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Research Article |
1 Department of Chemical Engineering, Massachusetts Institute of Technology,
Cambridge, Massachusetts 02139, USA
2 Department of Material Science and Engineering, Massachusetts Institute of
Technology, Cambridge, Massachusetts 02139, USA
3 Division of Bioengineering and Environmental Health, Massachusetts Institute
of Technology, Cambridge, Massachusetts 02139, USA
4 Biotechnology Process Engineering Center, Massachusetts Institute of
Technology, Cambridge, Massachusetts 02139, USA
* Author for correspondence (e-mail: griff{at}mit.edu )
Accepted 2 January 2002
Integrin-mediated cell adhesion is central to cell survival,
differentiation and motility. Many cell responses induced by integrins require
both receptor occupancy and receptor aggregation, and appear to be regulated
by both biochemical and biophysical means. Multidomain extracellular matrix
molecules may serve to foster integrin aggregation by presenting local
clusters of adhesion ligands, a hypothesis supported by studies with synthetic
substrates showing that cell adhesion and migration are enhanced when adhesion
ligands are presented in nanoscale clusters. Here, we used a novel synthetic
polymer system to present the adhesion ligand GRGDSPK in nanoscale clusters
with 1.7, 3.6 or 5.4 peptides per cluster against a non-adhesive background,
where the peptide is mobile on a 2 nm polyethylene oxide tether. Average
ligand density ranged from 190 to 5270 RGD/µm2. We used these
substrates to study the effects of ligand density and clustering on adhesion
of wild-type NR6 fibroblasts, which express
vß3 and
5ß1, integrins known to bind to linear RGD
peptides. The strength of cell-substratum adhesion was quantified using a
centrifugal detachment assay to assess the relative number of cells remaining
adherent after a 10 minute application of defined distraction force. An
unusual relationship between cell detachment and distraction force at
relatively low values of applied force was found on substrates presenting the
clustered ligand. Although a monotonic decrease in the number of cells
remaining attached would be expected with increasing force on all substrates,
we instead observed a peak (adhesion reinforcement) in this profile for
certain ligand conditions. On substrates presenting clustered ligands, the
fraction of cells remaining attached increased as the distraction force was
increased to between 70 and 150 pN/cell, then decreased for higher forces.
This phenomenon was only observed on substrates presenting higher ligand
cluster sizes (n=3.6 or n=5.4) and was more pronounced at
higher ligand densities. Adhesion reinforcement was not observed on
fibronectin-coated surfaces. These results support previous studies showing
that biophysical cues such as ligand spatial arrangement and extracellular
matrix rigidity are central to the governance of cell responses to the
external environment.
Key words: Cell-substratum adhesion, RGD clustering, Force, Engineered ECM
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