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CELLULAR PATTERNS

A. Šiber
Institute of Physics, Zagreb, Croatia

P. Ziherl
Faculty of Mathematics and Physics, University of Ljubljana
and Jožef Stefan Institute, Ljubljana, Slovenia
CRC Press
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To Mira, Goga, and Katja
Contents

Chapter 1  Introduction 1

1.1 EMERGENCE OF PATTERNS 1

1.2 GROWING A FORM 4
1.3 WHY MODELS? 9
1.4 THE MICROSCOPE 12

Chapter 2  Cells as physical objects 15

2.1 CYTOSKELETON AND MEMBRANE 16

2.2 LIQUID-DROP-LIKE BEHAVIOR 19
2.2.1 Micropipette aspiration 20
2.2.2 Interpreting experiments 24
2.2.3 Viscoelasticity 29
2.3 CELLS IN CONTACT 31
2.3.1 Adhesion 31
2.3.2 Traction 35
2.4 DIFFERENTIAL ADHESION HYPOTHESIS 38
2.4.1 Tissue envelopment and cell dispersal 40
2.4.2 Cell surface tension vs. tissue surface tension 41
PROBLEMS 44

Chapter 3  In-plane structure of single-layer tissues 49

3.1 GEOMETRY OF TILINGS 50

3.2 RANDOM TILINGS 57
3.2.1 Lewis’ law 61
3.2.2 Aboav–Weaire law 64
3.2.3 Statistical-mechanical considerations 65
3.3 PHYSICAL MODELS 67
3.3.1 Area- and perimeter-elasticity model 68
3.3.2 Topological mitosis-only model 75
3.3.3 Fixed-area/fixed-perimeter model 79

vii
viii  Contents

3.3.4 Dirichlet-tessellation perspective 83

3.3.5 Binary and ternary tissues 86
PROBLEMS 94

Chapter 4  Shape of epithelia 99

4.1 TISSUE AS SUPPORTED LAYER 103

4.1.1 Area-mismatch buckling 104
4.1.2 Polarity-induced folding 111
4.1.3 Epithelial dysplasia 115
4.2 AGENT-BASED MODELS 119
4.2.1 Curvature-dependent division in renewing epithelium 122
4.2.2 Shape of crypts 126
4.2.3 Rapid folding 130
PROBLEMS 134

Chapter 5  Morphogenesis 139

5.1 INVAGINATION 143

5.1.1 Drying-drop model 145
5.1.2 Spontaneous-curvature model 147
5.1.3 Localized active deformation 151
5.1.4 Excitable epithelium 154
5.1.5 Global active deformation 158
5.1.6 Measuring forces 163
5.2 CONVERGENT EXTENSION 167
5.2.1 Anisotropic differential adhesion model 169
5.2.2 Passive deformation 173
5.2.3 Active hydrodynamic model 175
5.3 INTERCALATION 183
5.4 INGRESSION 186
5.5 MESENCHYMAL STRUCTURES 187
5.6 EPIBOLY 192
5.7 INVOLUTION 195
PROBLEMS 197

Chapter 6  Bulk tissues 201

6.1 SPACE-FILLING PATTERNS 209

6.1.1 The Kelvin problem 209
6.1.2 Random foam 211
 Contents  ix

6.1.3 Melzak’s problem 215

6.1.4 Vesicle-aggregate model 217
6.1.5 Sequential cell sheet formation 221
6.2 TISSUE ELASTICITY 223
6.2.1 Liquid foams 226
6.2.2 Cellular solids 228
PROBLEMS 233

Chapter 7  Afterthoughts 235

References 241

Index 255
Preface

he idea that living matter can be viewed as a mechanical system is hardly new. In
T addition to physiological functions characteristic of life alone, animals and plants grow,
move, deform, push on their environment, and lift loads, etc., just like a machine, and these
processes must involve forces and expended work except that the energy is provided in the
form of food rather than fuel. Yet over the past decade or two the mechanistic aspect of
biophysics has become increasingly more central both at the macroscopic level revolving
around the shape of tissues and at the microscopic level, say in the context of molecular
motors and elaborate protein machinery resembling pumps, levers, articulated arms, and
other hardware. In part, the recent advances in the field coincide with the advent of ex-
treme mechanics as an umbrella term encompassing large deformations, active materials,
instabilities, and nonlinear response of materials.
A hundred years after Thompson’s remarkable treatise On Growth and Form, the mecha-
nistic view of biological systems is fairly comprehensive, drawing both from the ever more
detailed experimental studies and from the theoretical developments in physics, especially
in soft condensed matter. In this book, we outline the understanding of tissue structure and
form by combining observations and measurements with models, which inevitably differ in
the level of description as well as in the premises and objectives. Instead of providing a
review of the state of the art, we offer a more pedagogical approach, which amalgamates
toy models and sophisticated theories, some of which address the same phenomenon. While
we were writing the book our personal opinion of the different approaches matured, and
we arrived at the conclusion that few models are completely wrong and none of them is
completely correct. We hope that the book will help readers to appreciate the best in each
model and encourage them to develop their own theories.
So far no single monograph or textbook has influenced the field as much as On Growth
and Form, which is still a source of inspiration. Naturally, there exist many fine volumes
that discuss similar or related topics, each from a different angle, and our book offers yet
another perspective. In terms of length scale, it is one level beyond Boal’s Mechanics of the
Cell which addresses the physical principles behind the polymeric networks within the cell,
biological membranes, intermembrane forces, and related phenomena. The topics covered
by Davies’ Mechanisms of Morphogenesis are similar to those in our book but the approach
is much more descriptive, going deeper in the biochemical and biological details but hardly
addressing the theoretical aspects and physical modeling. Forgacs and Newman’s Biological
Physics of the Developing Embryo is focused specifically on embryogenesis, morphogenesis,
and organogenesis with more emphasis on theoretical models than Mechanisms of Morpho-
genesis. Our book is technically somewhat more involved than Forgacs and Newman’s but
not as detailed as Cowin and Doty’s Tissue Mechanics, which is concerned primarily with
the various tissues as bulk materials and their description using effective theories of elastic-
ity at an advanced engineering level. Bulk tissues are also discussed in Gibson and Ashby’s
book Cellular Solids, which contains an excellent account of the mechanics of foams.
Three more references come to mind. Aste and Weaire’s The Pursuit of Perfect Pack-
ing is dedicated to efficient space-filling arrangements of various objects from disks and
spheres to soap bubbles. As this subject matter is best described graphically, The Pursuit

xi
xii  Preface

of Perfect Packing includes many images and our book is similar in this respect. As far as
the level of mathematical detail is concerned, our book is reminiscent of Nelson’s Biological
Physics, which in turn deals with biophysics from a more general perspective at a molecular,
statistical-mechanical level. Finally, readers eager for a contemporary view of the theory of
elasticity may want to look at Audoly and Pomeau’s superb Elasticity and Geometry.
The material covered here may be of interest to researchers with a background in physics,
biology, or engineering as well as to students, possibly as a resource for a graduate course on
tissue biophysics or pattern formation. Some prior knowledge in elasticity, hydrodynamics,
geometry, and developmental biology is desirable but not required as the book is dotted
with boxes summarizing the general concepts in these fields. In many derivations, we work
out the main steps but redoing them on a piece of paper will still be a good idea. Also
included is a set of 64 homework problems of various degrees of difficulty; these are divided
among Chapters 2–6 depending on subject matter and can be found at the end of these
chapters. Some of the problems are strongly anchored in the chapter in question and ask
for very precise answers, whereas others are thought provoking and meant to extend the
discussion a bit beyond the scope of the chapter. All problems are pen-and-paper style but
the book also offers many trailheads for a numerical analysis or re-assessment of a given
topic.
In the use of mathematical symbols we opted for the conventional choice in a given
field, knowing that this implies a non-unique notation so that, e.g., C stands for curvature
wherever we talk about elasticity, but in Section 3.3.1 it denotes the contractility of the
acto-myosin ring and in the Box on p. 206 dealing with the Euler formula it stands for
the number of cells. We made sure that the meaning of a symbol in a given context is
still unambiguous. We often use dimensionless quantities, and these too are referred to as
reduced [such as the reduced volume defined by Eq. (5.8)], relative [such as the relative
density introduced in Eq. (6.17)], or dimensionless [such as the dimensionless surface area
in Eq. (6.4)] depending on the practice in a given field. As much of the book is about
the mechanics of continuous media where the Einstein summation convention is common,
we could have used it but decided not to as not all of the readers may not be completely
comfortable with it. Typesetting of the mathematical material follows the convention where
scalars, vectors, and tensors are printed using italic S, bold upright S, and sans-serif S font,
respectively; often it is more convenient to deal with the components of vectors denoted by
Si or tensors denoted by Sij . In a few introductory cases where a single component of a
tensor is of interest we make an exception and typeset it as if were a scalar just so as to
lighten the discussion. When referring to a certain species, we follow the inconsistent but
usual practice where, e.g., Drosophila melanogaster is more often referred to by the genus
rather than as the fruit fly whereas the sea urchin Lytechinus variegatus is more known by
the English name. In the index, we compensate for this by also including the other name
and referring to that used in the book.
Given that the book is about spatial structures and shapes, it contains a considerable
amount of graphical material simply because speaking of a physical form without showing
it makes little sense. Much of this material is adapted or reproduced from other sources as
acknowledged in figure captions or elsewhere as suitable. Many of the original figures were
redrawn, primarily so as to ensure readability in grayscale and a uniform graphical style
but also to use the book format as best as possible. In some cases, additional elements were
included in the figures in order to emphasize a part that is important for the discussion
at hand; where appropriate, figure parts that are inessential or distracting within a given
context were removed. Having said this, we stress that the scientific content of all adapted
figures is unaltered.
While working on the book we learned to better appreciate the value of freely available
public-domain material. We thank all authors whose work included in the book is available
 Preface  xiii

under the Creative Commons license, and organizations such as Wellcome Images which
facilitate the dissemination of these works. We are very grateful to M. Bačič, W. Drenckhan-
Andreatta, R. J. Goodyear, B. Guirao, J. Heuberger, T. Hutton, M. Imai, A. M. Kraynik,
M. Leptin, D. R. McClay, J. Nance, J. Nase, M. Rauzi, D. Taimina, and R. C. Wagner
for providing their previously unpublished images and letting us use them. We also thank
A. Campbell from Above All Images for the aerial photograph of Giant’s Causeway and
T. Knapič from the Slovenian Museum of Natural History for help with the photographs of
sea shells from the Hohenwart collection.
Our understanding of the topic has developed largely through interactions with col-
leagues, collaborators, and friends, often united in a single person. We are grateful to all
of them for sharing their knowledge and ideas, which sometimes inadvertently made us
think of a given problem in a different way. In the final stages of writing, we benefited
very much from the advice and suggestions of Y. Bellaı̈che, C. P. Heisenberg, B. Kavčič,
M. Kokalj Ladan, M. Krajnc, M. Leptin, P. Mrak, P. C. Nelson, M. Popović, M. Rauzi,
J. Rozman, and X. Trepat, and we sincerely thank them all.
We appreciate the continuing support of our institutions—the Institute of Physics in
Zagreb and the Faculty of Mathematics and Physics, University of Ljubljana and the Jožef
Stefan Institute in Ljubljana—as well as the hospitality of the Erwin Schrödinger Interna-
tional Institute for Mathematics and Physics at the University of Vienna (P. Ziherl) and
the Jožef Stefan Institute (A. Šiber) where we spent extended periods of time as visiting
researchers. Much of the book ripened both conceptually and physically while we worked
next door to each other at the Jožef Stefan Institute, but most of it was written in our
homes. We are indebted to our families.
We hope that the readers will like the book and that they will let us know of any
inconsistencies and shortcomings.

A. Šiber and P. Ziherl

 CHAPTER 1

Introduction

ll forms of life are marked by some kind of spatial regularity. The evenly spaced
A arms of the starfish are an example of a high body-scale symmetry (Figure 1.1a). Its
many tube feet neatly arranged around the perimeter, all perpendicular to it and equidistant
from each other, constitute yet another pattern at a smaller length scale. Equally amazing is
the hierarchical order of veins in plant leaves, with the midvein running lengthwise and the
secondary veins branching out at similar angles. The edge of some leaves is flat but in others
(like in the bay leaf in Figure 1.1b) it is decorated with ripples of a well-defined wavelength.
It is easy to find countless examples of patterns in both animals and plants—just think of
fish scales, wild goat horns, fern leaves, sunflower seeds, sea shells, etc.

a) b)

Astropecten aranciacus, a five-arm starfish found in the Mediterranean

Figure 1.1
and east Atlantic (a). A bay tree leaf with a wavy edge (b).

1.1 EMERGENCE OF PATTERNS

Patterns and other types of symmetric forms and structures are very often seen in inanimate
matter too. Take, for example, curtain ripples or waves on the sea, or the von Kármán vortex
street in the wake behind an obstacle in flow (Figure 1.2). This sophisticated spatial and
temporal pattern consists of pairs of vortices swirling in opposite directions and flushed
downstream, with new ones being generated by the backflow behind the obstacle. Even
more fascinating than the pattern itself is that it can be explained solely by the equation

1
2  Cellular Patterns

Von Kármán vortex street in fluid flow past a cylindrical obstacle. The
Figure 1.2
arrow indicates the direction of incoming flow. (Adapted from a photograph by
J. Wagner.)

of motion for a viscous fluid known as the Navier–Stokes equation. Having said this, we
must admit that in the regime where the vortex street is seen this equation cannot really be
solved using pen and paper but this is unimportant. What matters is that we can explain
it theoretically.
Moreover, the main principle behind the Navier–Stokes equation is Newton’s second law,
the basic law of mechanics. In fluids, this simple statement relating force and acceleration—
or, in a more abstract sense, cause and effect—assumes a somewhat different form than
in motion of rigid or elastic bodies but its essence remains the same. Evidently, neither
Newton’s law nor the Navier–Stokes equation contain the blueprint for the vortices; they
are far too general for this. Yet the vortices do emerge in given circumstances provided that
the control parameter of the problem known as the Reynolds number is within a certain
range, neither too small nor too large. In a similar fashion, the equilibrium shape of a
liquid drop is not determined directly by interactions between the molecules but the drop
still assumes the form of a perfect sphere as the minimal-energy state, as we discuss in
Section 2.2.
With the discovery of DNA and the spectacular developments of genetic engineering, it
has become quite common, at least in the general public, to think that genes encode all the
details of an organism. However, we now know that the complex traits such as height and
intelligence are neither completely nor simply written in genes; moreover, they do not have
to be. To enjoy the beauty of the von Kármán vortex street, one does not need to describe
every single feature of each swirl. Just put a cylindrical obstacle in a fast enough flow—and
the pattern is there.
Think of clouds (Figure 1.3). The absence of a blueprint, the “cloud code,” and even
its impossibility are evident. The amount of data needed to encode all structural details
of a particular cloud is obviously huge and irrelevant because cloud formation is deter-
mined by the thermodynamic state of the atmosphere. Although extremely intricate, the
different physical forms of clouds (stratiform, cirriform, stratocumuliform, cumuliform, and
cumulonimbiform) result from specific conditions which promote their development and
growth. To tune the form of clouds, one thus needs to control parameters that are much
more mundane than the form itself—temperature, pressure, humidity, and possibly chemical
composition. These physical parameters define a developmental path leading to a certain
cloud shape consistent with the underlying physical processes. The form is not encoded;
what is encoded is the developmental path that leads to it.
To physicists, relying on general principles rather than on a precise blueprint is just fine.
Compress an elastic rod with enough force and it will buckle forming an arch-like shape.