# Stochasticity in mammalian cell growth rates drives cell-to-cell variability independently of cell size and divisions

## TL;DR

Genetically identical cells show growth rate variability due to internal randomness in metabolism, not cell size or division.

## Contribution

The study identifies intrinsic stochasticity in growth rates as the source of cell-to-cell variability in leukemia cells.

## Key findings

- Cell growth variability is driven by intrinsic noise in growth rates, not size regulation or division.
- Growth fluctuations persist across lineages independently of cell cycle or size.
- Short-term growth fluctuations lead to long-term growth patterns in single cells.

## Abstract

Genetically identical cells can grow at different rates. This cell-to-cell growth variability can influence, for example, tumor biology, drug efficacy, and immune responses. Yet, the origin of this variability among genetically identical cells remains unresolved. Here, we track the growth of leukemia cells across different timescales to characterize patterns and fluctuations in cell growth. We find that cell-to-cell growth variability within cell lineages is explained by continuous, cell intrinsic noise in growth rates rather than size regulation or cell division specific growth changes. This suggests that, in the absence of cell-to-cell communication, cell-to-cell growth variability is primarily a byproduct of the stochasticity in metabolism.

Cell growth rates exhibit cell-intrinsic cell-to-cell variability, which influences cell fitness and size homeostasis from bacteria to cancer. It remains unclear whether this variability arises from stochasticity in cell growth or division processes, or from cell-size-dependent growth regulation. To separate these potential sources of growth variability, single-cell growth rates need to be examined across different timescales. Here, we study cell size and growth regulation by tracking lymphocytic leukemia cell mass accumulation with high precision and minute-scale temporal resolution along long ancestral lineages. We first show that correlations between growth rates and cell-size nor asymmetric divisions explain cell-to-cell growth variability. We then isolate growth fluctuations by smoothing and detrending the growth rate dynamics using a Gaussian process regression. We find that these growth fluctuations drive cell-to-cell growth variability within ancestral lineages despite being independent of cell divisions, cell cycle, and cell size. Overall, our results provide a quantitative framework for understanding single-cell growth rates, and indicate that cell-intrinsic long-term patterns in growth are a byproduct of short-term growth fluctuations.