Inferring time-dependent population growth rates in cell cultures undergoing adaptation

Abstract

Background The population growth rate is an important characteristic of any cell culture. During sustained experiments, the growth rate may vary due to competition or adaptation. For instance, in presence of a toxin or a drug, an increasing growth rate indicates that the cells adapt and become resistant. Consequently, time-dependent growth rates are fundamental to follow on the adaptation of cells to a changing evolutionary landscape. However, as there are no tools to calculate the time-dependent growth rate directly by cell counting, it is common to use only end point measurements of growth rather than tracking the growth rate continuously. Results We present a computer program for inferring the growth rate over time in suspension cells using nothing but cell counts, which can be measured non-destructively. The program was tested on simulated and experimental data. Changes were observed in the initial and absolute growth rates, betraying resistance and adaptation. Conclusions For experiments where adaptation is expected to occur over a longer time, our method provides a means of tracking growth rates using data that is normally collected anyhow for monitoring purposes. The program and its documentation are freely available at https://github.com/Sandalmoth/ratrack under the permissive zlib license.

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“…Using the ratrack tool for deriving growth rates 25 we calculated how the growth rate changed over time during the treatment. A grouping by protocol, and an individual calculation were both performed for each separate well.…”

“…Dose–response relationships were calculated using R scripts and the drc package. A time dependent growth rate for all cells over time was calculated using ratrack 25 , both separately for each individual culture, and grouped by treatment. The carrying capacity of KCL-22 cells was estimated to be 3 × 10 6 cells/mL.…”

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“…To explore whether the treatment of SOECs with P4 had effects on the cells' growth and division, we evaluated the cells doubling time (DB) [41]. The cell doubling time is an important parameter used for the description of the cell development dynamics [42] and corresponds to the time it takes for a cell population to double in size [43]. It depends on different parameters: the time required for cell adhesion to the substrate; the cell adaptation to the artificial environment they are exposed to; and the time necessary for cell division [43].…”

“…The cell doubling time is an important parameter used for the description of the cell development dynamics [42] and corresponds to the time it takes for a cell population to double in size [43]. It depends on different parameters: the time required for cell adhesion to the substrate; the cell adaptation to the artificial environment they are exposed to; and the time necessary for cell division [43]. In a cell culture, after the initial growth suppression a fast increase in the growth rate can be observed, followed by a constant exponential growth phase during the rest of the cell cycle [44].…”

“…In a cell culture, after the initial growth suppression a fast increase in the growth rate can be observed, followed by a constant exponential growth phase during the rest of the cell cycle [44]. Thus, with an exponential growth curve, the DB is an accurate measure of population cell growth [43]. We have calculated the DB of SOECs at two time points, 48 h and seven days.…”