Quantitative Analysis of the Correlation between Cell Size and Cellular Uptake of Particles

Abstract

The size of a cell is central to many functions, including cellular communication and exchange of materials with the environment. This modeling and experimental study focused on understanding how the size of a cell determines its ability to uptake nanometer-scale extracellular materials from the environment. Several mechanisms in the cell plasma membrane mediate cellular uptake of nutrients, biomolecules, and particles. These mechanisms involve recognition and internalization of the extracellular molecules via endocytic components, such as clathrin-coated pits, vacuoles, and micropinocytic vesicles. Because the demand for an external resource could be different for cells of different sizes, the collective actions of these various endocytic routes should also vary based on the cell size. Here, using a reaction-diffusion model, we analyze single-cell data to interrogate the one/one mapping between the size of the MDA-MB 231 breast cancer cells and their ability to uptake nanoparticles. Our analysis indicates that under both reaction-and diffusion-controlled regimes, cellular uptake follows a linear relationship with the cell radius. Furthermore, this linear dependency is insensitive to particle size variation within 20-200 nm range. This result is counterintuitive because the general perception is that cellular uptake is proportional to the cell volume (mass) or surface area and hence follow a cubic or square relationship with the cell radius. A further analysis using our model reveals a potential mechanism underlying this linear relationship.

Dissecting Particle Uptake Heterogeneity in a Cell Population Using Bayesian Analysis

“…Equation 3 indicates a simple relationship between the cellular endocytic capacity j, cell size r, and cell-surface transporter density n. However, in this relationship, the two variables r and n may not necessarily be independent. Indeed, our recent study (19) indicates that n and r are anticorrelated. Here, we further investigate this previous finding.…”

“…A population of cells incubated with particles, molecules, or peptides displays a distribution of uptake, indicating heterogeneity in the cellular endocytic capacities. In our earlier work (19), we demonstrated that the endocytic capacity of a cell is determined by its size (radius r, assuming the cell is spherical) and endocytic transporter density in the plasma membrane (n). Here, we focus on dissecting how these two variables independently and jointly dictate the heterogeneity in particle uptake by cells.…”

“…Images of 1500 MDA-MB-231 cells were analyzed to collect their size statistics. These actual sizes obtained from the confocal images were used to correct the FSC-based estimate for the entire cell population in the flow cytometer sample following the procedure in (19).…”

“…However, in addition to this, the size of a cell could also be a crucial determinant of its endocytic capacity (16,17). Cells are naturally heterogeneous in size and typically follow a lognormal distribution (18,19). A cell having a larger volume should experience a greater demand for external materials.…”

“…Moreover, a larger cell, because of its greater transcriptional output, may express more endocytic components in the plasma membrane as well. Therefore, the heterogeneity in the endocytic capacity in a cell population may reflect the distribution in cell size, relative abundance of specific transporter proteins, and interdependency of these two variables (19).…”