Abstract
Despite decades of research, how mammalian cell size is controlled remains unclear because of the difficulty of directly measuring growth at the single-cell level. Here we report direct measurements of single-cell volumes over entire cell cycles on various mammalian cell lines and primary human cells. We find that, in a majority of cell types, the volume added across the cell cycle shows little or no correlation to cell birth size, a homeostatic behavior called “adder”. This behavior involves modulation of G1 or S-G2 duration and modulation of growth rate. The precise combination of these mechanisms depends on the cell type and the growth condition. We have developed a mathematical framework to compare size homeostasis in datasets ranging from bacteria to mammalian cells. This reveals that a near-adder behavior is the most common type of size control and highlights the importance of growth rate modulation to size control in mammalian cells.
Highlights
Despite decades of research, how mammalian cell size is controlled remains unclear because of the difficulty of directly measuring growth at the single-cell level
Studies of single-celled yeast and bacteria have revealed that in order to achieve size homeostasis, cells must modulate the amount of growth produced during the cell cycle such that, on average, large cells at birth grow less than small ones
The current understanding of size homeostasis in mammalian cells derives in large part from indirect evidence, due to experimental limitations
Summary
How mammalian cell size is controlled remains unclear because of the difficulty of directly measuring growth at the single-cell level. An “adder” mechanism relies on the addition of a constant volume at each cell cycle that is independent of initial size[5,6], causing cells to converge on an average size after a few generations This behavior has been reported for several types of bacteria, cyanobacteria and in budding yeast[7,8,9,10,11]. The contribution of S-G2 duration in size control and the effective homeostatic behavior from birth to mitosis has not been characterized yet To address these questions as directly as possible, we recently developed two methods to precisely measure the volume of large numbers of single live cells over several days[37,38,39]. We develop a quantitative framework that characterizes the relative contributions of timing and growth modulation to size homeostasis from bacteria to mammalian cells
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