Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Coping with the inevitable: how cells repair a torn surface membrane

Abstract

Disruption of the cell plasma membrane is a commonplace occurrence in many mechanically challenging, biological environments. 'Resealing' is the emergency response required for cell survival. Resealing is triggered by Ca2+ entering through the disruption; this causes vesicles present in cytoplasm underlying the disruption site to fuse rapidly with one another (homotypically) and also with the adjacent plasma membrane (heterotypically/exocytotically). The large vesicular products of homotypic fusion are added as a reparative 'patch' across the disruption, when its resealing requires membrane replacement. The simultaneous activation of the local cytoskeleton supports these membrane fusion events. Resealing is clearly a complex and dynamic cell adaptation, and, as we emphasize here, may be an evolutionarily primitive one that arose shortly after the ancestral eukaryote lost its protective cell wall.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Three resealing mechanisms.
Figure 2: The key experiment showing that cytoplasm can rapidly erect an extensive membrane barrier when exposed to its natural external environment.
Figure 3: Scanning electron microcrographs of eggs sheared to produce plasma-membrane disruptions directly from a syringe needle into fixative.
Figure 4: The evolution of fusion-based resealing may have occurred soon after the acquisition of endocytotic apparatus.

Similar content being viewed by others

References

  1. Fuchs, E. & Cleveland, D. W. A structural scaffolding of intermediate filaments in health and disease. Science 279, 514–519 (1998).

    Article  CAS  Google Scholar 

  2. Galou, M. et al. The importance of intermediate filaments in the adaptation of tissues to mechanical stress: evidence from gene knockout studies. Biol. Cell 89, 85–97 (1997).

    Article  CAS  Google Scholar 

  3. McNeil, P. L. & Steinhardt, R. A. Loss, restoration and maintenance of plasma membrane integrity. J. Cell Biol. 137, 1–4 (1997).

    Article  CAS  Google Scholar 

  4. Clarke, M. S., Caldwell, R. W., Chiao, H., Miyake, K. & McNeil, P. L. Contraction-induced cell wounding and release of fibroblast growth factor in heart. Circ. Res. 76, 927–934 (1995).

    Article  CAS  Google Scholar 

  5. McNeil, P. L. & Khakee, R. Disruptions of muscle fiber plasma membranes. Role in exercise-induced damage. Am. J. Pathol. 140, 1097–1109 (1992).

    CAS  Google Scholar 

  6. Clarke, M. F. C., Khakee, R. & McNeil, P. L. Loss of cytoplasmic basic fibroblast growth factor from physiologically wounded myofibers of normal and dystrophic muscle. J. Cell Sci. 106, 121–133 (1993).

    CAS  Google Scholar 

  7. Petrof, B. J., Shrager, J. B., Stedman, H. H., Kelly, A. M. & Sweeney, H. L. Dystrophin protects the sarcolemma from stresses developed during muscle contraction. Proc. Natl Acad. Sci. USA 90, 3710–3714 (1993).

    Article  CAS  Google Scholar 

  8. Lemasters, J. L., DiGuiseppi, J., Nieminen, A.-L. & Herman, B. Blebbing, free Ca2+ and mitochondrial membrane potential preceding cell death in hepatocytes. Nature 325, 78–81 (1987).

    Article  CAS  Google Scholar 

  9. Swanson, J. A. & Taylor, D. L. Local and spatially coordinated movements in Dictyostelium discoideum amoebae during chemotaxis. Cell 28, 225–232 (1982).

    Article  CAS  Google Scholar 

  10. Olfers-Weber, R., Stockem, W. & Wohlfarth-Bottermann, K. E. in Ion and Enzyme Electrodes in Biology and Medicine (eds Kessler, M. et al.) 205–216 (University Park Press, Baltimore, 1976).

    Google Scholar 

  11. Casademont, J., Carpenter, S. & Karpati, G. Vacuolation of muscle fibers near sarcolemmal breaks represents T-tubule dilatation secondary to enhanced sodium pump activity. J. Neuropathol. Exp. Neurol. 47, 618–628 (1988).

    Article  CAS  Google Scholar 

  12. Swanson, J. A. & McNeil, P. L. Nuclear reassembly excludes large macromolecules. Science 238, 548–550 (1987).

    Article  CAS  Google Scholar 

  13. Terasaki, M., Miyake, K. & McNeil, P. L. Large plasma membrane disruptions are rapidly resealed by Ca2+-dependent vesicle–vesicle fusion events. J. Cell Biol. 139, 63–74 (1997).

    Article  CAS  Google Scholar 

  14. Lieber, M. R. & Steck, T. L. A description of the holes in human erythrocyte membrane ghosts. J. Biol. Chem. 257, 11651–11659 (1982).

    CAS  Google Scholar 

  15. Lieber, M. R. & Steck, T. L. Dynamics of the holes in human erythrocyte membrane ghosts. J. Biol. Chem. 257, 11660–11666 (1982).

    CAS  Google Scholar 

  16. Parsegian, V. A., Rand, R. P. & Gingell, D. Lessons for the study of membrane fusion from membrane interactions in phospholipid systems. Ciba Found. Symp. 103, 9–27 (1984).

    CAS  Google Scholar 

  17. Chernomordik, L. V., Melikyan, G. B. & Chizmadzhev, Y. A. Biomembrane fusion: a new concept derived from model studies using two interacting planar lipid bilayers. Biochim. Biophys. Acta 906, 309–352 (1987).

    Article  CAS  Google Scholar 

  18. Steinhardt, R. A., Bi, G. & Alderton, J. M. Cell membrane resealing by a vesicular mechanism similar to neurotransmitter release. Science 263, 390–393 (1994).

    Article  CAS  Google Scholar 

  19. Xie, X. Y. & Barrett, J. N. Membrane resealing in cultured rat septal neurons after neurite transection: evidence for enhancement by Ca2+-triggered protease activity and cytoskeletal disassembly. J. Neurosci. 11, 3257–3267 (1991).

    Article  CAS  Google Scholar 

  20. Miyake, K. & McNeil, P. L. Vesicle accumulation and exocytosis at sites of plasma membrane disruption. J. Cell Biol. 131, 1737–1745 (1995).

    Article  CAS  Google Scholar 

  21. Togo, T., Alderton, J. M., Bi, G. Q. & Steinhardt, R. A. The mechanism of facilitated cell membrane resealing. J. Cell Sci. 112, 719–731 (1999).

    CAS  Google Scholar 

  22. Bi, G.-Q., Alderton, J. M. & Steinhardt, R. A. Calcium-regulated exocytosis is required for cell membrane resealing. J. Cell Biol. 131, 1747–1758 (1995).

    Article  CAS  Google Scholar 

  23. Coorsen, J. H., Schmitt, H. & Almers, W. Ca2+ triggers massive exocytosis in Chinese hamster ovary cells. EMBO J. 15, 3787–3791 (1996).

    Article  Google Scholar 

  24. Penner, R. & Neher, E. The role of calcium in stimulus–secretion coupling in excitable and non-excitable cells. J. Exp. Biol. 139, 329–345 (1988).

    CAS  Google Scholar 

  25. Rodriguez, A., Webster, P., Ortego, J. & Andrews, N. W. Lysosomes behave as Ca2+-regulated exocytotic vesicles in fibroblasts and epithelial cells. J. Cell Biol. 137, 93–104 (1997).

    Article  CAS  Google Scholar 

  26. McNeil, P. L., Vogel, S. S., Miyake, K. & Terasaki, M. Patching plasma membrane disruptions with cytoplasmic membrane. J. Cell Sci. 113, 1891–1902 (2000).

    CAS  Google Scholar 

  27. Wallace, R. A., Opresko, L., Wiley, H. S. & Selman, K. The oocyte as an endocytic cell. Ciba Found. Symp. 98, 228–248 (1983).

    CAS  Google Scholar 

  28. Dai, J. & Sheetz, M. P. Membrane tether formation from blebbing cells. Biophys. J. 77, 3363–3370 (1999).

    Article  CAS  Google Scholar 

  29. Raucher, D. & Sheetz, M. P. Characteristics of a membrane reservoir buffering membrane tension. Biophys. J. 77, 1992–2002 (1999).

    Article  CAS  Google Scholar 

  30. Needham, D. & Hochmuth, R. M. Electro-mechanical permeabilization of lipid vesicles. Role of membrane tension and compressibility. Biophys. J. 55, 1001–1009 (1989).

    Article  CAS  Google Scholar 

  31. Raucher, D. & Sheetz, M. P. Cell spreading and lamellipodial extension rate is regulated by membrane tension. J. Cell Biol. 148, 127–136 (2000).

    Article  CAS  Google Scholar 

  32. Togo, T., Krasieva, T. B. & Steinhardt, R. A. A decrease in membrane tension precedes successful cell-membrane repair. Mol. Biol. Cell 11, 4339–4346 (2000).

    Article  CAS  Google Scholar 

  33. Clarke, M. S. F. & McNeil, P. L. Syringe loading introduces macromolecules into living mammalian cell cytosol. J. Cell Sci. 102, 535–541 (1992).

    Google Scholar 

  34. Bakker, A. C., Webster, P., Jacob, W. A. & Andrews, N. W. Homotypic fusion between aggregated lysosomes triggered by elevated [Ca2+]i in fibroblasts. J. Cell Sci. 110, 2227–2238 (1997).

    CAS  Google Scholar 

  35. McNeil, P. L. & Baker, M. Cell surface events during resealing visualized by scanning electron microscopy. Cell Tiss. Res. (in the press).

  36. Rothman, J. E. The protein machinery of vesicle budding and fusion. Protein Sci. 5, 185–194 (1996).

    Article  CAS  Google Scholar 

  37. Nichols, B. J., Ungermann, C., Pelham, H. R., Wickner, W. T. & Haas, A. Homotypic vacuolar fusion mediated by t- and v-SNAREs. Nature 387, 199–202 (1997).

    Article  CAS  Google Scholar 

  38. Mayorga, L. S. et al. Calcium-dependent fusion among endosomes. J. Biol. Chem. 269, 30927–30934 (1994).

    CAS  Google Scholar 

  39. Eddleman, C. S., Bittner, G. D. & Fishman, H. M. Barrier permeability at cut axonal ends progressively decreases until an ionic seal is formed. Biophys. J. (in the press).

  40. Eddleman, C. S., Ballinger, M. L., Smyers, M. E., Fishman, H. M. & Bittner, G. D. Endocytotic formation of vesicles and other membranous structures induced by Ca2+ and axolemmal injury. J. Neurosci. 18, 4029–4041 (1998).

    Article  CAS  Google Scholar 

  41. Eddleman, C. S. et al. Repair of plasmalemmal lesions by vesicles. Proc. Natl Acad. Sci. USA 94, 4745–4750 (1997).

    Article  CAS  Google Scholar 

  42. Godell, C. M. et al. Calpain activity promotes the sealing of severed giant axons. Proc. Natl Acad. Sci. USA 94, 4751–4756 (1997).

    Article  CAS  Google Scholar 

  43. Howard, M. J., David, G. & Barrett, J. N. Resealing of transected myelinated mammalian axons in vivo: evidence for involvement of calpain. Neuroscience 93, 807–815 (1999).

    Article  CAS  Google Scholar 

  44. Gitler, D. & Spira, M. E. Real time imaging of calcium-induced localized proteolytic activity after axotomy and its relation to growth cone formation. Neuron 20, 1123–1135 (1998).

    Article  CAS  Google Scholar 

  45. Spira, M. E., Benbassat, D. & Dormann, A. Resealing of the proximal and distal cut ends of transected axons: electrophysiological and ultrastructural analysis. J. Neurobiol. 24, 300–316 (1993).

    Article  CAS  Google Scholar 

  46. Ziv, N. E. & Spira, M. E. Localized and transient elevations of intracellular Ca2+ induce the dedifferentiation of axonal segments into growth cones. J. Neurosci. 17, 3568–3579 (1997).

    Article  CAS  Google Scholar 

  47. Jedd, G. & Chua, N. H. A new self-assembled peroxisomal vesicle required for efficient resealing of the plasma membrane. Nature Cell Biol. 2, 226–231 (2000).

    Article  CAS  Google Scholar 

  48. Bi, G. Q. et al. Kinesin- and myosin-driven steps of vesicle recruitment for Ca2+-regulated exocytosis. J. Cell Biol. 138, 999–1008 (1997).

    Article  CAS  Google Scholar 

  49. Taylor, D. L. & Fechheimer, M. Cytoplasmic structure and contractility: the solation–contraction coupling hypothesis. Phil. Trans. R. Soc. Lond. B 299, 185–197 (1982).

    Article  CAS  Google Scholar 

  50. Bement, W. M., Mandato, C. A. & Kirsch, M. N. Wound-induced assembly and closure of an actomyosin purse string in Xenopus oocytes. Curr. Biol. 9, 579–587 (1999).

    Article  CAS  Google Scholar 

  51. Ziv, N. E. & Spira, M. E. Induction of growth cone formation by transient and localized increases of intracellular proteolytic activity. J. Cell Biol. 140, 223–232 (1998).

    Article  CAS  Google Scholar 

  52. Detrait, E. et al. Axolemmal repair requires proteins that mediate synaptic vesicle fusion. J. Neurobiol. (in the press).

  53. Martinez, I. et al. Synaptotagmin VII regulates Ca2+-dependent exocytosis of lysosomes in fibroblasts. J. Cell Biol. 148, 1141–1149 (2000).

    Article  CAS  Google Scholar 

  54. Miki, N. et al. Role of annexin in membrane resealing. Mol. Biol. Cell 11, 384 (2000).

    Google Scholar 

  55. Chen, W. T. Mechanism of retraction of the trailing edge during fibroblast movement. J. Cell Biol. 90, 187–200 (1981).

    Article  CAS  Google Scholar 

  56. Kreitzer, A. C., Gee, K. R., Archer, E. A. & Regehr, W. G. Monitoring presynaptic calcium dynamics in projection fibers by in vivo loading of a novel calcium indicator. Neuron 27, 25–32 (2000).

    Article  CAS  Google Scholar 

  57. Weiner, D. B. & Kennedy, R. C. Genetic vaccines. Scient. Am. 281, 50–57 (1999).

    Article  CAS  Google Scholar 

  58. Wolff, J. A. et al. Direct gene transfer into mouse muscle in vivo. Science 247, 1465–1468 (1990).

    Article  CAS  Google Scholar 

  59. Delaney, K., Davison, I. & Denk, W. Odour-evoked [Ca2+] transients in mitral cell dendrites of frog olfactory glomeruli. Eur. J. Neurosci. (in the press).

  60. McNeil, P. L., Murphy, R. F., Lanni, F. & Taylor, D. L. A method for incorporating macromolecules into adherent cells. J. Cell Biol. 98, 1556–1564 (1984).

    Article  CAS  Google Scholar 

  61. Grembowicz, K. P., Sprague, D. & McNeil, P. L. Temporary disruption of the plasma membrane is required for c-fos expression in response to mechanical stress. Mol. Biol. Cell 10, 1247–1257 (1999).

    Article  CAS  Google Scholar 

  62. McNeil, P. L., Muthukrishnan, L., Warder, E. & D'Amore, P. A. Growth factors are released by mechanically wounded endothelial cells. J. Cell Biol. 109, 811–822 (1989).

    Article  CAS  Google Scholar 

  63. Ku, P. & D'Amore, P. A. Regulation of basic fibroblast growth factor (bFGF) gene and protein expression following its release from sublethally injured endothelial cells. J. Cell. Biochem. 58, 328–343 (1995).

    Article  CAS  Google Scholar 

  64. Zhelev, D. V. & Needham, D. Tension-stabilized pores in giant vesicles: determination of pore size and pore line tension. Biochim. Biophys. Acta 1147, 89–104 (1993).

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Paul L. McNeil or Mark Terasaki.

Rights and permissions

Reprints and permissions

About this article

Cite this article

McNeil, P., Terasaki, M. Coping with the inevitable: how cells repair a torn surface membrane. Nat Cell Biol 3, E124–E129 (2001). https://doi.org/10.1038/35074652

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/35074652

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing