The Differential Interfacial Tension Hypothesis (DITH): A Comprehensive Theory for the Self-Rearrangement of Embryonic Cells and Tissues

[+] Author and Article Information
G. Wayne Brodland

Department of Civil Engineering, University of Waterloo, Waterloo ON N2L 3G1, Canada

J Biomech Eng 124(2), 188-197 (Mar 29, 2002) (10 pages) doi:10.1115/1.1449491 History: Received June 07, 2001; Revised December 05, 2001; Online March 29, 2002
Copyright © 2002 by ASME
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Townes,  P. S., and Holtfreter,  J., 1955, “Directed Movements and Selective Adhesion of Embryonic Amphibian Cells,” J. Exp. Zool., 128, p. 53.
Moscona, A., 1960, “Patterns and Mechanisms of Tissue Reconstruction from Dissociated Cells,” in Developing Cell Systems and Their Control, D. Rudnick, ed., Academic Press, New York, pp. 45–70.
Steinberg,  M. S., 1962, “On the Mechanism of Tissue Reconstruction by Dissociated Cells. I. Population Kinetics, Differential Adhesiveness, and the Absence of Directed Migrations,” Proc. Natl. Acad. Sci. U.S.A., Vol. 48, pp. 1577–1582.
Steinberg,  M. S., 1962, “On the Mechanism of Tissue Reconstruction by Dissociated Cells. II. Time-course of Events,” Science, 137, pp. 762–763.
Steinberg,  M. S., 1962, “On the Mechanism of Tissue Reconstruction by Dissociated Cells. III. Free Energy Relations and the Reorganization of Fused, Heronomic Tissue Fragments,” Proc. Natl. Acad. Sci. U.S.A., Vol. 48, pp. 1769–1776.
Steinberg,  M. S., 1970, “Does Differential Adhesion Govern Self-Assembly Processes in Histogenesis? Equilibrium Configurations and the Emergence of a Hierarchy Among Populations of Embryonic Cells,” J. Exp. Zool., 173, pp. 395–434.
Steinberg,  M. S., 1975, “Adhesion-Guided Multicellular Assembly: A Commentary upon the Postulates, Real and Imaged, of the Differential Adhesion Hypothesis, With Special Attention to Computer Simulations of Cell Sorting,” J. Theor. Biol., 55, pp. 431–443.
Harris,  A., 1975, “Is Cell Sorting Caused by Differences in the Work of Intercellular Adhesion? A Critique on the Steinberg Hypothesis,” J. Theor. Biol., 61, pp. 267–285.
Ohmoro,  T., and Maeda,  Y., 1986, “Implications of Differential Chemotaxis and Cohesiveness for Cell Sorting in the Development of Dictyostelium Discoideum,” Dev., Growth Differ., 28, pp. 169–175.
Foty, R., and Steinberg, M. S., 1995, “Liquid Properties of Living Cell Aggregates: Measurement and Morphogenetic Significance of Tissue Interfacial Tensions,” in Interplay of Genetic and Physical Properties in the Development of Biological Form, D. Beysens, G. Forgacs, and F. Gaill, eds., World Scientific, Pub. Co. Pte. Lt., pp. 63–73.
Marrs,  J. A., and Nelson,  W. J., 1996, “Cadherin Cell Adhesion Molecules in Differentiation and Embryogenesis,” Int. Rev. Cytol., 165, pp. 159–205.
Armstrong,  P., 1989, “Cell Sorting Out: The Self-Assembly of Tissues In Vitro,” Crit. Rev. Biochem. Mol. Biol., 24, pp. 119–149.
Steinberg,  M. S., 1996, “Adhesion in Development: An Historical Overview,” Dev. Biol., 180, pp. 377–388.
Brodland,  G. W., and Chen,  H. H., 2000, “The Mechanics of Cell Sorting and Envelopment,” J. Biomech., 33, pp. 845–851.
Kuhn, T., 1962, The Structure of Scientific Revolutions, University of Chicago Press, Chicago, IL.
Phillips,  H., Steinberg,  M. S., and Lipton,  B. H., 1977, “Embroyonic Tissues as Elasticoviscous Liquids II. Direct Evidence for Cell Slippage in Centrifuges Aggregates,” Dev. Biol., 59, pp. 124–134.
Antonelli,  P. L., Rogers,  T. D., and Willard,  M. A., 1973, “Geometry and the Exchange Principle in Cell Aggregation Kinetics,” J. Theor. Biol., 41, pp. 1–21.
Goel,  N. S., and Rogers,  G., 1978, “Computer Simulation of Engulfment and Other Movements of Embryonic Tissues,” J. Theor. Biol., 71, pp. 103–140.
Rogers,  G., and Goel,  N. S., 1978, “Computer Simulation of Cellular Movements: Cell-sorting, Cellular Migration Through a Mass of Cells and Contact Inhibition,” J. Theor. Biol., 71, pp. 141–166.
Honda,  H., Yamanaka,  H., and Eguchi,  G., 1986, “Transformation of a Polygonal Cellular Pattern During Sexual Maturation of the Avian Oviduct Epithelium: Computer Simulation,” J. Embryol. Exp. Morphol., 98, pp. 1–19.
Graner,  F., and Sawada,  Y., 1993, “Can Surface Adhesion Drive Cell Rearrangement? Part II: A Geometrical Model,” J. Theor. Biol., 164, pp. 477–506.
Glazier,  J., and Graner,  F., 1993, “Simulation of the Differential Adhesion Driven Rearrangement of Biological Cells,” Phys. Rev. E, 47, pp. 2122–2154.
Mochizuki,  A., Iwasa,  Y., and Takeda,  Y., 1996, “A Stochastic Model for Cell Sorting and Measuring Cell-Cell Adhesion,” J. Theor. Biol., 179, pp. 129–146.
Chen,  H. H., and Brodland,  G. W., 2000, “Cell-Level Finite Element Studies of Viscous Cells in Planar Aggregates,” ASME J. Biomech. Eng., 122, pp. 394–401.
Chen, H. H., and Brodland, G. W., 1997, “Finite Element Simulation of Differential Adhesion-Driven Cell Sorting and Spreading,” 16th Canadian Congress of Applied Mechanics (CANCAM), L. Cloutier and D. Rancourt, eds., June 1–5, Quebec, pp. 597–598.
Brodland,  G. W., and Chen,  H. H., 2000, “The Mechanics of Heterotypic Cell Aggregates: Insights from Computer Simulations,” ASME J. Biomech. Eng., 122, pp. 402–407.
Davies, J., and Rideal, E., 1963, Interfacial Phenomena, Academic Press, New York.
Foty,  R. A., Pfleger,  C. M., Forgacs,  G., and Steinberg,  M. S., 1996, “Surface Tensions of Embryonic Tissues Predict their Mutual Envelopment Behavior,” Development, 122, pp. 1611–1620.
Friedlander,  D. R., Mege,  R., Cunningham,  B. A., and Edelman,  G. M., 1989, “Cell Sorting-Out is Modulated by Both the Specificity and Amount of Different Cell Adhesion Molecules (CAMs) Expressed on Cell Surfaces,” Proc. Natl. Acad. Sci. U.S.A., Vol. 86, pp. 7043–7047.
Aplin,  A. E., Howe,  A. K., and Juliano,  R. L., 1999, “Cell Adhesion Molecules, Signal Transduction and Cell Growth,” Curr. Opin. Cell Biol., 11, pp. 737–744.
Huynh-Do,  U., Stein,  E., Lane,  A. A., Liu,  H., Cerretti,  D. P., and Daniel,  T. O., 1999, “Surface Densities of Ephrin-B1 Determine EphB1-Coupled Activation of Cell Attachment through αvβ3 and α5β1 Integrins,” EMBO J., 18, pp. 2165–2173.
Petruzzelli,  L., Takami,  M., and Humes,  D., 1999, “Structure and Function of Cell Adhesion Molecules,” Am. J. Med., 106, pp. 467–476.
Xu,  Q., Mellitzer,  G., Robinson,  V., and Wilkinson,  D. G., 1999, “In Vivo Cell Sorting in Complementary Segmental Domains Mediated by Eph Receptors and Ephrins,” Nature, 399, pp. 267–271.
Honda,  H., 1983, “Geometrical Models for Cells in Tissues,” Int. Rev. Cytol., 81, pp. 191–248.
Phillips,  H., and Steinberg,  M. S., 1978, “Embryonic Tissues as Elasticoviscous Liquids I. Rapid and Slow Shape Changes in Centrifuges Cell Aggregates,” J. Cell. Sci., 30, pp. 1–20.
Chen, H. H., 1998, “Finite Element-Based Computer Simulations of Motility, Sorting, and Deformation in Biological Cells,” Ph.D. thesis, University of Waterloo, Waterloo, Canada.
Brodland, G. W., 2000, “Conditions for Cell Sorting, Mixing and Checkerboard Pattern Formation Determined Using Mechanics and Computer Simulations,” 2000 Advances in Bioengineering (BED Vol. 48), (IMECE), Nov. 5–10 Orlando, T. A. Conway, ed., ASME, New York.
Steinberg,  M. S., 1963, “Reconstruction of Tissues by Dissociated Cells,” Science,141, pp. 401–408.
Gumbiner,  B. M., 1996, “Cell Adhesion: The Molecular Basis of Tissue Architecture and Morphogenesis,” Cell, 84, pp. 345–357.
Opas,  M., 1995, “Cellular Adhesiveness, Contractility, and Traction: Stick, Grip and Slip Control,” Biochem. Cell Biol., 73, pp. 311–316.
Alberts, B., Bray, D., Lewis, J., Raff, M., Roberts, M., and Watson, J., 1997, Molecular Biology of the Cell, 2nd Edition, Garland Publishing Inc., New York.
Clausi,  D. A., and Brodland,  G. W., 1993, “Mechanical Evaluation of Theories of Neurulation Using Computer Simulations,” Development, 118, pp. 1013–1023.
Torza,  A., and Mason,  S. G., 1969, “Coalescence of Two Immiscible Liquid Drops,” Science, 163, pp. 813–814.
Torza,  A., and Mason,  S. G., 1970, “Three-Phase Interactions in Shear and Electric Fields,” J. Colloid Interface Sci., 33, pp. 67–83.
Beysens,  D. A., Forgacs,  G., and Glazier,  J. A., 2000, “Cell Sorting is Analogous to Phase Ordering in Fluids,” Proc. Natl. Acad. Sci. U.S.A., Vol. 97, pp. 9467–9471.
Mochizuki,  A., Wada,  N., Ide,  H., and Iwasa,  Y., 1998, “Cell-Cell Adhesion in Limb-Formation, Estimated From Photographs of Cell Sorting Experiments Based on a Spatial Stochastic Model,” Dev. Dyn., 211, pp. 204–214.
Mombach,  J. C. M., and Glazier,  J. A., 1996, “Single Cell Motion in Aggregates of Embryonic Cells,” Phys. Rev. Lett., 76, pp. 3032–3035.


Grahic Jump Location
Phenomena that occur in aggregates of embryonic cells. Expanded from Armstong 12.
Grahic Jump Location
The cell model. (a) Structural components important to cells include microfilaments, microtubules, the cell membrane, cell adhesion molecules (CAMs), the cell cytoplasm and networks of intermediate filaments (IFs). (b) The mechanical effects of these components are approximated by an equivalent interfacial tension γLD and an effective cytoplasmic viscosity μ, and represented, respectively, by rod-like and triangular elements in the finite element model. After Brodland and Chen 26, although in the present context, a cross-section rather than a plan view is intended.
Grahic Jump Location
The forces acting at a generic triple junction
Grahic Jump Location
A summary of the conditions for cell sorting, mixing, and checkerboard-pattern formation. The arrows along the top of the figure indicate where the simulations shown in Fig. 5 fall along the γLD continuum.
Grahic Jump Location
Some of the phenomena that can occur in a heterotypic planar aggregate. (a) Initial configuration with γLL=12 and γDD=20.(b) Total mixing and partial checkerboard (γLD=3).(c) Partial mixing (γLD=14).(d) Partial sorting (γLD=22).(e) Strong sorting, but edges do not release from the boundaries for the reasons described in the text (γLD=40).(f) Fluid behavior starting from configuration (e), as characterized by no tensions along the homotypic interfaces (γLLDD=0 and γLD=40).
Grahic Jump Location
Triple junctions involving two cells and a medium. Part (b) of the figure can be interpreted as two individual cells of types L and D or as two homotypic cell masses of types L and D.
Grahic Jump Location
A summary of the conditions for engulfment and separation of tissues. The arrow marked A corresponds to the simulation shown in Fig. 8, while that marked B corresponds to one in which separation occurs (unpublished) and for which γLMDM=20 and γLD=150.
Grahic Jump Location
Total engulfment of one type of tissue (L) by another (D)(γLLDD=5,γLD=25,γLM=150,γDM=70)
Grahic Jump Location
An aggregate consisting of three cell types. (a) Initial configuration of dark (D), intermediate (I) and light (L) cells (γDD=25,γIILLIMLM=20,γDIDL=50,γIL=10,γDM=100).(b) Final configuration showing total engulfing of the dark cells by the intermediate and light cells (with one exception), active mixing of the light and intermediate cells with each other, and sorting of the dark cells from the other two types, all as predicted by the theory. The dark cell masses do not totally round up due to mechanical interactions with the surrounding cells.
Grahic Jump Location
Sorting in three-dimensions versus two-dimensions. Cells that appear to be isolated islands in a cross-sectional plane or two-dimensional simulation may be connected together by bridges that exist if the third dimension were included. Contraction along the surfaces of such bridges would cause them to shorten and would draw islands such as A and B together, while in other locations taking cells out of the plane, as implied at C.



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