A generalized adder for cell size homeostasis: Effects on stochastic clonal proliferation

Area of Science:

• Cell biology
• Quantitative biology
• Biophysics

Background:

• Cell size homeostasis is crucial for cell function and proliferation across organisms.
• The 'adder' model proposes cell cycle duration compensates for birth size variations, ensuring constant division size.
• Understanding the mechanistic basis of cell size control is key to explaining population-level heterogeneity.

Purpose of the Study:

• To provide a generalized mechanistic formulation of the adder model applicable to arbitrary cell growth laws.
• To investigate the implications of the generalized adder model on clonal cell proliferation and size fluctuations.
• To explain observed broad fluctuations in clonal sizes within populations, such as in barcoded human cell lines.

Main Methods:

• Developed a mechanistic mathematical model for the adder mechanism incorporating nonexponential cell size growth.
• Analyzed the production rate of cell cycle regulators and division trigger thresholds.
• Investigated clonal size fluctuations under different cell size growth dynamics (exponential vs. nonexponential) with adder control.

Main Results:

• The adder mechanism requires cell cycle regulators to be produced at a rate proportional to the cell growth law, with division triggered at a threshold concentration.
• Under exponential growth, clonal size fluctuations decay over time, leading to population homogeneity.
• Nonexponential growth combined with adder control results in monotonically increasing clonal size fluctuations, reaching a stable nonzero value.

Conclusions:

• The generalized adder model provides a unified framework for cell size homeostasis across diverse growth laws.
• The interplay between single-cell size control and population-level proliferation dynamics explains clonal size heterogeneity.
• This work offers a mechanistic explanation for broad clonal size fluctuations observed in experimental systems like barcoded human cell lines.