Tissue confinement regulates cell growth and size in epithelia

Cell proliferation is a central process in tissue development, homeostasis and disease. Yet how proliferation is regulated in the tissue context remains poorly understood. Here, we introduce a quantitative framework to elucidate how tissue growth dynamics regulate cell proliferation. We show that a limiting rate of tissue expansion creates confinement that suppresses cell growth; however, this confinement does not directly affect the cell cycle. This leads to uncoupling between rates of cell growth and division in epithelia and, thereby, reduces cell volume. Division becomes arrested at a minimal cell volume, which is consistent across diverse epithelia in vivo. Here, the nucleus approaches the minimum volume capable of packaging the genome. The loss of Cyclin D1-dependent cell volume regulation results in an abnormally high nuclear-to-cytoplasmic volume ratio and DNA damage. Overall, we demonstrate how epithelial proliferation is regulated by the interplay between tissue confinement and cell volume regulation. Overall design: Epithelial monolayers were produced with cells overexpressing p27 or p27ck - this lead to a ~3 fold change in final cell volume. Transcription was assayed to look for a transcriptional response to changes in cell volume.