Collective and single cell behavior in epithelial contact inhibition

TL;DR

This study quantitatively characterizes contact inhibition in epithelial cells, revealing it results from mechanical constraints rather than just cell contact, and introduces a computational model to explain this behavior.

Contribution

It provides a detailed quantitative analysis of contact inhibition dynamics at tissue and single cell levels, emphasizing mechanical interactions over contact alone, and presents a simple growth mechanics model.

Findings

Contact inhibition follows motility inhibition and occurs when mechanical constraints limit cell expansion.

Cell cycle arrest occurs when cell area drops below a critical threshold.

A computational model captures the observed contact inhibition behavior.

Abstract

Control of cell proliferation is a fundamental aspect of tissue physiology central to morphogenesis, wound healing and cancer. Although many of the molecular genetic factors are now known, the system level regulation of growth is still poorly understood. A simple form of inhibition of cell proliferation is encountered in vitro in normally differentiating epithelial cell cultures and is known as "contact inhibition". The study presented here provides a quantitative characterization of contact inhibition dynamics on tissue-wide and single cell levels. Using long-term tracking of cultured MDCK cells we demonstrate that inhibition of cell division in a confluent monolayer follows inhibition of cell motility and sets in when mechanical constraint on local expansion causes divisions to reduce cell area. We quantify cell motility and cell cycle statistics in the low density confluent regime and their change across the transition to epithelial morphology which occurs with increasing cell density. We then study the dynamics of cell area distribution arising through reductive division, determine the average mitotic rate as a function of cell size and demonstrate that complete arrest of mitosis occurs when cell area falls below a critical value. We also present a simple computational model of growth mechanics which captures all aspects of the observed behavior. Our measurements and analysis show that contact inhibition is a consequence of mechanical interaction and constraint rather than interfacial contact alone, and define quantitative phenotypes that can guide future studies of molecular mechanisms underlying contact inhibition.