Spatial restriction defines the behavior of epithelial cells

Cell confinement, by controlling cell spreading, defines the behavior of epithelial cells in the tissues. Low cell confinement limits peripheral actin contractility and promotes centrosome positioning and lumen initiation. This peripheral actin contractility depends on the RhoA–ROCK–myosin II pathway, which is downstream of master kinase Par-4/LKB1.

HFSP Career Development Award holder Fernando Martin-Belmonte and colleagues
authored on Fri, 28 September 2012

Human body cells, particularly epithelial cells, exhibit a high degree of confinement within the tissues, which fundamentally affects their behavior. During tumor transformation this confinement is lost, which significantly modifies cell behavior.

Epithelial cells, when in normal conditions in the tissue, are able to perceive the physical and chemical signals coming from their environment, both neighboring cells and the extracellular matrix that surrounds them. In fact, it has been found that alteration of these signals, such as alterations of the extracellular matrix (ECM), promotes cell migration and metastasis in tumor cells. How cellular confinement affects these processes, however, is still poorly understood.

To analyze the effect of cell confinement on epithelial morphogenesis and lumen formation, we devised a method to control the adhesive microenvironment using micropatterned surfaces of different sizes coated with different types of ECM to induce 3D morphogenesis from single epithelial cells, MDCK cell line.

We show that cell confinement, by controlling cell spreading, limits peripheral actin contractility and promotes centrosome positioning and lumen initiation after the first cell division.

We have also characterized the pathway that induces peripheral actin contractility in cells in low confinement, which depends on the master kinase Par-4/LKB1 via the RhoA–ROCK–myosin II pathway. In fact, we show that the inhibition of this pathway restores lumen initiation in minimally confined cells

This new methodology for growing 3D epithelial organoids in micro-patterns, which will be available through the French company Cytoo, will facilitate the study of cell behavior using simple cell models in highly physiological conditions. We expect that this technology will be useful for academic studies and also for testing the development of new drugs against important human diseases such as cancer.

Reference

Cell confinement controls centrosome positioning and lumen initiation during epitelial morphogenesis. Alejo E- Rodríguez-Fraticelli, Muriel Auzan, Miguel A. Alonso, Michel Bornens y Fernando Martín-Belmonte.  Journal Cell Biology. DOI: 10.1083/jcb.201203075.

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