RE estimates provide a means of predicting the value of minimum specific growth rate (mu min) below which net growth cannot take place.

Regulation of mammalian cell growth by autocrine growth factors: Analysis of consequences for inoculum cell density effects

Effects of inoculum cell density on mammalian cell growth in culture have been observed in a variety of experimental systems. Although these effects have been attributed generally to medium conditioning by the cells, there has previously been no quantitative theory proposed for this phenomenon based on developments in molecular and cell biology. In this article, we offer such a theory founded on the regulatory action of autocrine growth factors. A particularly relevant example of these is platelet- derived growth factor (PDGF), which is produced by fibroblastic cells in response to stimulation by transforming growth factor beta (TGFbeta), a common serum constituent, and provides a mitogenic signal for the same cells. A simple mathematical model for the production, diffusive transport, and binding of autocrine growth factors to cell surface receptors, coupled to a model for the dependence of cell proliferation on growth factor receptor binding allows prediction of initial cell population growth rate as a function of inoculum cell density. We focus on situations involving anchorage-dependent cell growth, in which the cells are attached to a surface. A number of clear results are obtained, most notably the following: 1) for cells cultured on spherical microcarrier bead surfaces, the inoculum cell density needed to produce a given growth rate is linearly proportional to the bead radius; and 2) all other factors being equal, the inoculum cell density on a unit surface area basis needed to produce a given growth rate is greater for spherical microcarrier surfaces than for flat culture dish surfaces. These two results are consistent with the experimental observations of Hu and coworkers(1,2) for fibroblast growth in minimal medium plus serum. The model also allows elucidation of the influence of other system parameters, both biological and physical, on initial cell proliferation rate and the inoculum cell density dependence.

Epithelial and fibroblastoid cell lines derived from the normal canine prostate. II. Cell proliferation in response to steroid hormones.

AbstractEpithelial and fibroblastoid cell lines derived from the adult canine prostate, have been used as model systems in a preliminary study of the effects of steroid hormones on isolated cell populations. The mitogenic activities of various androgens and one estrogen were assessed during logarithmic growth in replicate subcultures by measurement of population size and radiolabeled nucleotide uptake in the presence of concentration ranges of these steroids. [H3]‐Leucine incorporation rate was used as an estimate of protein synthesis in the epithelial cell line during the latter phase of log growth. Of the androgens examined, elevated cell population growth rate was only demonstrated in either epithelial or fibroblastoid cell cultures supplemented with 5α‐androstane‐3α, 17β‐ and 17α‐diols at physiological concentrations. No significant qualitative differences were observed between individual prostatic cell types in their proliferative response to the androgens tested. Contrasting effects were observed in the growth rates of epithelial and fibroblastoid cell types in cultures supplemented with estradiol‐17β. This estrogen was significantly mitogenic in fibroblast cultures, but did not significantly affect epithelial proliferation at the concentrations studied. These results are reviewed with reference to current concepts of steroid action in the canine prostate. The importance of the characterization of culture conditions and procedures has been emphasized as a prerequisite to the study of cell proliferation, and potential mitogens, using cell culture models.The relevance of these findings in the consideration of stromal‐epithelial interaction, and glandular differentiation, is discussed.

Failure of 5-fluorouracil and methotrexate to destroy the reproductive integrity of a human breast cancer cell line (MCF-7) growing in vitro

Human breast cancer cell (MCF- 7) in continuous culture were exposed to clinically achievable extra-cellular concentrations of methotrexate and 5-fluorouracil. A 24-hr treatment with 5-fluorouracil (up to 7.7 × 10 −6 M ) or methotrexate (up to 10 −5 M ) failed to reduce the colony-forming ability of MCF- 7 cells, although marked dose-dependent effects on the incorporation of [ 3H ]-deoxyuridine into DNA were observed immediately after treatment. These effects correlated with a dose-dependent delay in cell population growth rate. However, following treatment with concentrations of the anti-metabolites which failed to reduce colony-forming ability, control cell population growth rate ultimately resumed. Increasing the dose of methotrexate to 10 −4 M resulted in a reduction in MCF- 7 cell colony-forming ability, inhibition of [ 3H ]-thymidine incorporation into DNA and a fall in cell number within three days of treatment. Thymidine failed to modulate the growth inhibitory effects of the two antimetabolites. It is concluded that methotrexate and 5-fluorouracil appear to exert a cytostatic rather than a cytotoxic effect on MCF- 7 cells.

The relative biological effectiveness of tritium beta particles compared to gamma radiation--its dependence on dose-rate.

Abstract The RBE of the β particles from 3H in water relative to radium or 60Co γ radiation was determined for HeLa cells cultured in vitro. For cell population growth rate under continuous irradiation at 0·5–3 rads/hour the RBE was about 2·0. For cell survival following exposures at 32 rads/hour the RBE was about 1·0. Using inhibition of root growth of Vicia seedlings as a test system RBE values of 1·6 and 1·0 were measured at dose rates of 1·52 and 46·3 rads/hour respectively. Such a dose-rate dependence of RBE is consistent with previously published results and the value of 1·7 used in the I.C.R.P. recommendations appears to be relevant to exposure at very low dose-rates.