REVIEW

published: 05 August 2020

doi: 10.3389/fcell.2020.00684

Cellular Membranes, a Versatile

Adaptive Composite Material
Lucas Lamparter 1,2† and Milos Galic 1,2* †
1
Institute of Medical Physics and Biophysics, Faculty of Medicine, University of Münster, Münster, Germany, 2 Cells in Motion
Interfaculty Centre, University of Müenster, Münster, Germany

Cellular membranes belong to the most vital yet least understood biomaterials of live
matter. For instance, its biomechanical requirements substantially vary across species
and subcellular sites, raising the question how membranes manage to adjust to such
dramatic changes. Central to its adaptability at the cell surface is the interplay between
the plasma membrane and the adjacent cell cortex, forming an adaptive composite
material that dynamically adjusts its mechanical properties. Using a hypothetical
composite material, we identify core challenges, and discuss how cellular membranes
solved these tasks. We further muse how pathological changes in material properties
affect membrane mechanics and cell function, before closing with open questions and
future challenges arising when studying cellular membranes.
Edited by: Keywords: composite material, adaptive material, lipid bilayer, plasma membrane, cell cortex
Falk Nimmerjahn,
University of Erlangen-Nuremberg,
Germany
INTRODUCTION
Reviewed by:
Congbao Kang, The cellular membrane is one of the most vital and complex biomaterials in live matter. It is
Experimental Drug Development therefore not surprising that it has over the last decades been the subject of extensive studies, giving
Centre (EDDC), Singapore
insights into a fascinating world of regulatory processes that control localization and activity of
Zheng Shi,
Rutgers, The State University
proteins and lipids in cellular membranes (Singer and Nicolson, 1972; Edidin et al., 1991; Eggeling
of New Jersey, United States et al., 2009). These studies established that biomechanical requirements vary across species and
subcellular sites, indicative of tremendous diversity and adaptability (Vasanji et al., 2004; van Meer
*Correspondence:
Milos Galic
et al., 2008). Yet, despite substantial advancements over the last few decades, we are still lacking a
[email protected] comprehensive understanding of membrane mechanics at the cell surface.
† These authors have contributed
Individual lipids spontaneously self-assemble into a bilayer that is then subject to thermal
equally to this work fluctuations (Faucon et al., 1989), changes in local lipid composition (Estep et al., 1979), and
sustained membrane deformations (Baumgart et al., 2003). Besides lipids, cellular membranes
Specialty section: further contain proteins that not only influence the local lipid environment (Contreras et al.,
This article was submitted to 2011; Laganowsky et al., 2014) and mechanical membrane properties (Shi et al., 2018), but also
Cellular Biochemistry, render the membrane transmissive to incoming stimuli. These signals can alter, among many others
a section of the journal things, membrane potential (Nernst, 1889), shape (Chen et al., 2016; Graber et al., 2017) and lipid
Frontiers in Cell and Developmental
composition (Sugimoto et al., 1984). Importantly, signal-induced changes also affect localization
Biology
and activity of membrane-bound (Carpenter et al., 1978) and cytosolic (Hancock et al., 1989)
Received: 26 January 2020
proteins. One principal target for such signals is the membrane-associated cortical cytoskeleton
Accepted: 06 July 2020
(Svitkina, 2020). Possibly the most striking of its many features is the ability of the cytoskeleton to
Published: 05 August 2020
generate mechanical push and pull forces (Peskin et al., 1993; Huxley and Simmons, 1971). Hence,
Citation:
by coupling membranes to the adjacent cell cortex yields a composite material that is equally able
Lamparter L and Galic M (2020)
Cellular Membranes, a Versatile
to sense and respond to external stimuli.
Adaptive Composite Material. In this review, we will explore the intricate mechanical properties of this adaptive composite
Front. Cell Dev. Biol. 8:684. material. Readers interested in learning more on signaling across cellular membranes or cytoskeletal
doi: 10.3389/fcell.2020.00684 mechanics, we refer to the many excellent reviews written elsewhere (Huber et al., 2013;

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Lamparter and Galic Membranes as Adaptive Composite Material

Lundberg and Borner, 2019; Svitkina, 2020). We begin by four essential material properties mechanical adaptation can be
defining core mechanical terms, before investigating the achieved. Readers interested in learning more about this topic, we
material properties of the cell membrane. Next, we show how refer to work written elsewhere (Kamm and Grodzinsky, 2015).
these properties are affected by its manifold interaction with Finally, let’s recapitulate the types of deformations a material
the cell cortex under physiological and pathophysiological can experience. The properties of a material determine its
conditions. We conclude by pointing out future challenges response to a mechanical stimulus. In its most basic form, such
toward understanding the mechanical properties of this a response can be purely elastic or viscous. An elastic material
exciting biomaterial. returns to its original shape upon distortion, while a viscous
material stays distorted after the load is released. This behavior
can be envisioned as a spring (elastic) or dashpot (viscous),
FUNDAMENTAL CELL MECHANICS respectively (Figure 1B). However, many materials display a
viscoelastic response, where viscous and elastic properties are
The plasma membrane and the cortical cytoskeleton jointly coupled. Basic models for such a behavior are the Maxwell
form a composite material with unique biomechanical features and the Kelvin body (Figure 1C). In a Maxwell body, elastic
(Nicolson, 2014). To fully appreciate this elaborate structure, we and viscous elements are paired in series, thus leading to an
first need to introduce a number of terms that will repeatedly elastic response for fast distortions, while slowly applied load
show up over the following pages. Let’s begin by answering what is captured in a plastic manner. In contrast, the Kelvin body
a composite material actually is. This term – originating from displays elastic and viscous elements in parallel. Hence, under
manufacturing engineering – depicts two or more connected stress the deformation will over time approach the strain response
materials, where the resulting compound exhibits properties of the elastic component, whereby it is slowed down by the
that neither of the individual components by itself possesses viscous element. Consequently, the Maxwell body is capable of
(Westkämper and Warnecke, 2011). The material properties of plastic deformation (i.e., viscoelastic fluid), while the Kelvin body
the composite are a function of the individual material properties will always return to its original shape when the load is released
of its components, their geometry and its interface (i.e., the way (i.e., viscoelastic solid). As above, we refer readers interested in
those materials are connected). Therefore, by changing one of this topic to work written elsewhere (Meyers and Chawla, 2010).
those parameters the overall properties of the composite will be
affected. If this happens by design, for instance in response to
a stimulus, the material is referred to as an adaptive composite ENGINEERING A HYPOTHETICAL
material. For biological membranes, the main components of BIOMIMETIC MEMBRANE
this composite material are the plasma membrane (PM) that
encapsulates the cell, the cell cortex lining the cytosolic site of the Inspired by the famous quote “what I cannot create, I do not
PM, and the membrane-cortex-attachment (MCA) that describes understand” from Richard Feynman, we will attempt on the
the interface connecting PM and cell cortex. In the following, we following pages to conceive a hypothetical biomimetic membrane
refer to the composite material emerging from the combination with the following features: It should reliably separates internal
of PM, MCA and cell cortex as “cell surface.” from external space. The boundary should further be flexible,
Having introduced the basic terms, we next need to tunable, and able to transiently change its material properties in
recapitulate the essential material properties. For small strains, response to incoming signals. For simplicity and didactic reasons,
any membrane deformation can be regarded as the superposition we designed this as an engineering challenge (Supplementary
of three basic types of deformation: pure stretch, shear and Figure S1 and Supplementary Material), sequentially expanding
bending (Figure 1A). A membrane subject to a force acting the number of requirements (i.e., requested functions) of the
normal to its edges will experience an extensional stress and an hypothetical material. In each section, we begin by musing how
area stretch. The resistance against this stretch is called the stretch such a biomimetic structure could be designed, before exploring
modulus Ke . Similarly, a membrane that is subject to forces acting in detail how this has been accomplished in biological systems.
parallel to its edges will experience shear stress, whereby the
resistance against the shear deformation is given by the shear The Lipid Bilayer, the Core Module of
modulus Ks . While stretch and shear modulus relate strain to Cellular Membranes
a certain stress, the bending stiffness KB relates a curvature The most fundamental function of our biomimetic material is
to a bending moment (i.e., the energy necessary to bend the to reliably separate the interior from the external environment.
membrane to its current state). The deformations described so To achieve such a continuous barrier in an aqueous solution,
far are purely elastic, and therefore not time dependent. However, a biomimetic material must be able to oppose differences in
biomaterials often exhibit fluid-like behavior, including time osmotic and hydrostatic pressure without leakage. Ideally, the
dependent plastic deformation. Therefore, we need to introduce material would spontaneously assemble, thus limiting the need
a fourth material property, the viscosity η (Figure 1A, right). for energy and control systems.
It depicts the resistance of a fluid against shear stress at a In cellular membranes, amphipathic lipids spontaneously self-
specific shear velocity du dy . In contrast to the shear modulus, assemble into a 5–7 nm thick lipid bilayer, with the hydrophobic
the viscosity does not relate stress to strain, but to the rate carbohydrate chains facing toward the inside (Huang and
of deformation. By changing one or a combination of these Thompson, 1965). This occurs to minimize the free energy

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Lamparter and Galic Membranes as Adaptive Composite Material

FIGURE 1 | Basic material properties and deformation types. (A) From left to right, membrane exposed to uniform extensional stress σ, which is acting normal to its
edges, causes an increase of the area (from A0 to A). Membrane exposed to forces acting parallel to its surface inducing shear stress τyx . Membrane exposed to a
point load (F) acting perpendicular to its surface, which is inducing curvature and therefore a bending moment. Viscosity η, the resistance of a fluid against shear
stress τ given at a specific shear velocity du
dy . (B) Basic properties of a purely elastic (spring, left) and viscous (dashpot, right) material. A purely elastic material always
returns to its original state after deformation and exhibits a linear relationship between stress and strain, while a purely viscous material exhibits plastic (permanent)
deformations and a linear relationship between stress and shear velocity. (C) Models of viscoelastic materials. Maxwell body (left) consisting of a dashpot and a
spring in series displays, like a viscoelastic fluid, permanent deformation after the load is removed. Kelvin body (right) returns, like a viscoelastic solid, to its original
state when the load is removed. Images adapted from Seidel et al. (2009) and Kamm and Grodzinsky (2015).

of water arising from continuous formation and disassembly With respect to the material properties mentioned at the
of hydrogen bonds (Figure 2A, right). Pure lipid bilayers are beginning of the section, the lipid bilayer already provides
reported to have a stretch modulus Ke in the range of 100 excellent stretch resistance. However, it is readily deformed in the
to 1000 mN/m (Waugh and Evans, 1979), with a value of presence of forces within the plane (i.e., low shear resistance Ks )
∼200 mN/m as most widely accepted (Rawicz et al., 2000). or perpendicular to it (i.e., low bending rigidity KB ). Hence, to
Considering a pure lipid bilayer with a possible areal stretch of 5% strengthen the structural integrity of the boundary, and render it
(Hallett et al., 1993), and neglecting thermal fluctuation (Evans tunable, additional support is required.
and Rawicz, 1990), Eq. 2.5 in Box 1 gives us a rupture tension of
10 mN/m. This value is in accordance to published reports that
measured a rupture tensions of 3 to 10 mN/m, depending on the The Membrane-Cortex Interface Forms a
lipid composition of the bilayer (Olbrich et al., 2000). Following Composite Material
Laplace’s law. For our hypothetical biomimetic material, the mechanical
2N properties of the hull could be further improved by combining
1p = , (1.1) it with a self-assembling scaffold that binds with high affinity to
R
the flexible hull to form a tri-partite composite: hull, supporting
where N depicts the surface tension and R the principal radius scaffold and the connecting glue (Figure 2B, left). As one can
of curvature, we find that the PM can therefore withstand a easily imagine, size, density and rigidity of the scaffold units
pressure difference 1p of up to 0.2 bar or 20 kPa assuming a will directly affect the material properties of the composite.
radius of 1 µm before ripping, a remarkable performance given However, these properties equally rely on the assembly pattern
its thickness of only 5–7 nm. of the scaffold along the hull. For instance, scaffolds formed

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Lamparter and Galic Membranes as Adaptive Composite Material

FIGURE 2 | Modules of cellular membrane. (A) To the left, hypothetical biomimetic membrane that separates the inside from outside. To the right, the lipid bilayer
presents the outermost structure of the cell membrane. Magnification depicts the 5–7 nm thick bilayer composed of individual lipids. (B) To the left, hypothetical
composite material composed of a flexible hull associated to a rigid scaffold. To the right, the plasma membrane is tightly coupled to the cell cortex, creating a
composite material. Individual actin proteins assemble into filaments that are facing the cell membrane with the growing end. (C) To the left, hypothetical adaptive
composite material that changes material properties upon an external stimulus (red). To the right, the membrane/cortex continuum readily responds to external
stimuli (red), reminiscent of an adaptive composite material. Note that changes in actin dynamics can also serve as signal (red, dotted line).

from elongated structures that align along a pre-defined axis cortex (Figure 2B, right). The cell cortex consist of straight
will yield polarized (i.e., different) bending moduli along the and branched actin filaments that are crosslinked among each
principal curvatures. In contrast, an omnidirectional assembly of other (Mullins et al., 1998), forming a 100–200 nm thick layer
the same structures will produce isotropic mechanical properties. at the inner side of the PM (Chugh and Paluch, 2018). In
Besides the form of the supporting structure, the spacing addition to actin, the cell cortex contains, to a lesser degree,
between individual subunits also influences the bending stiffness intermediate filaments and microtubules (Koning et al., 2008;
(Naghieh et al., 2018). One such example is agarose gel, Singh et al., 2018), providing the ability to exert mechanical forces
which exhibits substantially higher resistance to shear stresses and change local material properties. Membrane association
than its primary component water. Hence, by wisely designing of the cell cortex is achieved through a specialized protein
the geometry of a supporting structure, or the composition group, the FERM domain proteins (named after its founding
of matrix particles, materials with very diverse mechanical members 4.1 protein, ezrin, radixin, and moesin), which
properties may emerge. simultaneously bind to lipids and proteins (Chishti et al.,
A lipid bilayer substantially differs from the cell surface, 1998). This dynamic interface, also termed membrane-cortex-
which is not only stiffer but also displays slower lateral diffusion attachment (Diz-Muñoz et al., 2010), transforms the two
(Edidin et al., 1991; Shi et al., 2018). This clearly posits the separate structures into one composite material. From Eq. 2.2
presence of an additional supportive material that interacts with in Box 1, we learn that the energy to buckle a material
the lipid bilayer. In cells, this composite material is formed scales with the thickness cubed. Consequentially, the energy
through the interaction of the plasma membrane with the cell to bend a 200 nm thick cell cortex is orders of magnitude

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Lamparter and Galic Membranes as Adaptive Composite Material

BOX 1 | Physics at the Cell Surface.

In the following, we consider the cell surface as a plate or shell encapsulating the cytoplasm, following the description by Kamm and Grodzinsky (2015). In general,
any deformation can be envisioned as the superposition of three fundamental types of deformation: stretch, bending and shear. Surface tension is defined as the
derivation of energy with respect to area, meaning the energy needed to stretch the plate by a certain amount is given by.

Eh E h 1A 1A
N=σh= ε= = Ke , (2.1)
1−ν 2(1 − ν) A0 A0

where σ depicts the uniform normal stress, N the in plane tension in force per unit length (N/m), E the elastic modulus (Young’s modulus), ν the Poisson ratio, h the
E h
plate thickness, ε the strain and Ke the area stretch modulus defined as Ke = 2(1−ν) . The energy needed to bend a plate of the thickness h in one dimension given by

E h3 δ2 uz δ2 uz
Mx = Ebend = − = −KB 2 , (2.2)
12(1 − ν2 ) δx2 δx

where δδxu2z depicts the deflection of the plate in z direction and KB the bending stiffness defined as KB = 12(1−ν
2 3
E h
2 ) . Elastic materials exhibit resistance against shear
deformation arising when the lateral surfaces of the plate are exposed to two different surface tensions. This resistance is given by the shear modulus Ks , with the
unit N/m, relating the arising shear force per unit length Nxy to the amount of shear deformation, the strain εxy . The shear force per unit length is the product of the
shear stress τxy times the plate thickness h, which can also be described by the shear modulus G and the shear deformation εxy . Corresponding to Eq. 2.2 the
shear modulus can be expressed by Young’s modulus E and the Poisson ratio υ:

E
σxy = τxy h = 2G εxy = εxy = Ks εxy , (2.3)
1+ν

Considering the cells surrounding, we must apply for thermal fluctuation by adding a random force term ξ(t) and, for the damping of membrane movement by the
δuz
extracellular fluid, we add a term in form of ηe δ(t) with the effective viscosity of the surrounding fluid ηe dissipating its energy. Adding thermal fluctuation and energy
dissipation due to external fluid damping, neglecting shear stress, yields
! !
δ4 uz δ4 uz δ4 uz δ2 uz δ2 uz δuz
1p + ξ(t) = KB +2 2 2 + −N + + ηe , (2.4)
δx 4 δx δy δy4 δx 2 δy2 δt

which is giving us a more complete picture of the cell membrane behavior. Note that the principle of superposition is only valid for small strains, where linearization is
appropriate (e.g., small discretization of time and space). Neglecting all terms except of pressure and surface tension – as it can be appropriate for small curvatures,
Eq. 2.4 gives rise to the famous Laplace equation. !
δ2 uz δ2 uz ∼
 
1 1
1p = −N + =N + . (2.5)
δx 2 δy 2 R1 R2

Biomaterials often exhibit viscoelastic properties. Therefore, we also have to consider the materials viscosity η. In contrast to the elastic modulus E, the viscosity
relates the stress not to the deformation of the material but to the rate of change of the deformation dε(t)
dt . One way to describe the properties of a viscoelastic solid is
the Kelvin-Voigt model (see Figure 2C), which can be envisioned by an elastic spring and a viscous damper connected in parallel. The elastic properties of the
material are given by the elastic modulus E, and the viscous properties by the viscosity η. The experienced stress σ is then given by

dε(t)
σ(t) = E ε(t) + η . (2.6)
dt

However, the cell surface exhibits the ability of plastic deformation and therefore behaves more like a fluid. Regarding the cell cortex this property arises from the
turnover rate of the linking proteins. In contrast to a viscoelastic solid, a viscoelastic fluid can be modeled by a Maxwell body, which can be envisioned by an elastic
spring and viscous damper connected in series (see Figure 2C). The experienced stress σ is here given by

η σ(t) dε(t)
σ(t) + =η . (2.7)
E dt dt

higher than for a 5–7 nm thin lipid bilayer. Hence, the The connection from cell cortex to membrane also affects
contribution of the lipid bilayer to the overall cell surface surface tension (Chugh et al., 2017). The cell membrane is
stiffness can be neglected for shape changes at cellular length attached to the cortex via linker proteins, which in turn are put
scales. Intriguingly, the high frequency regime of the fluctuation under tension by the cortical surface tension Ncor , yielding.
spectrum of membrane fluctuation assays seems to depend
to a large extent on the mechanical properties of the PM 2
(Gárate et al., 2015), suggesting that the membrane is at Ncor = ρlink Flink , (1.2)
R
least partly able to swing freely at small length-scales. Similar
high fluctuation modes at the scale of dozens of nanometers where ρlink depicts the linker protein density and Flink the force
were also observed in vesicles (Betz and Sykes, 2012). Thus, applied by each linker. Using Laplace law (see also Box 1, Eq. 2.5),
the bending stiffness of the cell surface (see Figure 1A) we find.
is likely dominated by the cell cortex on the cellular level
and by a partly unattached PM on sub-micron length scales 2 2
(Salbreux et al., 2012). 1p = NPM + ρlink Flink = (NPM + Ncor ) , (1.3)
R R

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Lamparter and Galic Membranes as Adaptive Composite Material

which means that cell surface tension Ncell is the sum of Finally, let’s consider membrane viscosity. PM viscosity differs
membrane tension NPM and cortical tension Ncor (Sens and from the viscosity of a pure lipid bilayer due to the embedded
Plastino, 2015). Let’s have a closer look at membrane tension. integral membrane proteins (IMPs). For a suspension with no
In a lipid bilayer, local gradients in membrane tension (e.g., interparticle interactions (i.e., low concentration), the effective
induced by rapidly pulling on a tether) equalize over the rest of viscosity of such a suspension can be approximated by.
the membrane in a matter of milliseconds (Shi and Baumgart,
2015), which is reminiscent of a fluid lacking shear stress. This, µe = µ0 (1 + Bφ), (1.9)
however, changes as soon as the PM is attached to the cellular
cortex. Roughly one quarter of the total PM area is occupied where µ0 is the viscosity of the suspending liquid, φ volume
by transmembrane proteins, half of which are connected to the fraction of the embedded particles and B a coefficient depending
cellular cortex (Bussell et al., 1995). These proteins, if attached to on the particle shape (e.g., spheres, cylinders, disks) (Bird
the cell cortex, serve as obstacles that limit membrane flow (u). et al., 2007). Hence, it is possible that the attachment, and
therefore immobilization of IMPs, may also affect PM viscosity.
k Despite the existence of some approximations on the effective
u= ∇N, (1.4)
ηlipid viscosity (Larson and Higdon, 1986, 1987; Kolodziej, 1988), this
complex topic remains unresolved and is beyond the scope of
with Darcy permeability k of a porous medium (i.e., the array this review (see also Supplementary Material). Importantly,
of obstacles) and lipid viscosity ηlipid (Shi et al., 2018). The the sole plasma membrane exhibits viscous material properties.
lateral permeability k can be described as a function of the area Attachment of to the PM to the cell cortex (i.e., the cell
fraction φ occupied by the integral proteins and their radius a surface), however, displays a combination of viscous and elastic
(Happel, 1959). properties on the cellular length scale (Bausch et al., 1998). This
a2 (1 + ln(φ)) means that on short time scales (i.e., ∼1 s) the cell surface
k≈− . (1.5)
8φ responds like an elastic material, while it shows properties
of a viscous material on longer time scales (i.e., 10–100 s).
Hence, if confined into two dimensions, the flow resistance Considering that the cortex consist of interlinked actin filaments,
decreases logarithmically with the distance to the obstacle (rather which are subject to continuous turnover of cross-linking
than exponential). Since the logarithmic function diverges for proteins and actin filaments, the cell cortex is able to perform
large distances, the effect will be noticeable no matter how far plastic deformation reminiscent of a viscoelastic fluid. This
away from the obstacle we evaluate the system - a phenomenon behavior can, in its simplest form, be modeled as a Maxwell
called the Stokes paradox. The same study further noted that the body (Begemann et al., 2019) described by Eq. 2.7 in Box 1
surface tension of a PM attached to the cell cortex propagate over (see also Figure 1C).
time in a diffusive manner, given by. In conclusion, our short survey demonstrates how interactions
δN Ek 2 of membranes with the cell cortex alter the mechanical properties
= ∇ N, (1.6) of the PM itself as well as of the cell surface. Yet, despite
δt ηlipid
the versatility in material properties that can be achieved, the
where E depicts the elastic modulus of the PM and ηlipid the resulting composite material at this point still lacks the ability
viscosity of the lipids (i.e., the fluid’s viscosity flowing through to readily respond to changes from the environment (i.e.,
these obstacles). Note that Eq. 1.6 exhibits a striking similarity adaptive response).
to Fick’s second law of diffusion. In their elegant study, Shi and
Cohen defined a tension diffusion coefficient DN The Cell Surface Is an Adaptive
Composite Material
Ek
DN = , (1.7) In the form described this far, the composite material will
ηlipid always thrive to adopt the minimal energy state. Strikingly,
mechanical properties of membrane and cortex can be separately
yielding
δN tuned with high spatial and temporal accuracy, providing the
= DN ∇ 2 N. (1.8) possibility to turn the passive composite into an active material.
δt
In our hypothetical composite material, such adaptivity could be
Consequently, the cortex bound integral proteins cause achieved by rendering its components sensitive to a transient
local and long lived gradients of membrane tension. It is stimulus (e.g., light, temperature). The response to such a
plausible to envision that cells may locally alter the tension stimulus, which triggers local changes in one (or a combination)
diffusion coefficient through MCA-induced changes in number of the four essential material properties (Figure 1A), yields an
and position of transmembrane obstacles (i.e., change φ). adaptive composite material (Figure 2C, left).
Consistently, recent work showed a positive correlation between Following, we will discuss how stimulus-induced transient
membrane-proximal actin density and membrane tension changes in mechanical properties of membrane or cortex yield
(Bisaria et al., 2020). If and how membrane tension gradients an adaptive composite material. We begin with tension. As
influence cortical tension Ncor , and in consequence cell tension mentioned above in Eq. 1.3, the tension of the cell surface is
Ncell , remains elusive. the sum of the PM tension and cortex tension, and therefore a

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Lamparter and Galic Membranes as Adaptive Composite Material

function of the density of linker proteins ρlink and the stretch the respective viscosities. In case of the cortex, the dominating
moduli of the plasma membrane KePM and cell cortex Kecor . These control variable (i.e., target for adaptive stimuli) are the relative
parameters, in turn, rely on the respective elastic moduli E, turnover rates of actin and its cross-linkers, as well as the
thickness h, and the Poisson ratio ν (Eq. 2.1, Box 1). Hence, relative mesh size of the cell cortex (Boulbitch et al., 2000; Kasas
signal-induced changes to any of those properties will necessarily et al., 2005). Regarding the PM, and recalling the description
influence the cells surface stretch modulus Kecell . The stretch of Stokes paradox from the previous paragraph, viscosity of the
resistance of the lipid bilayer KePM , for instance, arises from PM could be modulated by signal-induced changes to the total
energy penalty caused by exposure of the hydrophobic core concentration of integral proteins, its spatial distribution (e.g.,
to the surrounding aqueous solution. It could therefore, in clustering), and the fraction of cortex bound units.
theory, be tuned by changing the membrane lipid composition, The findings summarized in this section highlight the
which may also effect the membrane thickness h. However, manifold strategies for signal-induced changes in individual
with a modulus of ∼200 mN/m (Rawicz et al., 2000), the material properties that render the cell surface an adaptive
lipid bilayer is not a strongly extendable structure, and thus composite material. How these material properties are changed
not well suited. Note that most values in literature describe under pathophysiological conditions is the topic of the
the apparent stretch modulus of the PM, which integrate large following chapter.
scale changes in membrane area originating from membrane
undulation, membrane folds, vesicle fusion, the smoothening of
membrane fluctuations and other sources (Le Roux et al., 2019). FAULTY MATERIAL PROPERTIES CAUSE
Complementing membrane-based tension, cortex-based tension DISEASE
can be modulated by signal-dependent changes in actin cross-
linker density, the MCA (i.e., density of PM-cortex linker proteins In any engineered structure, incorporation of faulty materials
ρlink ) and cortical myosin (Stewart et al., 2011). In particular, the yields catastrophic consequences for the over-all stability
latter renders the composite material suitable to adaptation on of the object. In cells, such faulty materials manifest
physiological timescales (i.e., order of seconds), whereby lipid as disease. Following, we survey disease arising from
composition as well as the cortex geometry (e.g., mesh size) will individual materials, the resulting composite and its adaptive
affect the respective elastic moduli. features, respectively.
As described in the previous section, changes in relative lipid
Bending Stiffness levels within the membrane may not only deplete components
As membrane and cortical stiffness critically depend on the involved in signaling, but could also alter its material properties.
length scale, we will consider their contribution separately. Mounting evidence exist for changes in lipid balance [e.g.,
The bending stiffness of the PM, which is relevant in the (cholesterol)↑, (sphingomyelin)↑ and (phosphatidylinositol)↓]
sub-micron regime, depends on the composition of the lipid during aging, but also in lipidosis such as Niemann-Pick disease
bilayer (Helfrich, 1973). By changing length and saturation of types A and C (Karten et al., 2002; Arroyo et al., 2014),
individual carbohydrate chains, the lipid bilayer thickness, and establishing how mechanical properties of the membrane may be
thereby the bending energy, can be modulated (see Eq. 2.2 in altered in disease.
Box 1). Adding hydrophobic heads with varying size further Intriguingly, faulty materials that lead to disease can also
renders lipids curvature-sensitive, while differences in charge be found in cell cortex proteins. For instance, mutations
will influence protein-lipid interactions with peripheral cytosolic in smooth muscle α-actin (ACTA2), which alter interactions
proteins (Ebrahimkutty and Galic, 2019; Bassereau et al., 2018). between actin and myosin (Lu et al., 2015), cause vascular
The bending stiffness of the cell cortex, which is relevant in the disease and stroke (Guo et al., 2009). Mutations in ACTB, the
µm regime, can be influenced by changes to the actin mesh gene encoding cytoplasmic β-actin, change actin polymerization
size (depicted by the density of cortex linker proteins) or the dynamics (Hundt et al., 2014), resulting in deafness, cancer
thickness of the cortex itself. In addition, signals that change and developmental disorders (Procaccio et al., 2006). Mutations
the elastic moduli of both materials (discussed above) will also in the gene encoding α-actinin-4 (ACTN4), an actin cross-
influence their respective bending rigidities KBPM and KBcor (see linking protein, cause proteinuric kidney disease (Kaplan et al.,
Eq. 2.2 in Box 1). 2000). Collectively, these few examples illustrate how changes in
material properties of cell cortex components yield substantial
Shear Resistance and Viscosity physiological effects.
Pure lipid bilayers behave like a fluid void of shear stress Disease can further be traced back to errors of the composite
(Mofrad and Kamm, 2006). This is not always the case in cellular material. As described above, lipid composition determines
membranes (Shi et al., 2018). From Eq. 2.3 in Box 1, we deduce rigidity and fluidity of membranes. Strikingly, some of these
that all cellular stimuli that influence the shear modulus (and lipids form highly dynamic and heterogeneous membrane
therefore Young’s modulus E as well as the Poisson’s ratio υ, as nanodomains (Head et al., 2014; Sechi and Wehland, 2000),
discussed above) will also affect the elastic shear stress response which can be stabilized to form larger signaling platforms that
of both materials, and therefore also of the cell surface. As the are associated with actin filaments (Oliferenko et al., 1999; Galic
cell cortex as well as the attached PM both exhibit viscoelastic et al., 2012; Begemann et al., 2019). As lipid availability or
properties, we further have to consider the control variables of dynamics is changed in certain disease, the resulting mechanical

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Lamparter and Galic Membranes as Adaptive Composite Material

properties of the membrane-cortex composite are likely altered in fluctuations drops as tension increases (Betz and Sykes, 2012).
such conditions. Notably, fluctuation spectroscopy can also be used to gain
Finally, mutations can also affect the adaptability of the insights into bending rigidity and viscosity of the material (Betz
composite. One major family of disease originates from and Sykes, 2012). Quantitative measurements on membrane
mutations in receptor proteins, which disturb signal-induced viscosity can also be acquired using high-throughput single
changes in material properties of the composite. One such molecule tracking or fluorescence correlation spectroscopy
example are G-protein coupled receptors (GPCRs), which (Barbotin et al., 2019).
alter among others the material properties of the cell cortex Yet, as mentioned above, changes in cortex bound protein
(Bhattacharya et al., 2004). Here, mutations cause aberrant spacing will affect membrane fluidity (Cohen and Shi, 2020).
signaling by disrupting surface expression (Ward et al., 2012), Hence, measurements from tether pulling and membrane
basal activity (Seifert and Wenzel-Seifert, 2002), or ligand binding fluctuation present a convolute of membrane and cell cortex
(Venkatakrishnan et al., 2013). Furthermore, GPCRs directly properties (Shi et al., 2018). Thus, while each of these approaches
interact with lipids, which means that changes in membrane allows exciting novel insights into the mechanical properties of
composition or mutations in the lipid-recognition motifs can cell membranes, it remains a challenging task to unequivocally
alter GPCR signaling by changing its stability, subcellular dissect the contribution of the individual components of the
localization or activity (Keri and Barth, 2018; Pucadyil and composite material.
Chattopadhyay, 2006). Importantly, errors in signal-induced
changes in material properties can also be traced back to other
receptor families (Jiang and Gonen, 2012; Fruman et al., 2017; CONCLUSION AND OUTLOOK
Zakany et al., 2020), giving rise to an ever-growing family of
membrane-related disease. A second major family of disease Seminal work one pure lipid bilayers, which are the topic of
that influences the adaptability of the composite material relies other reviews in this special issue, have substantially contributed
on membrane curvature. Here, transiently deformed membrane to our current understanding of membrane mechanics. Yet
sections trigger recruitment of curvature-sensitive proteins (Peter recent studies argue that some cellular membranes should be
et al., 2004) and lipids (Wang et al., 2007; James et al., 2010). considered an adaptive composite material (Shi et al., 2018;
Notably, many of the more than 100 known curvature-sensing Cohen and Shi, 2020). In this review, we used a hypothetical
molecules identified in cells directly alter actin polymerization, biomimetic material to elucidate the astounding versatility
thus changing mechanical forces applied to the PM. This dual of cellular membranes. We discussed how small changes in
ability of selected molecules to sense and modify actin-induced the mechanical properties of individual core modules allow
PM curvature is important, as it posits the core properties the material to readily adapt its properties, thus fulfilling
of an adaptive composite material. Consistently, defects of highly diverse functions, while relying on the same building
individual force-regulatory feedback loops (e.g., OPHN1 and materials. Strikingly, the composite nature of the cell surface
SRGAP2) result in very specific diseases (Billuart et al., 1998; not only allows cellular membranes to rapidly adjust its
Charrier et al., 2012). mechanical properties to the given situation, but also provides
While by far not complete, these selected examples illustrate explanations to disease and some seemingly contradicting
how the material properties of individual components critically properties of the cell surface. One such example is the need
influence the overall mechanical state of the cell surface – for efficient transport of large objects across the cell cortex,
both, in health and disease. How the mechanical properties of while maintaining structural integrity at all times (Wollman and
this versatile adaptive composite material are measured will be Meyer, 2012). As mentioned above, the lipid-cortex interface
discussed in the next section. largely relies on non-covalent interactions. In consequence, the
cytoskeleton continuously de- and reattaches from the lipid
bilayer. These transient detachments not only open up the
MEASURING MATERIAL PROPERTIES IN possibility to readily adjust interactions, but also the ability
CELLULAR MEMBRANES to transport and fuse vesicles (i.e., large objects) without
permanent detachment of the plasma membrane from the
The picture drawn this far depicts the importance of a underlying cortex.
functioning interplay between cortex, membrane and MCA. Using the analogy of a hypothetical biomimetic material
Considering its small scale, separating cell cortex from we realize that man-made materials still lag far behind
membranes in living cells is a challenging task (Diz-Muñoz its biological counterparts. It is encouraging, however, that
et al., 2018). To gain insights into membrane tension, previous this opportunity has been recognized, nucleating a rapidly
studies have taken advantage of pipets and optical tweezers to growing research field (Amaral and Pasparakis, 2019; Chen
measure the force needed to extract a membrane tether from and Li, 2020). Future advancements into bioinspired and
the cell surface (Raucher and Sheetz, 2000). Another approach biomimetic material will likely benefit from computational
relies on time-resolved membrane fluctuation spectroscopy approaches (Sun et al., 2018; Schroer et al., 2020), which allow
(Betz and Sykes, 2012). Here, an optical tweezer is being used to rapid advancement of theoretical and experimental data of
measure membrane deformations rather than to pull tethers. In membrane-MCA-cortex dynamics at an ever-increasing spatio-
such measurements, the power spectral density of low-frequency temporal resolution.

Frontiers in Cell and Developmental Biology | www.frontiersin.org 8 August 2020 | Volume 8 | Article 684
Lamparter and Galic Membranes as Adaptive Composite Material

AUTHOR CONTRIBUTIONS ACKNOWLEDGMENTS

Both authors listed have made a substantial, direct and We would like to thank members of the Galic lab for critical
intellectual contribution to the work, and approved it for feedback and discussion.
publication.

FUNDING SUPPLEMENTARY MATERIAL

This work was supported by funds from the DFG (EXC-1003, The Supplementary Material for this article can be found online
CRC1348/A06) and the Faculty of Medicine of the University of at: https://www.frontiersin.org/articles/10.3389/fcell.2020.00684/
Muenster to MG (IMF IGA-121610). full#supplementary-material

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Frontiers in Cell and Developmental Biology | www.frontiersin.org 11 August 2020 | Volume 8 | Article 684