Collective and single cell behavior in epithelial contact inhibition
- Alberto Puliafitoa,1,
- Lars Hufnagela,b,1,
- Pierre Neveua,
- Sebastian Streichanb,
- Alex Sigalc,
- D. Kuchnir Fygensond, and
- Boris I. Shraimana,d,2
- aKavli Institute for Theoretical Physics, University of California, Santa Barbara, CA, 93106;
- bEuropean Molecular Biology Laboratory, Meyerhofstrasse 1, 69117 Heidelberg, Germany;
- cDivision of Biology, Caltech, Pasadena, CA 91125; and
- dDepartment of Physics and Program in Biomolecular Science & Engineering, University of California, Santa Barbara, CA, 93106
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Edited by* Robert H. Austin, Princeton University, Princeton, NJ, and approved November 21, 2011 (received for review June 11, 2010)
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 Madin-Darby canine kidney 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.
Footnotes
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↵1A.P. and L.H. contributed equally to this work.
- ↵2To whom correspondence should be addressed. E-mail: shraiman{at}kitp.ucsb.edu.
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Author contributions: A.P., L.H., A.S., D.K.F., and B.I.S. designed research; A.P., L.H., P.N., S.S., and B.I.S. performed research; A.P. and L.H. analyzed data; A.P., L.H., P.N., and B.I.S. wrote the paper.
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The authors declare no conflict of interest.
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*This Direct Submission article had a prearranged editor.
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This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1007809109/-/DCSupplemental.
