The review by Robert Kay and colleagues (Changing directions in the study of chemotaxis. Nature Rev. Mol. Cell Biol. 9, 455–463 (2008))1 is a masterly and much-needed overview of the problems that prevent a full understanding of the underlying mechanisms behind directional finding and chemotaxis by Dictyostelium discoideum and neutrophils. Kay and colleagues discussed the neglected but important topic of the 'surface-area problem' — the mechanism by which the apparent surface area of the chemotactic cell expands (and contracts). It has been argued that without the ability to expand its surface membrane area, cell polarization, pseudopod formation, phagocytosis and chemotaxis would not be possible, and thus actin polymerization and other cytoplasmic changes are subordinate to membrane expansion2,3. However, Kay and colleagues have underestimated the surface-area problem for neutrophils that increase their surface by far more than the 20–30% increase in surface area reported during D. discoideum migration4.
Neutrophils that undergo phagocytosis2 or undergo a transition from a spherical to a flattened morphology3 can approximately double their apparent surface area. In their review, Kay and colleagues suggest that 'folds' in the cell surface as possible reservoirs of additional membrane are unlikely, and focus on endocytic cycling as the potential mechanism. However, scanning electron microscopy of neutrophils show that this cell type has a wrinkled surface5, which we estimate could double the apparent cell surface area (Fig. 1). Furthermore, the wrinkles disappear during expansion of the apparent surface area by osmotic swelling, and quantification shows that this membrane reservoir produces an additional surface-area increase of approximately 100% (Ref. 6). The unwrinkling of the membrane can also be achieved by pulling the neutrophil membrane by an antibody-coated bead7 or by suction through a micropipette8,9, both producing extra membrane (and thus increasing the surface area). Mathematical modelling of the kinetics and forces that are required suggests that this extra membrane results from the unfurling of plasma-membrane wrinkles, which are held in place by a 'molecular velcro' (Ref. 10). Significantly, the force required to 'unwrinkle' the membrane is significantly reduced during phagocytosis10, which suggests that the velcro holding the wrinkles together can be released by intracellular signals that are associated with phagocytotic stimulation. We have suggested that these signals might include the cleavage of proteins that hold the wrinkles in place2,3, and involve Ca2+ activation of μ-calpain11. Thus, although endocytic cycling has been suggested as a way of replacing integrin to the front of neutrophils12, the wrinkled cell surface must not be discounted as a possible solution to the surface-area problem as, in neutrophils, it is a potentially very large reservoir for providing apparent membrane expansion.
References
Kay, R. R., Landridge, P., Traynor, D. & Hoeller, O. Changing directions in the study of chemotaxis. Nature Rev. Mol. Cell Biol. 9, 455–463 (2008).
Hallett, M. B. & Dewitt, S. Ironing out the wrinkles of neutrophil phagocytosis: membrane reservoirs for surface area expansion. Trends Cell Biol. 17, 209–214 (2007).
Dewitt, S. & Hallett, M. B. Leukocyte membrane “expansion”: A central mechanism for leukocyte extravasation. J. Leukoc. Biol. 81, 1160–1164 (2007).
Traynor, D. & Kay, R. R. Possible roles of the endocytic cycle in cell motility. J. Cell Sci. 120, 2318–2327 (2007).
Bessis, M. Living Blood Cells and their Ultrastructure (Springer, Berlin, 1973).
Ting-Beall, H. P., Needham, D. & Hochmuth, R. M. Volume and osmotic properties of human neutrophils. Blood 81, 2774–2780 (1993).
Shao, J. Y. & Hochmuth, R. M. Micropipette suction for measuring piconewton forces of adhesion and tether formation. Biophys. J. 71, 2892–2901 (1996).
Evans. E., Leung, A. & Zhelev, D. Synchrony of cell spreading and contraction force as phagocytes engulf large pathogens. J. Cell Biol. 122, 1295–1300 (1993).
Herant, M., Heinrich, V. & Dembo, M. Mechanics of neutrophil phagocytosis: experiments and quantitative models. J. Cell Sci. 119, 1903–1913 (2006).
Herant, M., Heinrich. V. & Dembo, M. Mechanics of neutrophil phagocytosis: behavior of the cortical tension. J. Cell Sci. 118, 1789–1797 (2005).
Dewitt, S. & Hallett, M. B. Cytosolic free Ca2+ changes and calpain activation are required for β2 integrin-accelerated phagocytosis by human neutrophils. J. Cell Biol. 159, 181–189 (2002).
Lawson, M. A. & Maxfield, F. R. Ca2+-and calcineurin-dependent recycling of an integrin to the front of migrating neutrophils. Nature 377, 75–79 (1995).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Hallett, M., von Ruhland, C. & Dewitt, S. Chemotaxis and the cell surface-area problem. Nat Rev Mol Cell Biol 9, 662 (2008). https://doi.org/10.1038/nrm2419-c1
Issue Date:
DOI: https://doi.org/10.1038/nrm2419-c1
This article is cited by
-
Nonlocal wrinkling instabilities in bilayered systems using peridynamics
Computational Mechanics (2021)
-
Bioinspired Multiscale Wrinkling Patterns on Curved Substrates: An Overview
Nano-Micro Letters (2020)
-
Topographical interrogation of the living cell surface reveals its role in rapid cell shape changes during phagocytosis and spreading
Scientific Reports (2017)
-
Cellular blebs: pressure-driven, axisymmetric, membrane protrusions
Biomechanics and Modeling in Mechanobiology (2014)
-
Surface area regulation: underexplored yet crucial in cell motility
Nature Reviews Molecular Cell Biology (2008)