Detection of Cell Adhesion Molecules in Lens Epithelial
Cells of Human Cataracts
Okihiro Nishi* Kayo Nishi* Takahiro Akaishi,~\ and Eiichi Shirasawa\

Purpose. To detect the expression of cell adhesion molecules (CAMs), including 0 integrins,intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1, leukocyte endothelial cell adhesion molecule-2, E-cadherin, and CD44, in cultured lens epithelial cells(LECs) of human cataracts. To show that LECs attach to cells or extracellular matrix components by the detected adhesion molecules.
Methods. A circular section of the anterior capsule with attached LECs obtained by anterior
capsulotomy during cataract surgery was cultured in a well of an eight-chamber slide. The
LEC immediately after surgery and the cell outgrowth beyond the capsular margin at 2 weeks
of culture were observed after the culture was stained immunohistochemically. Functional
assays of LEC growth on collagen- or laminin-coated plates were performed in the presence
and absence of the antibody blocking the detected adhesion molecules.
Results. f3\ integrin, ICAM-1, and CD44 were detected in both the original specimens and thecultured cells. When the antihuman anti-/?i integrin monoclonal antibody (mAb), anti-ICAM1 mAb, or anti-CD44 mAb was added at 10 //g/ml to the incubation medium, LEC migrationand proliferation were inhibited significantly on the collagen- or laminin-coated plates. Whenthe mAb blocking these three CAMs were added each at 1 /^g/ml, LEC proliferation also
were inhibited.
Conclusions. (3\ integrin, ICAM-1, and CD44 are all involved in LEC attachment and growth
on collagen and laminin in vitro. It can be assumed that these CAMs are involved in adhesionof LECs to extracellular matrix components of the lens capsule. Understanding the characteristics of the adhesion molecules in LEC may lead to the development of a new approach toinhibit secondary cataract formation. Invest Ophthalmol Vis Sci. 1997;38:579-585.

l^ell adhesion molecules (CAMs) play a central rolein the cellular adhesion mechanisms characterized bycell-to-cell and cell-to-extracellular matrix (ECM) interactions. They are known to serve as adhesion receptors as well as biologic signal transducers in these interactions. The presence of various adhesion molecules
has widely been reported in normal or inflamed human cornea,1"4 iris,5 uvea,6"8 retina,9 epiretinal membrane,10'11 and diabetic epiretinal membranes.12 They
were found in the serum of patients with uveitis.13
After cataract surgery, residual lens epithelial cells
From *Nishi Eye Hospital, Osaka, Japan; and •fSajiten Pharmaceutical Co., Ltd.,Nara Research and Development Center, Nara, Japan.
Presented in part at the 33rd Congress ofJapanese Cataract Society, June 17 to 19,
1994, in Tokyo and the 3rd International Conference Interdisciplinary Club for
Biomaterials in Ophthalmology, June 25, 1994, in Toronto.
Submitted for publication August 28, 1996; revised November 4, 1996; accepted
November 6, 1996.
Proprietary interest category: N.
Reprint requests: Okihiro Nishi, 4-14-26, Nakamichi, Higashinari-ku, Osaka 537,
Japan.

(LECs) proliferate in the defective lens capsule andmigrate onto the posterior capsule after surgery. The
LECs undergo fibrous pseudometaplasia at the capsulotomy site as an expression of wound healing or when
they come in contact with the implanted intraocularlens (IOL). Through this process, the blood-aqueous
barrier can be disrupted.14 A model system that parallels this is LECs in culture that proliferate and undergo a fibroblast-like cell change in die culture plate
well and consequendy produce various cytokines suchas interleukin-1 (IL-1),15 interleukin-6,16 transforming
growth factor-/?17 and b-fibroblast growth factor,18 andprostaglandin E2.15 We have proposed that this interrelation between LEC and IOL should be considered
as a criterion for evaluating the biocompatibility of an
IOL. Adhesion molecules in the LEC may be involved
and play an important role in all these processes. Regarding the expression of CAM in LEC, to our knowledge, there is one report by Menko and Philip19 that

Investigative Ophthalmology & Visual Science, March 1997, Vol. 38, No. 3
Copyright © Association for Research in Vision and Ophthalmology

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Investigative Ophthalmology & Visual Science, March 1997, Vol. 38, No. 3

Px integrin was noted in the embryonic lens. Here wehave attempted to characterize the expression of fix
integrins and some other families of adhesion molecules in the cultured human cataract LEC by the immunohistochemical technique. In addition, we performed functional assays on LECs growing on collagen- or laminin-coated plates in the presence andabsence of blocking antibodies against the detected
CAM to confirm that the LECs attach to the cell or
extracellular matrix components through the CAM.
MATERIALS AND METHODSThis study was approved by the Institutional Ethical
Review Committee at the Jinshikai Medical Foundation, Nishi Eye Hospital, Osaka, Japan. All proceduresin this study were performed in full accordance withthe tenets of the Declaration of Helsinki.
Culture of Human Cataract Lens Epithelial
Cells
Human cataract LECs were cultured as described previously.15 Briefly, a circular section of the anterior capsule with LECs attached was obtained by capsulotomy
during cataract surgery and cultured directly without
dispersion of the cells. It was placed immediately intoa chamber of an eight-chamber slide containing 0.35
ml of Eagle's minimum essential medium containing
10% fetal calf serum, penicillin G (100 U/ml), andstreptomycin sulfate (100 /zg/ml). The specimen thenwas cultured in 100% humidity at 37°C in a 5% carbon
dioxide atmosphere for 2 weeks. The culture medium
was replaced every 7 days.

respectively, with phosphate-buffered saline [—] containing 1% bovine serum albumin and 0.1% azide sodium; Sumitomo Denko, Yokohama, Osaka, Japan),
ICAM-1 mAb (diluted 1:100; Genzyme, Cambridge,MA), VCAM-1 mAb (diluted 1:100; Genzyme),
LECAM-2 mAb (diluted 1:10; Seikagaku Industries,
Osaka,Japan), E-cadherin mAb (diluted 1:100 with*20
mM Tris buffer solution, 1% bovine serum albumin,
0.1% azide sodium, and 10 mM calcium chloride; Takara Breweries, Kyoto, Japan), or CD44 mAb (diluted
1:100; Cosmo Bio, Tokyo, Japan) as the primary antibody for 60 minutes at room temperature. After intensive rinsing, fluorescein isothiocyanate-conjugatedgoat antimouse immunoglobulin G (H + L) (diluted
1:300; ZYMED, San Francisco, CA) was used as thesecondary antibody fluorescein isothiocyanate-conjugated mouse immunoglobulin G (Dako, Glostrup,
Denmark) served as the negative control specimen.
In Situ Lens Epithelial Cells. Each of the specimens
taken immediately after surgery was placed on a silane(amino-propyl-triethoxy silane)-coated slide glass with
the LEC facing the slide and left for 2 minutes. The
capsule of the specimen was removed, leaving the cellson the slide, which then were stained. Five to sevenspecimens were used for the detection of each CAM
for both cultured and in situ LECs.
Functional Assays of Lens Epithelial Cells to
Collagen- and Laminin-Coated Plates
The specimen was incubated on a collagen IV- or laminin-coated plate for 2 weeks. At each medium change,
mouse antihuman anti-integrin mAb (Sumitomo Denko) was added to the incubation medium at the concentration of 0.01, 0.1, 1, or 10 //g/ml. Mouse antihuman anti-ICAM-1 mAb (Genzyme) or anti-CD44 mAb(Cosmo Bio, Tokyo, Japan) was added at a concentration of 0.1, 1, or 10 /ig/ml. In one experiment, acombination of all three antibodies (1 /lig/ml each)
was added at the medium change. As the control specimen, immunoglobulin Gl (Bethyl Lab, Montgomery,TX) was used. Nonadherent cells were removed byaspiration at each medium change. Five to seven specimens were used for each adhesion molecule at eachconcentration. The number of attached viable cells
was counted at the end of culture as reported previously.15

Immunohistochemical Detection of Adhesion
Molecules
Cultured Lens Epithelial Cells. After the incubation
medium was removed at 2 weeks of culture, the culture
was washed twice with calcium- and magnesium-freephosphate-buffered saline (-), while the chamber slide
containing the LECs was placed on ice. The LEC specimens then were stained for /? t , f52, and /33 integrins,intercellular adhesion molecule-1 (ICAM-1), vascularcell adhesion molecule-1 (VCAM-1), leukocyte-endothelial cell adhesion molecule-2, E-cadherin, andCD44. The specimens at 2 weeks of culture were used,because LECs were growing, but none of the LEC
Statistical Analyses
had reached the well wall, so there was no contact
The statistical analyses of the results in the functional
inhibition.
assays were performed by Scheffe's multiple compariThe LECs were incubated with 5% goat serum
son after the Kruskal-Wallis test.
(Cappel, Durham, NC) for 60 minutes at room temperature to block nonspecific binding. After intensive
RESULTSrinsing with phosphate-buffered saline containing
Detection of Adhesion Molecules
0.05% polysolvate, the culture then was stained withmouse antihuman /3 ( , /32> and (3$ integrin monoclonal Definite positive expressions of (3\ integrin (n = 5 andantibodies (mAb) (diluted 1:300, 1:100, and 1:100,
n = 7, immediately after surgery and at 2 weeks of

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Adhesion Molecules in Lens Epithelial Cells
culture, respectively), ICAM-1 (n = 5 and n = 5), andCD44 (n = 6 and n = 5) were observed (Figs. 1, 2,
and 3) immediately after surgery and at 2 weeks ofculture in all the cells of each specimen. Numerous
small, round adhesion plaques on the cell were stainedbrightly by the antibodies for /3, integrin, ICAM-1,
and CD44. Table 1 summarizes the data from theseexperiments. Of the specimens taken immediately
after surgery, 80% showed strong staining for CD44
and 20% stained moderately. After 2 weeks of culture,
60% exhibited strong CD44 staining, whereas 40%
were moderately positive for this antigen. The control
specimens did not show any positive staining. The
monoclonal antibodies used are specific to each of
the detected human CAM: /?i integrin mAb binds toa- and /^-chains; CD44 recognizes a transmembrane
molecule with extensive glycosylation (O-linked andN-linked).
In the specimens stained /52 (n = 5, n = 6) andPs (n = 5, n = 6) integrins, VCAM-1 (n = 5, n = 5)
and LECAM-2 (n = 5, n = 6), E-cadherin (n = 5, n
= 6), no cells were stained positively in either the
specimens obtained both immediately after surgery or
those at 2 weeks of culture.
Functional Assay of Lens Epithelial Cells to
Collagen- or Laminin-Coated Plates
Cell growth was inhibited significantly by anti-/?i integrin mAb at 1 ££g/ml (P < 0.01) and 10 ^g/ml (P <0.01), anti-ICAM-1 mAb at 1 //g/ml (P < 0.05) and
10 /ag/ml (P < 0.01), and anti-CD44 mAb at 10 fig/
ml (P < 0.01) on the collagen IV-coated well. Bothwere inhibited significantly on the laminin-coated wellby anti-/?! integrin mAb at 0.1 fj,g/m\ (P < 0.05), 1(j,g/m\ (P < 0.01), and 10 fj,g/m\ (P < 0.01) dose
dependently; by anti-ICAM-1 mAb at 1 fj,g/m\ (P <0.01) and 10 fig/m\ (P < 0.01); and anti-CD44 mAb
at 10 fj,g/m\ (P < 0.01). The combined addition of
the three mAbs together, each at 1 /ig/ml, inhibited
significantly LEC migration and proliferation both on
the collagen IV- and laminin-coated wells (Figs. 4, 5,
and 6).
DISCUSSION
The results show that human cataract LEC express /3\
integrin, ICAM-1, and CD44 in the specimens thatwere stained immediately after surgery. This suggeststhat these adhesion molecules are expressed in situ,
being participants in the interactions between LEC
and LEC and between LEC and the capsule as well.
These CAM also could be detected in the specimens
at 2 weeks of culture in vitro. VCAM-1 and E-cadherin
were not detectable either immediately after surgery
or at 2 weeks of culture. In our previous report,20 there
was positive staining for /?, integrin and VCAM-1, but

581

ICAM-1 was not present at 2 weeks of culture. The
difference in the results may have been caused by the
specimen fixation with 95% ethanol in the previous
report, which could alter the cellular surface. The
specimen may have been stained nonspecifically or
the CAM may have been denatured. In contrast, inthe current study, the specimens were stained without
any fixation procedure, which ensured specific staining with the corresponding monoclonal antibody.
Results from the functional assays of the P\ integrin and CD44 using collagen IV- or laminin-coatedwells showed clearly that these adhesion molecules are
involved in cell adhesion and growth on ECM in vitro.
Fibronectin, collagen, or laminin on the cell surface
is a ligand belonging to the integrin family or CD44.
Blocking of ICAM-1 inhibited significantly cell growthon these ECMs, although they do not belong to theligand family of ICAM-1. This suggests the blocking
of ICAM-1 may inhibit cell adhesion through otherpathways.
Our current findings suggest that the detected
CAM may serve directly or indirectly in the attachmentof the LEC to the underlying basement membrane(i.e., lens capsule) because collagen and laminin are
major components of the lens capsule's ECM. Also, in
LEC migration and the attachment onto the posterior
capsule in the defective lens capsule after cataract surgery, such molecules presumably are involved in theformation and disruption of cell-to-cell and cell-toposterior capsule interactions.
Olivero and Furcht21 reported that fibronectin in
addition to collagen IV and laminin promoted theadhesion and migration of rabbit LEC. We did notinvestigate fibronectin into our study, because normally it is not present in the adult lens. However,fibronectin plays a role in the embryonic developmentof the lens.21 Therefore, it would be of interest to
determine in further studies how human cataract
LECs respond to fibronectin in the presence and absence of blocking antibodies, because the authors
cited above assumed that the introduction of fibronectin into die eye after cataract surgery may play a
critical role in the posterior migration of LECs.
Our results may have clinical implications for thedevelopment of new approaches to inhibit posterior
capsule opacification and postoperative inflammation
caused specifically by residual LECs. When residual
LECs come in contact with the IOL after surgery, thesecells are induced to undergo fibrous metaplasia andproduce prostaglandin E2, resulting in capsular fibrosis and blood-aqueous barrier disruption.1'1 In thisprocess, the IOL can be regarded to act as an ECM. We
speculate that residual LECs may receive a pathologic
signal from the IOL through such adhesion molecules, when the IOL functions as an ECM, because aproteinaceous coating around the IOL was found afterDownloaded From: http://iovs.arvojournals.org/pdfaccess.ashx?url=/data/journals/iovs/933197/ on 06/27/2018

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Investigative Ophthalmology & Visual Science, March 1997, Vol. 38, No. 3

FIGURE l. Expression of /?, integrin in situ immediately after surgery (A) and at 2 weeks ofculture (B) in human cataract lens epithelial cells. Lens epithelial cells show immunoreactivity for j3\ integrin. Magnifications, X400 and X1000 for A and B, respectively.
FIGURE 2. Expression of intercellular adhesion molecule-1 in situ immediately after surgery(A) and at 2 weeks of culture (B) in human cataract lens epithelial cells. Lens epithelial
cells show immunoreactivity for intercellular adhesion molecule-1. Magnifications, X1000
and X200 for A and B, respectively.
FIGURE 3. Expression of E-cadherin in situ immediately after surgery (A) and at 2 weeks ofculture (B) in human cataract lens epithelial cells. Lens epithelial cells show immunoreactivity for E-cadherin. Magnification, X1000.

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Adhesion Molecules in Lens Epithelial Cells

583

TABLE i. Expression of Adhesion Molecules by Lens Epithelial Cells of Human Cataracts
2 Weeks of Culture

Before Culture
Number of Donors

P\ Integrin
P-i Integrin
Pa Integrin
ICAM-1
VCAM-1LECAM-2E-cadherin
CD 44

5
5
5
5
5
5
5
6

Staining

Number of Donors

5 (strong)

7
6
6
5
5
6
6
5

0
0
5 (moderate to strong)000
6 (strong)

cataract surgery, and collagen and fibronectin wereidentified.22'23 Inhibition of the adhesion molecules
may reduce such interactions between the IOL and
LECs. The antibodies to some adhesion molecules reduced significantly anterior uveitis caused by intravitreous injection of IL-1 or endotoxin.24 Our results
suggest that migration of residual LECs onto the posterior capsule also might be hindered by the inhibition of integrin families or CD44 expressed by LECs.
Integrins are composed of two noncovalently associated transmembrane glycoprotein subunits, the aand /0-chains, both of which contribute to the binding
to the matrix proteins. The binding of integrins totheir ligands depends on the extracellular divalentcations (Ca2+ or Mg2+) present in the a-chain. The 0chain of the integrins recognizes the RGD sequence(arginine-glycine-aspartic acid) present in ECM proteins. Therefore, chelation of Ca2+ by ethylenedi-

Staining
7 (strong)00
5 (moderate to strong)000
5 (strong)aminetetraacetic acid may inhibit LEC migration by
disrupting the adhesion to the lens capsule. The peptide RGD also may disrupt LEC migration by competitive binding to the integrins present on the surface ofLEC, thereby inhibiting their binding to integrins on
the lens capsule, as used experimentally for tumor
metastasis inhibition.25'26 We reported that sustained
release of ethylenediaminetetraacetic acid significantly inhibited LEC migration onto the posterior capsule in rabbit eyes.27 The results of sustained releaseof RGD will be reported elsewhere.
In conclusion, LECs of human cataracts express
Pi integrin, ICAM-1, and CD44 in situ and at 2 weeks
of culture. These adhesion molecules may serve in theattachment of the LECs to the underlying lens capsuleand be involved in the formation and disruption ofcell-to-cell and cell-to-posterior capsule interactions
when the LECs migrate after surgery onto the posterior capsule. Suppression or control of adhesion mole-Control
Anti-/3 1 Integrin

1

LJLJ

Control

Anti-ICAM-1

Anti-fl 1 Integrin

Anti-CD44

Anti-ICAM-1
Anti-CD44

-Q
TO

>2

-Q1

E
3
0

Control

O.OIfig/mB

O.lug/nt

1 fig/raO

10«xg/mB

Concentration of Antibodies

FIGURE 4. Functional assays of human cataract lens epithelial
cell adhesion to the collagen-coated well. * and ** indicate
significant differences at the level of P < 0.05 and P < 0.01,
respectively, compared to the control.

Control

O.OiMg/mS O.lug/mO

lug/ntf

Concentration of Antibodies
FIGURE 5. Functional assays of human cataract lens epithelial
cell adhesion to the laminin-coated well.

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Investigative Ophthalmology 8c Visual Science, March 1997, Vol. 38, No. 3

LU
Q)

03
*+—
O

Control

CollagenCoated Well

LamininCoated Well

FIGURE 6. Functional assays of human cataract lens epithelial
cell adhesion to the collagen-and laminin-coated plate whenanti-/3-l integrin monoclonal antibody, anti-intercellular adhesion molecule-1 monoclonal antibody, and anti-CD44
monoclonal antibody were added to the incubation medium.

cules being produced by residual LECs may offer a
new approach for inhibiting LEC proliferation or migration and, therefore, secondary cataract formationand inflammation. However, further investigations
must be performed to delineate clearly the roles ofadhesion molecules in LEC mitogenesis and migration.
Key Words
adhesion molecules, /3t integrin, CD44, ICAM-1, lens epithelial cells, secondary cataract
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