Abstract
Cell size is believed to influence cell growth and metabolism. Consistently, several studies have revealed that large cells have lower mass accumulation rates per unit mass (i.e., growth efficiency) than intermediate-sized cells in the same population. Size-dependent growth is commonly attributed to transport limitations, such as increased diffusion timescales and decreased surface-to-volume ratio. However, separating cell size- and cell cycle-dependent growth is challenging. To address this, we monitored growth efficiency of pseudodiploid mouse lymphocytic leukemia cells during normal proliferation and polyploidization. This was enabled by the development of large-channel suspended microchannel resonators that allow us to monitor buoyant mass of single cells ranging from 40 pg (small pseudodiploid cell) to over 4,000 pg, with a resolution ranging from ∼1% to ∼0.05%. We find that cell growth efficiency increases, plateaus, and then decreases as cell cycle proceeds. This growth behavior repeats with every endomitotic cycle as cells grow into polyploidy. Overall, growth efficiency changes 33% throughout the cell cycle. In contrast, increasing cell mass by over 100-fold during polyploidization did not change growth efficiency, indicating exponential growth. Consistently, growth efficiency remained constant when cell cycle was arrested in G2 Thus, cell cycle is a primary determinant of growth efficiency. As growth remains exponential over large size scales, our work finds no evidence for transport limitations that would decrease growth efficiency.
Highlights
Cell size is believed to influence cell growth and metabolism
One explanation for the decreased growth in large cells is that, when cells grow beyond a certain size, their growth becomes constrained by transport limitations [2, 8,9,10,11,12,13,14,15,16]
Transport limitations are considered to result in allometric scaling of metabolism, a phenomenon where larger animals display lower metabolic and growth rates [12, 13]
Summary
Luye Mua,, Joon Ho Kanga,b,1,2, Selim Olcuma, Kristofor R. Larger cells have longer diffusion distances and lower surface-to-volume ratios, both of which could reduce the maximal rate at which they can transfer metabolites and information Such transport limitations can exist even when cellular components scale isometrically with cell size. The correlation observed between cell mass and growth efficiency [4,5,6,7] could reflect cell cycle-dependent growth, where each specific cell cycle stage has differential growth signaling and metabolism This growth regulation can be entirely independent of cell size or can be coupled to size-dependent titration/dilution effects, where the concentration of cellular components is lowered as cells grow larger. We use the large-channel SMRs together with previously published small-channel SMRs to monitor the growth of vastly different sized single cells and quantify the extent to which cell size and cell cycle influence growth
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