Moreover, mass-based investigations have revealed that the growth rate of mammalian cells is not constant across the cell cycle 31, 32, and the influence of cellular noise on the trade-offs between the naturally evolved and engineered metabolic pathways 33.Ĭlearly, growing cells need to coordinate both size and mass accumulation, with the latter being enthalpically more pertinent than the former 33. In this context, mass-based investigations have unmasked the exponential nature of mass production 29, as well as the presence of ATP-driven high-frequency mass fluctuations 30. Essentially, these measurements capture the underlying metabolic dynamics of nutrient conversion to building blocks, such as amino acids, lipids, and nucleotides 28. In parallel, single-cell growth has also been examined by recording the dynamics of mass accumulation 28. To a similar end, size-based investigations have informed about the mutation dynamics of single cells and resulting fitness effects 27. These, size-based, investigations have unraveled key size homeostasis mechanisms, including the critical accumulation of division proteins and timing of chromosome duplication 22, 23, 24, 25, 26. In this context, some cells divide considerably sooner or later than the population average, thus, yielding population-level fitness effects that occur at shorter timescales than what mutations can confer 18, 19, 20, 21.Ĭommonly, single-cell growth is investigated by recording the elongation rates (i.e., the cell length, area, or volume per unit time). Variability in the reproduction rates between isogenic cells has also been observed 18, 19, 20. This form of non-genetic variability has been attributed to fluctuations in enzyme abundance 11, generally emanating from the stochastic nature of gene expression 12, 13, 14, 15, 16, 17. Recent investigations at the single-cell level have revealed significant variability in the rates of growth among clonal cells 10. As such, growth is a key parameter in cellular physiology 5, evolution 6, the production of high-value chemicals 7, as well as human, animal, and plant health 8, 9. Infections and natural communities start from a few cells, thus, emphasizing the significance of density-fluctuations when taking non-genetic variability into consideration.Īcross all domains of life, cell growth relies on a series of processes through which cells synthesize new components, replicate their genetic material, increase their size, and eventually divide 1, 2, 3, 4. We detail our experimental approach and the “invisible” microfluidic arrays that enabled increased precision and throughput. Further, we observe that density fluctuations can affect the reproduction rates of single cells, suggesting a link between the levels of macromolecular crowding with metabolism and overall population fitness. This differentiation yields a density homeostasis mechanism that we support mathematically. As such, the average rates of mass and size accumulation of a single cell are generally not the same, but rather cells differentiate into increasing one rate with respect to the other. Here, we report that while mass and size accumulation rates of single Escherichia coli cells are exponential, their density and, thus, the levels of macromolecular crowding fluctuate during growth. Single-cells grow by increasing their biomass and size.
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