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Journal Club Theme of Aug. 1 2008: Regulation and stabilization of cell adhesion by external forces


Cell adhesion
plays a fundamental role in a variety of physiological processes, ranging from differentiation of stem cells to regulating metastasis.  While studies on cell adhesion originated decades ago, it has been only recently that researchers have begun to understand the role of external forces and stresses in stabilizing cell adhesion at a single molecule and bulk level.  The original hypothesis in the field was that cell adhesion is regulated by adhesion receptors (mainly integrins) that operate in a stochastic on/off manner, with little input from the mechanical domains of the cell’s interior or exterior.  However, recent studies, both in experiments and in theory, have shown that cell adhesion is stabilized in the presence of an external force.

Growth of Adhesion Domains:

The effect of external force in affecting cell matrix contacts was originally proposed in 2001 by Balaban et al. (Nature Cell Biology,5: 466-472).  However a clear understanding of the underlying mechanism was unknown until recently.  In Smith et al, (Proc Natl Acad Sci U S A.2008 May 13;105(19):6906-11 ), this issue is addressed using a cell-mimetic model.  The experimental model consists of fluid membranes decorated with RGD, interacting with integrin coated substrates.  Using this simple, yet elegant model, the authors study the growth of adhesion domains under force.  The use of mimetic systems allows the authors to deconstruct the individual contributions of membrane viscoelasticity, adhesion strength and the role of external force, without having to worry about signaling from inside or outside the cell. The researchers postulate that simple thermodynamics is responsible for growth of adhesion domains and enthalpic /entropic balance regulates the growth and stabilization of adhesion domains. The authors also argue that this phenomenon is independent of cell type, and hence it may be present in a majority of cell types.

Theoretical treatment of adhesion growth:

The problem of adhesion domain stabilization has also been dealt theoretically by Erdmann et al (Phys Rev Lett. 2004 Mar12;92(10):108102 ). By solving stochastic equations for a cluster of parallel bonds with shared constant loading, they characterize adhesion under small force regime.  According to the model, the key to the stabilization of the cluster is rebinding of the receptors to the surface.  The model captures the lifetime of an individual cluster, its stabilization and dissociation under external forces.  The model presents an interesting and a mathematically convincing approach to study cell adhesion to substrates, but needs more biological input for it to be applicable to in vivo and in vitro scenarios.  Additionally, incorporation of the molecular architecture, including the viscoelastic properties at the cell-substrate interface will improve the applicability of the model.

Viscoelastic properties of membrane tethers :

The receptor viscoelastic properties that may improve the model of Erdmann et al. have been characterized by Schmitz et al. (BiophysJ. 2008 Aug;95(3):1448-59).  Their approach to the problem is rooted in AFM measurements.  Schmitz et al. model the cell as a “Kelvin body” (i.e., a body consisting of a spring parallel to a series of dashpot and a second spring) to derive their conclusions.  They assume that the first spring measures the stiffness of the membrane tether, the second spring models the bending rigidity of the membrane and the dashpot is used to describe the viscous contribution of the receptor-anchoring membrane.  This approach provides the authors with a tool to study the viscoelasticity of adhesion receptors (integrin VLA-4 )in T-lymphocyte cells.  While the study has not been extended to other cell types, it is hoped that the instrumentation will allow for characterization of cell-matrix interfaces in a variety of healthy and diseased cell systems.

Future prospects and challenges:

The interaction of cells with substrates is complex and dynamic.  The papers discussed above present some of the recent work aimed at understanding the role of external forces in regulating this interaction. It is clear that there is a lot of work that needs to be done, both in theory and in experiment.  For example, the theoretical work needs to incorporate molecular architecture of the receptors and the substrates. Similarly, studies using cell-mimetic systems will also benefit from inclusion of cytoskeletal components that provide structural integrity to the cells.  Additionally, the role of signaling can never be underestimated during adhesion and detachment.  Cells adhere, migrate and proliferate through synchronized events that integrate the mechanical interactions with numerous signaling cascades.  Finally, it may be worthwhile to expand some of these experimental and computational approaches to understand processes in 3D environments in order to develop a comprehensive understanding of cell adhesion in vivo. 

Dear Muhammad,

Thanks for the interesting information. But regarding
the role of integrin mobility in growth and stabilization of adhesion
patch, as it discussed in that paper by Smith et al (2008), one issue
is not  yet clarified for me. It is proposed by the authors that the
passive strengthening of adhesion (by interplay between entropy of the free
receptors and enthalpy of bond formation) and ab initio formation of domains under external force trigger
signaling events leading to mechanosensing. Although these contributions
are certainly influential, as clearly demonstrated by their results,
but considering them as triggering signaling events in "living cells"
is still unsubstantiated. We have to remind ourselves that generally in living
cells the response to "external cues" is initiated by the effect of
other proteins; for example
localization of PH domain-containing proteins and activation of G-proteins
which both take place much earlier than actin polymerization. The idea
that the recruitment of transmembrane mobile receptors precedes the effect of
such proteins in the stream of signaling pathways in living cells is something
that can not be figured out using cell mimetic vesicles.

Best-

Alireza 

Dear Alireza, 

Thanks for the comment -- I agree with you completely. Signaling, whether initiated from the transmembrane receptors or from the extra-cellular matrices, can not be studied using mimetic devices -- I think the value of these mimetic models is in understanding the physical basis of interaction and signaling and other biochemical pathways are beyond the scope of these model systems. 

 -M 

Muhammad, 

I haven't been able to access the PRL paper and therefore don't quite understand what you mean by a "fluid membrane".  Is it a lipid bilayer membrane or some other bubble-like or planar structure?

Also, to make things easier for your readers who are uninitiated in biology, I have added links to Wikipedia pages that claim to explain some of the terms that you have used.   Please comment on the accuracy of the Wikipedia descriptions (or point us to better sources) if you can.

-- Biswajit 

Biswajit,

Currently it is believed that the cell membrane is a two dimensional liquid whereon transmembrane molecules "float" and hence can freely diffuse. This is what is called "Fluid Mosaic Model" of plasma membrane.

-Alireza

Thanks. This is very interesting in terms of experiment. To measure cell adhesion is very challenging. This requres calibration of AFM lateral force. First one needs to image the cell using AFM and then in situ touch and pull the cell. It is better to find a calibration sample to accuartely measure this. I would like to see more papers or experience how to get the calibration well done. Any suggestions are welcome.

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