Journal of Adhesion Science and Technology, 2015
Vol. 29, No. 11, 1047–1059, http://dx.doi.org/10.1080/01694243.2015.1018731
The significance of cadherin for cell–cell interactions and cell
adhesions on biomaterials
Xingyou Hua, Gaotian Shena, Tao Huc, Guoping Guana,b and Lu Wanga*
a
Key Laboratory of Textile Science & Technology, Ministry of Education, College of Textiles,
Donghua University, Shanghai 201620, P.R. China; bEngineering Research Center of Technical
Textiles, Ministry of Education, College of Textiles, Donghua University, Shanghai 201620,
P.R. China; cDepartment of Immunology, Binzhou Medical College, Yantai 264003, P.R. China
(Received 29 August 2014; final version received 3 February 2015; accepted 9 February 2015)
Cadherins are surface glycoproteins on plasma membranes and exist in many forms:
T-cadherin, neuronal cadherin (N-cadherin), epithelial cadherin (E-cadherin), and
vascular endothelial (VE-cadherin). Cadherins play critical roles in cell–cell interactions and are involved in multiple functions related to cell growth and proliferation.
Findings from numerous reports have indicated that VE-cadherin regulates the
remodeling, gating, and maturation of vascular vessels. The surface morphology of
materials also impacts endothelial cell adhesion. This report is an overview of recent
research on the effects of cadherins on cell–cell interactions, along with cell adhesions as examined on different materials. This summary will provide novel insights
and approaches for research on cell–cell and cell–material interactions and illuminate
some of the mechanisms of cell growth on different materials.
Keywords: cadherin; endothelial cells; cell–cell reaction; surface morphology;
vascular vessels
1. Introduction
When cells adhere transmembrane adhesive glycoproteins, such as cadherins, are
directly or indirectly linked to the cytoskeleton.[1] Such glycoproteins play important
roles in cell–cell reactions through their capacity to function as adhesion-activated
receptors via interactions with other membrane or cytoplasmic proteins. An overexpression of cadherins increases this adhesion, while decreases in adhesion result from their
inactivation.[2,3] However, each individual cadherin exerts unique properties. For
example, T-cadherin regulates vascular tissue structure and remodeling, controls
attachment and spreading of vascular endothelial, and modulates cell migration.[4]
N-cadherin, which participates in vessel stabilization during vessel formation, can also
regulate the expression of VE-cadherin to control angiogenesis.[5] In addition, VE-cadherin is considered to play a critical role in the remodeling and maturation of vascular
vessels, as well as being a potential marker for blood vessel lesions.[1,4,6,7] E-cadherin
has been shown to be important for maintenance of blood–brain barrier function and
can regulate cell adhesion.[2,8]
Results from studies in the field of tissue engineering have revealed that the surface
morphology of materials exerts a significant impact upon the adhesion of endothelial
*Corresponding author. Email: wanglu@dhu.edu.cn
© 2015 Taylor & Francis
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X. Hu et al.
cells (ECs).[9] Furthermore, cells have the ability to create proteins equipped for
adhesion.[10] The surface morphology of various materials may then impact the adhesion of these proteins. Under such conditions, the expression of glycoprotein cadherins
on the plasma membrane would also be impacted. In this report, we review the
progress of recent research on cadherins and the potential influence of material surface
morphology on cell adhesion.
2. Cadherin and cell regulation
As many diverse cadherins are present on plasma membranes, the individual types of
cadherins show slightly different properties. Accordingly, details regarding the structure
and function of each type of cadherin will be presented.
2.1. T-cadherin
T-cadherin, also known as cadherin 13, is an atypical member of the cadherin family
whose primary function involves regulation of the cardiovascular system and adhesive
properties of vascular cells. It is expressed mainly in aortic ECs, smooth muscle cells,
and the vascular wall of adventitial vascular trophoblasts.[4,11,12] T-cadherin differs
from other cadherins in that it lacks transmembrane and cytoplasmic domains and is
anchored to the plasma membrane.[13] Based on in vitro preparations, T-cadherin has
been shown to induce angiogenic phenotypes, regulate EC migration, and control the
outgrowth of transmembrane transport. In vivo, the overexpression of T-cadherin has
the potential of producing pathological changes, such as atherosclerosis and
restenosis.[14,15]
Kyriakakis et al., investigated the interaction between T-cadherin and epidermal
growth factor receptor (EGFR) in A431 squamous cell carcinoma. They found that
EGFR activation may be impacted by T-cadherin and that epidermal growth factor
induced redistribution of T-cadherin from cell–cell contact results in the activation of
EGFR. Thus, the potential function of T-cadherin in the maintenance of epithelial architectural through its capacity to promote cell–cell adhesion or restrict the effects of
EGFR activation in cell proliferation and migration represents an intriguing possibility
for this cadherin.[3]
The upregulation of T-cadherin is always accompanied by stress responses of the
endoplasmic reticulum, with the result that ECs are protected from apoptosis.[16,17]
Ghosh et al., used a multicellular tumor spheroids model to investigate the interactions
between ECs and tumor cells by altering the expression of ECs. With this model, they
showed that T-cadherin induced vascular endothelial growth as demonstrated both
in vitro and in vivo.[17] Kyriakakis et al., took advantage of the findings that endoplasmic reticulum stress causes upregulation of T-cadherin during the early stages of cardiovascular disease (Figure 1) to establish a monitoring mechanism of angiocardiopathy
by monitoring the expression of T-cadherin levels as related to cardiovascular
problems.[16,18]
2.2. N-cadherin
N-cadherin represents one of the first of three cadherins to be identified and was
considered as a component in the regulation of vessel stabilization by interacting with
Journal of Adhesion Science and Technology
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Figure 1. An unfolded protein response produces protein kinase RNA-like endoplasmic reticulum kinase (PERK) stress, and the resultant oxidative stress will result in reactive oxygen species
(ROS) induced damage. Both of these processes will lead to cell apoptosis, while the upregulation of T-cadherin can protect cells from apoptosis by restricting the PERK arm and minimizing
ROS-induced damage.
periendothelial cells during the period of angiogenesis.[19] However, recent research
shows that it may control these processes by regulating the expression of VE-cadherin.[5] This protein is mainly expressed in the cytoplasm and plasma membrane and
is upregulated in response to lesions.[20,21]
Ishimine et al., found that N-cadherin can serve as a prospective marker on the
plasma membrane of human mesenchymal stem cells, as it may promote the differentiation of cardiomyocytes. When cardiomyogenic progenitor cells differentiate into mature
cardiomyocytes, high levels of N-cadherin expression are observed, which play an
essential role for the formation of cardiac intercalated disk structure. At these initial
stages of differentiation, N-cadherin expression is associated with cell co-localization
and the clustering of transmembrane adhesives. Cells with high expressions of N-cadherin are more likely to differentiate into cardiomyocytes. Such findings suggest that
N-cadherin is involved in the interactions of pericytes and ECs during vessel formation
in vivo.[22]
Hirofumi Toyama et al., used an anti-N-cadherin antibody to investigate the role of
N-cadherin in the process of fetal liver hematopoiesis. With this protocol, they found
that a markedly different expression of N-cadherin was observed during embryonic
development, which could then serve as a valuable marker for immature cells. Therefore, the potential for new insights into the mobility of fetal liver can be achieved
through monitoring the expression of N-cadherin.[23,24]
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2.3. E-cadherin
E-cadherin is a classical type I cadherin comprising a central constituent of adheren
junctions of epithelial cells. This cadherin regulates cell adhesion and migration by
coalescing tumor cells and aiding their invasion into the extracellular matrix. With an
increased expression of E-cadherin, a corresponding increase in cell adhesion is
observed, while diminished adhesion is associated with low expressions of
E-cadherin.[2,19,25,26]
Hall et al., reported that the aggregation and placement of E-cadherin at the cell–
cell border may be related to the strength of cell–cell interactions. By reducing the levels of cell surface N-glycans, which linked oligosaccharides to the side chain of amide
nitrogen, they were able to investigate the expression of E-cadherin. The reduction of
N-glycans weakened the recruitment and retention of E-cadherin at the cell–cell border
and lowered the strength of intercellular interactions. These findings indicated an
important role of N-glycans in regulating E-cadherin levels, which in turn influences
cell–cell interactions of epithelial cells.[27]
Results from studies by Fausto J. Rodriguez have revealed that collective cell
migration involves E-cadherin via two mechanisms. First, E-cadherin enhances the
interaction stress between cells thereby attracting subsequent cells to follow along, that
is, passive migration. Second, E-cadherin can directly regulate the traction forces to
help cells migrate, which often occurs with surface migration. Interestingly, these investigators also found that an abnormal expression of E-cadherin slows cell migration,
which can provide an approach to assess endothelialization of the cells.[28,29]
2.4. VE-cadherin
VE-cadherin represents a type of classical type II cell adhesion molecule found in
ECs.[19,30,31] It plays a significant role in forming the endothelial barrier and angiogenesis, and increased expression levels of VE-cadherin at endothelial contacts are critical for the control of vascular permeability.[32] Additionally, VE-cadherin is involved
in the regulation of cell cycle progression and cell–cell adhesion (Figure 2). The
expression of VE-cadherin is regulated by transcription factors, of which Ets-1 is the
transcription factor primarily involved with vasculogenesis and angiogenesis. If these
transcription factors are depleted, abnormal expression levels of VE-cadherin result
leading to a reduction in cell adhesion and apoptosis, ultimately influencing vessel
formation.[33–35]
It has been reported that the nascent vessels are fragile and susceptible to bleeding.
Rapid stabilization and endothelium permeability requires cell–cell interactions
involving increased activity of transmembrane adhesion molecules, in particular, VEcadherin.[36,37] In vivo, vessels are subject to fluid shear stress created by blood flow,
which may then regulate vascular morphogenesis. Conway et al., used biosensors to
measure the tension across VE-cadherins and found that VE-cadherin regulates the ECs
by inducing large amounts of myosin-dependent tension.
Cells experiencing shear stress show a rapid, 25% reduction in tension on VE-cadherins. A corresponding decrease in cell–cell and cell–matrix tension then follows with
the result that a loosening of cell adhesion occurs. Such processes demonstrate the
importance of VE-cadherin interactions.[38]
Muradashvili et al., investigated cellular expressions of VE-cadherins using Western
blot and immunohistochemical analyses. The expression of VE-cadherin is related to
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Figure 2. Cells can adhere via participation of VE-cadherins linked to α-catenin. In this way,
they will create a signal pathway by the interactions among of VE-cadherin, p120-catenin and
β-catenin; a process which promotes cell adhesion and proliferation.
two proteins, fibrinogen, and matrix metalloproteinase-9, and their interaction may lead
to enhanced cellular permeability.[39] Iurlaro et al., found that the expression and clustering of VE-cadherins may have an effect on the regulation of survivins, implying that
an upregulation of survivin occurs when vessels are wounded or undergoing angiogenesis.[40] From experiments involved with assessing endothelial VE-cadherin expression
in human lungs, it has been demonstrated that there is an increased expression of
VE-cadherin in arteries and arterioles and a decreased expression of VE-cadherin in
veins and venules.[41] These results indicate that VE-cadherin expression in vessels
subjected to high pressure strengthen vascular EC adhesion and, as a result, regulate
revascularization.
3. Surface morphology impacts cell adhesion
The biocompatibility and biofunctionality of biomaterials rely on their interaction with
cells. When cells prepare for adhesion, they secrete surface proteins which are
components of the extracellular matrix (ECM) that initially adhere to the surface of the
material. The glycoprotein on the plasma membrane then recognizes these proteins,
which is followed by cell–cell contraction and cell spreading.[9,42–44] Viscosity and
surface morphology of the fabric, including coarseness, topography, porosity, and structure, may influence the ability for cell adhesion, proliferation, and migration.[45]
Accordingly, cell behavior can vary as a function of the materials’ surface.
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X. Hu et al.
3.1. The viscosity
Generally, the viscosity of materials is defined by the water contact angle (WCA).
When the contact angle is <10°, the material is considered superhydrophilic, while
>150° is considered superhydrophobic. Additionally, the material is defined as hydrophilic when the WCA is between 10° and 90° and hydrophobic when between 90° and
−150°.[9] The viscosity strongly influences the adhesion of ECs. When the WCA is
between 90° and 180°, the ECM is less likely to adhere to the surface. Although the
glycoproteins can combine with proteins that have adhered to the surface, the cells cannot distribute due to the hydrophobic surface. When materials are superhydrophilic, the
ECM will be absorbed by the surface and the glycoproteins on the plasma membrane
will likely not combine with the materials. Although cells can diffuse over the surface,
the surface tension is very low, and therefore, the cells cannot form strong adherences.
The optimal WCA for cell adhesion has been reported to be between 40° and 70°.
Under such conditions, the ECM can diffuse across the surface, which can facilitate the
ability for glycoproteins to combine cells with materials. Finally, these cells can show
robust adherence and quickly undergo endothelialization (Figure 3).[9]
3.2. The structure of the fabric
Fabrics exhibit three-dimensional structures. They may be interlacing or consist of
loops, and when cells adhere to these structures they can significantly influence their
proliferation.
A recent report has been published describing cell adhesions and proliferations on
fabrics.[46] Cells were cultured in a 48-well plate with a density of 425,000 cells/cm2.
These cells were subjected to four different conditions with PET film serving as a
control group: (1) biomaterial knitted/velour, (2) biomaterial woven/velour, (3) cardial
knitted, and (4) cardial woven. The results reveal significant differences between EC
behavior as assessed on film vs. that on textile structures (Table 1).[47]
Figure 3. Endothelial cells (ECs) that adhere to the surface can result from four processes: (1)
ECs secrete ECM, which can then adhere to the surface, (2) cells recognize the ECM with the
participation of adhesion molecules, (3) ECs begin to diffuse across the surface and adhere to
newborn cells as facilitated with intercellular adhesion molecules and cadherins, and (4) an
increase in the number of ECs enables the formation of a new endothelium. The surface viscosity
may affect the second step of cell adhesion, which then represents an important component of
the adhesion process.
Journal of Adhesion Science and Technology
Table 1.
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The growth conditions of cells after 7 days adhesion [47].
1h
7 days
1
Cells adhere with a low density and
are mostly small and isolated
2
Cells adhere with a low density and
are mostly small and isolated
Cells adhere with a low density and
are mostly small and isolated
The number of cells increased and cells
grow along the isolated fiber with no
obvious cell–cell adhesion
The number of cells increased with most
growing along the texturized yarns
The number of cells substantially
increased and grew tightly and orderly
along the fiber
Clear increases in cell numbers are seen.
Cell–cell adhesion is readily apparent,
and there may be some cell aggregates
where interlacing is present
Cells aggregate and some cord-like
structures, which are the precursors of
angiogenesis, are present
3
4
Cells adhere with a low density and
are mostly small and isolated
PET film
Most cells show robust adherence,
and a typical endothelial cell
monolayer is present
Based upon these findings, we conclude that the fabric structure exerts a significant
effect upon EC adhesion. When the fabrics are close-fitting, cells are more likely to
make contacts, thus promoting endothelialization. However, if the fabric is loose-fitting
and the surface uneven, such as in sample 2, cells may be isolated along the fiber,
which may affect endothelialization.
3.3. Electrostatic spinning materials
Mounting evidence has indicated that modifications of surface electrostatic spinning
materials are conducive to biocompatibility.[48–52] Moreover, the special characteristics of electrospinning fibers, that consist of high surface area-to-volume ratio and
display high porosity, enable these fibers to be used in tissue engineering.[53] To obtain
electrospinning material, a number of critical parameters such as needle diameter,
polymer concentration, and applied voltage need to be achieved to exert, effects on the
morphology of electrospun samples.[54]
It is known that polyurethane (PU) demonstrates both good biocompatibility and
mechanical properties, but lacks cell affinity.[55] As an alternative, polyethylene glycol
(PEG), which also displays good biocompatibility, is often used as a hydrophilic polymer for surface modification. Wang et al., have attempted to fabricate a PU/PEG smalldiameter vascular graft as achieved using electrospinning technology. By altering the
percent of PU and PEG, they were able to fabricate the vascular graft and tested the
biocompatibility and mechanical properties of this new material. Their results indicated
that PU and PEG content may influence the mechanical properties of vascular grafts
and also cell adhesion properties.[48]
Tissue engineering has the potential to create a replacement for damaged or diseased tissues and to promote rapid endothelialization. Long-term patency of artificial
blood vessels represents an important objective for such techniques. Zhang et al., developed a double-layered membrane which can continuously release vascular endothelial
growth factor and platelet derived growth factor by electrospinning technology. After
four weeks of this treatment in vivo, no evidence of thrombus or rupture was observed.
Thus, this technique can be considered as a potential replacement for small-diameter
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X. Hu et al.
vascular grafts.[49] Based upon these results, it seems feasible that electrospinning
techniques can be applied to control the release of some drugs or growth factors with
the goal that cell adhesion and proliferation can be regulated manually to rectify problems such as thrombus or short durations of patency in small-diameter vascular vessels.
Poly l lactic acid (PLLA) represents another biomaterial with good biocompatibility
that can copolymerized with different materials to create electrospinning materials.[56]
P (LLA-CL), which is known for its high biocompatibility, is a copolymer of PLLA
and polycaprolactone (PCL) and has been used for surgery and as a drug delivery system. As the speed of degradation of P (LLA-CL) differs from the composition of PLLA
and PCL, it has the potential for use in tissue engineering.[57,58] Mo et al., fabricated
a series of P (LLA-CL) materials with different polymer concentration solutions (3, 5,
7, and 9 wt.%), and different applied voltages (9, 12, and 15 kV). They selected the
5 wt.% and 15 kV as the most suitable conditions for subsequent experiments. The
behavior of endothelial and smooth muscle cells suggests that the structure of electrospinning materials provides high surface area-to-volume ratios which may promote cell
attachment and proliferation.[59]
The porosity of biomaterials strongly influences the properties of these materials.
Therefore, cardiovascular tissue engineering scientists have attempted to establish a porous scaffold to support cell adhesion and tissue growth. As the layered structure of
electrospinning scaffold is similar to the anatomic structure of native blood vessels, it
can provide mechanically controllable and degradative properties, high porosity, as well
as biocompatibility.[60] Zhang fabricated a layered scaffold structure composed of
PCL, poliglecaprone, elastin, and gelatin and achieved satisfactory results. After 7 days
of in vitro cell culture, the human aortic ECs can shelter almost all of the fabric with
no platelet adhesion, which indicate a condition where good anti-thrombotic ability is
present. The results of these experiments show that a porous structure enables cells to
adhere tightly with adjacent cells and materials and these cells survived on this scaffold
for at least 11 days. Accordingly, this scaffold can be considered as a probable
prosthesis in the cardiovascular surgery.[61]
3.4. Surface micro-processing materials
The microstructure of materials may also influence cell behavior. Many attempts at surface modification on the microstructure of biomaterials have been performed in recent
years.[62–64] One example is that of research on TiO2 nanotubes, the micro-fabrication
of channel arrays and laser modifications.[65–68]
A.C. Duncan et al., proposed a new method for surface modification as achieved
with the use of laser-treated PET film. The advantage of this procedure is that only
minimal surface heating results and it maintains a clean surface with no other appreciable changes being observed. After co-culture with Human umbilical vein ECs for 24 h,
the materials were adhered by cells and displayed a particular orientation degree such
that the width and depth of the microgrooves clearly impacted cell adhesion. Therefore,
this method may prove effective for surface modification, especially with use on artificial blood vessels, as it may control the cell orientation during adhesion.[65]
Ranella et al., attempted to utilize the microstructure of nanosilicon materials as an
approach to impact cell adhesion. With the use of a femtosecond laser, they produced
silicon wafers with different surfaces that varied from smooth to very coarse. Their
results revealed that cell adherence was very effective on slightly coarse surfaces, but
unsatisfactory on very coarse surfaces. Moreover, a high level of molecular adhesion
Journal of Adhesion Science and Technology
1055
Figure 4. The surface becomes increasingly hydrophobic with increasing coarseness. As a
result, cell adhesion is compromised, due to an absence of cell–cell adhesion and low molecular
adhesion expression. However, neither is the smoothest surface optimal for cell adhesion. In fact,
the results indicate that a slightly coarse surface promotes maximal cell adhesion, due to an
enhanced cell–cell interaction and a probable upregulation of molecular adhesion expression.
expression was found on the plasma membrane, indicating that these slightly coarse
surfaces directly impact molecular adhesion expression, which then affects cell
adhesion (Figure 4).[64]
Pre-vascularization represents a critical process during the replacement of engineered tissue explants, as an effective blood supply provides the nutrients needed for
promoting tissue regeneration. Zieber successfully constructed micro-channels on alginate scaffolds with basic fibroblast growth factor (BFGF), which can then be used as a
major structural promoter of vascularization in scaffolds. Their results were quite exciting in that only the channeled, but not nonchanneled, scaffolds were covered with small
thin capsules, indicating a successful formation of stable vessel-like networks. Moreover, these channeled alginate scaffolds prolonged the existence of BFGF to induce the
formation of vessels. Thus, this micro-channel structure approach has the potential for
application in many other areas requiring cell adhesion and vascular formation.[67]
4. Conclusions
Cadherins have been found to be involved in various cell functions through the regulation of adhesion processes. For example, T-cadherin may protect cells from apoptosis,
E-cadherin may aid cell adherence and regulate migration, N-cadherin may play an
important role in the stabilization of ECs and regulation of VE-cadherin expression,
and VE-cadherin may promote EC adhesion and endothelialization on the materials.
Therefore, the expression of cadherin significantly impacts cell–cell and cell–material
interactions.
Cell responses may also be influenced by the viscosity and surface morphology,
such as, coarseness, topography, porosity, and fabric structure. Such factors will also
affect cell adhesion by influencing the cell–cell and cell–material attachments, as well
as regulate the orientation of cell growth by the microstructure.
To date, no literature exists which addresses the issue of whether biomedical textile
materials can exert a direct effect on the expression of cadherin which would then have
the potential of regulating cell adhesion and endothelialization. Given the importance
of this issue, efforts should be focused on examining the relationship between surface
morphologies and expression of the glycoprotein cadherin with the goal that surface
modification of biomedical materials could be designed to more effectively construct
surfaces for interaction with cadherin.
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X. Hu et al.
Acknowledgments
This work has been supported by the National Natural Science Foundation of China (grant
number 51003014 and Grant No. 81371648) and the 111 project ‘Biomedical Textile Materials
Science and Technology’ (grant number B07024) and the Fundamental Research Funds for the
Central Universities. Great appreciation to the help of Dr Ruixiu Wang and Dr Lixin Song.
Funding
This work has been supported by the National Natural Science Foundation of China [grant number 51003014], [grant number 81371648]; the 111 project ‘Biomedical Textile Materials Science
and Technology’ [grant number B07024].
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