Puliafito, Alberto and Hufnagel, Lars and Neveu, Pierre and Streichan, Sebastian and Sigal, Alex and Fygenson, D. Kuchnir and Shraiman , Boris I. (2012) Collective and single cell behavior in epithelial contact inhibition. Proceedings of the National Academy of Sciences of the United States of America, 109 (3). pp. 739-744. ISSN 0027-8424 http://resolver.caltech.edu/CaltechAUTHORS:20120203-152143213
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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.
|Additional Information:||© 2012 by the National Academy of Sciences. Edited by Robert H. Austin, Princeton University, Princeton, NJ, and approved November 21, 2011 (received for review June 11, 2010). Published online before print January 6, 2012. Authors acknowledge valuable interactions with T. Weimbs, M. Elowitz, D. Sprinzak, L. Peliti, and M. Vergassola. A.P., L.H., and P.N. were supported by NSF PHY05-51164. BIS acknowledges support of NSF PHY-08-44989. 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. The authors declare no conflict of interest|
|Official Citation:||Alberto Puliafito, Lars Hufnagel, Pierre Neveu, Sebastian Streichan, Alex Sigal, D. Kuchnir Fygenson, and Boris I. Shraiman Collective and single cell behavior in epithelial contact inhibition PNAS 2012 109 (3) 739-744; published ahead of print January 6, 2012, doi:10.1073/pnas.1007809109|
|Usage Policy:||No commercial reproduction, distribution, display or performance rights in this work are provided.|
|Deposited By:||Ruth Sustaita|
|Deposited On:||03 Feb 2012 23:49|
|Last Modified:||03 Feb 2012 23:49|
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