An In Silico Analogue of In Vitro Systems Used to Study Epithelial Cell Morphogenesis

  • Mark R. Grant
  • C. Anthony Hunt
Part of the Lecture Notes in Computer Science book series (LNCS, volume 4210)

Abstract

In vitro model systems are used to study epithelial cell growth, morphogenesis, differentiation, and transition to cancer-like forms. MDCK cell lines (from immortalized kidney epithelial cells) are widely used examples. Prominent in vitro phenotypic attributes include stable cyst formation in embedded culture, inverted cyst formation in suspension culture, and lumen formation in overlay culture. We present a low-resolution system analogue in which space, events, and time are discretized; object interaction uses a two-dimensional grid similar to a cellular automaton. The framework enables “cell” agents to act independent using an embedded logic based on axioms. In silico growth and morphology can mimic in vitro observations in four different simulated environments. Matched behaviors include stable “cyst” formation. The in silico system is designed to facilitate experimental exploration of outcomes from changing components and features, including the embedded logic (the in silico analogue of a mutation or epigenetic change). Some simulated behaviors are sensitive to changes in logic. In two cases, the change caused cancer-like growth patterns to emerge.

Keywords

Agent-based cystogenesis epithelial model morphogenesis simulation synthetic systems biology complex systems 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    O’brien, L.E., Zegers, M.M., Mostov, K.E.: Opinion: Building epithelial architecture: insights from three-dimensional culture models. Nat. Rev. Mol. Cell Biol. 3, 531–537 (2002)CrossRefGoogle Scholar
  2. 2.
    Hall, H.G., Farson, D.A., Bissel, M.J.: Lumen formation by epithelial cell lines in response to collagen overlay: a morphogenetic model in culture. Proc. Natl. Acad. Sci. 79, 4672–4676 (1982)CrossRefGoogle Scholar
  3. 3.
    Wang, A.Z., Og, K., Nelson, W.J.: Steps in the morphogenesis of a polarized epithelium I. Uncoupling the roles of cell-cell and cell-substratum contact in establishing plasma membrane polarity in multicellular epithelial (MDCK) cysts. J. Cell Sci. 95, 137–151 (1990)Google Scholar
  4. 4.
    Ojakian, G.K., Ratcliffe, D.R., Schwimmer, R.: Integrin regulation of cell-cell adhesion during epithelial tubule formation. J. Cell Sci. 114, 941–952 (2001)Google Scholar
  5. 5.
    Ropella, G.E.P., Hunt, C.A., Nag, D.A.: Using heuristic models to bridge the gap between analytic and experimental models in biology. In: Spring Simulation Multiconference, The Society for Modeling and Simulation International, San Diego, CA, April 2-8 (2005)Google Scholar
  6. 6.
    Ropella, G.E.P., Hunt, C.A., Sheikh-Bahaei, S.: Methodological considerations of heuristic modeling of biological systems. In: The 9th World Multi-Conference on Systemics, Cybernetics and Informatics, Orlando Fl, July 10-13 (2005b)Google Scholar
  7. 7.
    Steels, L., Brooks, R.: The artificial life route to artificial intelligence: building embodied, situated agents. Lawrence Earlbaum Associates, Hillsdale (1995)Google Scholar
  8. 8.
    Ermentrout, G.B., Edelstein-Keshet, L.: Cellular automata approaches to biological modeling. J. Theor. Biol. 160, 97–133 (1993)CrossRefGoogle Scholar
  9. 9.
    Taub, M., Chuman, L., Saier, M.H.J., Sato, G.: Growth of madin-darby canine kdiney epithelial cell (MDCK) line in hormone-supplemented, serum-free medium. Proc. Natl. Acad. Sci. 76, 3338–3342 (1979)CrossRefGoogle Scholar
  10. 10.
    Madin, S.H., Darby, N.B.: As catalogued (1958) in American Type Culture Collection Catalogue of Strains. 2 (1975)Google Scholar
  11. 11.
    Nelson, C.M., Jean, R.P., Tan, J.L., Liu, W.F., Sniadecki, N.J., et al.: Emergent Patterns of growth controlled by multicellular form and mechanics. Proc. Natl. Acad. Sci. 102, 11594–11599 (2005)CrossRefGoogle Scholar
  12. 12.
    Schwimmer, R., Ojakian, G.K.: The a2b1 integrin regulates collagen-mediated MDCK epithelial membrane remodeling and tube formation. Journal of Cell Science 108, 2487–2498 (1995)Google Scholar
  13. 13.
    Warren, S.L., Nelson, W.J.: Nonmitogenic morphoregulatory action of pp60v-src on multicellular epithelial structures. Molec. Cell Biol. 7, 1326–1337 (1987)Google Scholar
  14. 14.
    Wang, A.Z., Ojakian, G.K., Nelson, W.J.: Steps in the morphogenesis of a polarized epithelium. J. Cell Sci. 95, 153–165 (1990)Google Scholar
  15. 15.
    Lin, H.-H., Yang, T.-P., Jian, S.-T., Yang, H.-Y., Tang, M.-J.: Bcl-2 overexpression prevents apoptosis-induced Madin-Darby canine kidney simple epithelial cyst formation. Kidney International 55, 168–178 (1999)CrossRefGoogle Scholar
  16. 16.
    Nelson, W.J.: Epithelial cell polarity from the outside looking in. News Physiol. Sci. 18, 143–146 (2003)Google Scholar
  17. 17.
    Thiery, J.P.: Epithelial-mesenchymal transitions in tumor progression. Nat. Rev. Cancer 10, 442–454 (2002)CrossRefGoogle Scholar
  18. 18.
    Wodarz, A.: Tumor suppressors: linking cell polarity and growth control. Curr. Biol. 10, R624–R626 (2000)CrossRefGoogle Scholar
  19. 19.
    Chambard, M., Verrier, B., Gabrion, J., Mauchamp, J.: Polarity Reversal of inside-out Thyroid-Follicles Cultured within Collagen Gel - Reexpression of Specific Functions. Biology of the Cell 51, 315–326 (1984)Google Scholar
  20. 20.
    Tang, M.-J., Hu, J.-J., Lin, H.-H., Chiu, W.-T., Jiang, S.-T.: Collagen gel overlay induces apoptosis of polarized cells in culture: disoriented cell death? Am. J. Physiol. 275, C921–C931 (1998)Google Scholar
  21. 21.
    Meredith, J.E.J., Fazeli, B., Schwartz, M.A.: The extracellular matrix as a cell survival factor. Mol. Biol. Cell 4, 953–961 (1993)Google Scholar
  22. 22.
    Hayashi, T., Carthew, R.W.: Surface mechanics mediate pattern formation in the developing retina. Nature 431, 647–652 (2004)CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2006

Authors and Affiliations

  • Mark R. Grant
    • 1
  • C. Anthony Hunt
    • 1
  1. 1.Joint UCSF/UCB Bioengineering Graduate Group and The Biosystems Group, Department of Biopharmaceutical SciencesThe University of CaliforniaSan FranciscoUSA

Personalised recommendations