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First published online 4 December 2002
doi: 10.1242/jcs.00231
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Research Article |
5ß1 integrin mediates strong tissue cohesion
Department of Surgery, University of Medicine and Dentistry-Robert Wood Johnson Medical School, CAB Room 7070, New Brunswick, NJ 08648, USA
* Author for correspondence (e-mail: fotyra{at}umdnj.edu)
Accepted 16 October 2002
Integrins and cadherins are considered to have distinct and opposing functions. Integrins are traditionally cited for their role in cell-substratum interactions, whereas cadherins are thought to mediate strong intercellular cohesion. Together, these adhesion systems play crucial roles in a wide variety of cellular and developmental processes including cell migration, morphology, differentiation and proliferation. In this manuscript we present evidence that integrins possess the ability to mediate strong intercellular cohesion when cells are grown as 3D aggregates.
Much of the data elucidating the role of integrins as mediators of
cell-extracellular matrix (ECM) interactions have been generated using
conventional cell culture techniques in which cells are plated onto ECM-coated
2D surfaces. In vivo, cells are embedded in a 3D meshwork of ECM proteins. We
hypothesized that, within this meshwork, integrin-ECM interactions may impart
cohesivity to an aggregate of cells by linking adjacent cells together. To
test this hypothesis, we transfected Chinese hamster ovary (CHO-B2) cells to
express 
5ß1 integrin and found that these cells formed compact,
spherical aggregates. We measured aggregate cohesivity using tissue surface
tensiometry, a novel technique that quantifies cell-cell cohesivity of
spheroids under physiological conditions. We determined that 5ß1
integrin is capable of conferring strong cohesivity (
=8.22±0.68
dynes/cm) to aggregates of 5-integrin-transfected cells. This cohesion
was found to be independent of cadherin expression and was significantly
greater than the cohesivity conferred onto CHO-B2 cells transfected with
N-cadherin (=3.14±0.20 dynes/cm, P
0.0001), a more
traditional cell-cell cohesion system.
Fibronectin-null CHO cells that express 5ß1 integrin but do not
secrete endogenous fibronectin do not form aggregates in fibronectin-depleted
medium. Addition of increasing amounts of exogenous dimeric fibronectin to
these cells resulted in a dose-dependent compaction. However, compaction
failed to occur in the presence of fibronectin monomers. These data indicate
that fibronectin is required for 5ß1-mediated compaction and that
the dimeric structure of fibronectin is essential for this process.
Additionally, aggregate formation of the 5 integrin transfectants was
inhibited by an RGD peptide thus confirming 5ß1 integrin
specificity. Collectively, these data confirm our hypothesis that
5ß1 integrin acts through fibronectin to link adjacent cells
together, thus promoting strong intercellular cohesion in 3D cellular
aggregates.
Key words: Integrins, Cadherins, Cohesivity, Tissue surface tensiometry, 3D, Aggregates
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