By Kevin Doxzen1†, Sri Ram KrishnaVedula1†, Man Chun Leong2, Hiroaki Hirata1, Nir S. Gov3, Alexandre J. Kabla4, Benoit Ladoux1, 5,*, Chwee Teck Lim1, 6,*
Integrative Biology, 2013. Paper Accepted DOI: 10.1039/C3IB40054A
Collective behavior refers to the emergence of complex migration patterns over scales larger than the individual elements constituting a system. It plays a pivotal role in biological systems in regulating various processes such as gastrulation, morphogenesis and tissue organization. Here, by combining experimental approaches and numerical modeling, we explore the role of cell density (‘crowding’), strength of intercellular adhesion (‘cohesion’) and boundary conditions imposed by extracellular matrix (ECM) proteins (‘constraints’) in regulating the emergence of collective behavior within epithelial cell sheets.
Our results show that the geometrical confinement of cells into well-defined circles induces a persistent, coordinated and synchronized rotation of cells that depends on cell density. The speed of such rotating large-scale movements slows down as the density increases. Furthermore, such collective rotation behavior depends on the size of the micropatterned circles: we observe a rotating motion of the overall cell population in the same direction for sizes up to 200 μm. The rotating cells move as a solid body, with a uniform angular velocity. Interestingly, this upper limit leads to length scales that are similar to the natural correlation length observed for unconfined epithelial cell sheets. This behavior is strongly altered in cells that present a down regulation of adherens junctions and in cancerous cell types.
We anticipate that our system provides a simple and easy approach to investigate collective cell behavior in a well-controlled and systematic manner.
1Mechanobiology Institute, NUS, Singapore, 117411.
2NUS Graduate School for Integrative Sciences and Engineering, NUS, Singapore, 117576.
3 Department of Chemical Physics, Weizmann Institute of Science, Rehovot 76100, Israel
4Engineering Department, University of Cambridge, Cambridge, United Kingdom
5Institut Jacques Monod (IJM), CNRS UMR 7592 & Universite Paris Diderot, Paris, France
6Department of Bioengineering & Department of Mechanical Engineering, NUS, Singapore.
† Equal contribution *Corresponding authors