Institut National de la Santé et de la Recherche Médicale Unité 514, Institut Fédératif de Recherche 53, Université de Reims Champagne-Ardenne, Centre Hospitalier Universitaire Maison Blanche, 51092 Reims Cedex, France
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ABSTRACT |
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Development of human fetal airways requires interaction of the
respiratory epithelium and the extracellular matrix through integrins.
Nevertheless, the specific roles of 1-integrins during development and tubular morphogenesis are still unknown. To analyze
1-integrin localization and influence during migration,
we developed a model of human fetal tracheal explants growing on
collagen and overlaid with a second layer of collagen to form a
sandwich. In this configuration, cord and tubule formation proceeded
normally but were inhibited by incubation with
anti-
1-integrin subunit antibodies. On a collagen
matrix,
1-integrins were immunolocalized on the entire
plasma membrane of migrating epithelial cells and almost exclusively on
the basal plasma membrane of nonmigratory epithelial cells. In a
sandwich configuration,
1-integrins became detectable in
the cytoplasm of epithelial cells. Coating cultures with collagen
transiently altered the morphology of migrating cells and their speed
and direction of migration, whereas incubation with
anti-
1-integrin subunit antibodies irreversibly altered these parameters. These observations suggest that the matrix
environment, by modulating
1-integrin expression
patterns, plays a key role during tubular morphogenesis of human fetal
tracheal epithelium, principally by modulating epithelial cell migration.
cell-matrix interaction; collagen sandwich
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INTRODUCTION |
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TUBULAR
MORPHOGENESIS of epithelial cells leads to the formation of human
airways from the trachea to the distal bronchioles. This morphogenesis
occurs during fetal development and depends on cell-matrix interactions
(18) that are essential for cell proliferation, migration,
and differentiation (15, 22, 28, 29, 31, 33). The cell-matrix
interactions are mediated, at least partially, through epithelial cell
surface receptors called integrins. The integrins are a large family of
heterodimeric transmembrane glycoproteins composed of
noncovalently linked - and
-subunits. Until now,
investigations have identified 16
- and 8
-subunits that combine
to form at least 22 integrins. Each integrin recognizes more than one
ligand, and each ligand can be recognized by more than one integrin
(14, 23). Interactions between integrin
receptors and ligands have been shown to activate intracellular
signaling pathways involving mitogen-activated protein kinases,
tyrosine protein kinases, or GTP-binding proteins that are thought to
affect the cellular cytoskeleton (23, 35). The distribution of integrins has been studied in kidney and mammary glands where development is associated with tubular branched
morphogenesis (3, 19) and more recently in
fetal and adult human lungs (7, 34). The
involvement of integrins during angiogenesis and tubulogenesis of
kidney cells has been demonstrated (8, 10,
37) and partly elucidated from studies of murine
airways (20, 26), but to date, no study has
been devoted to the dynamics of epithelial cell migration during human
fetal airway development due to the lack of a human in vitro model.
To assess the possible roles of 1-integrins, the most
prevalent integrin subunit forming complexes with subunits
1-
9 and
v and mediating
cell adhesion to the majority of basement membrane proteins
(2), we developed an in vitro model culturing human fetal
tracheal explants on a type I collagen gel. The epithelial cells can
grow, migrate, and form a network of branched epithelial cords and
tubules when they are grown in a collagen sandwich. To determine
whether this new cellular organization observed after modification of
the matrix environment was dependent on cell receptors, we analyzed the
cellular distribution of the
1-integrin subunit and the
effect of blocking antibodies to the
1-integrin subunit on cell migration and tubular morphogenesis. The cellular distribution of the
1-integrin subunit was evaluated
immunocytochemically before and after modification of the matrix
environment and during tubule formation. Moreover,
anti-
1-integrin subunit blocking antibodies totally
inhibited the evolution of human fetal tracheal epithelial (HFTE) cell
cultures as assessed morphologically and by the speed and direction of
cell migration. These findings suggest that
1-integrins
mediate a critical role for human epithelial cell-matrix interactions
during tubular morphogenesis of human airways.
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METHODS |
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Tissues. Tracheae from 12 normal human embryos and fetuses ranging from the pseudoglandular (7-17 wk gestation; n = 4) to the canalicular (18-24 wk gestation; n = 5) and alveolar (25 wk gestation to birth; n = 3) stages of development were obtained after spontaneous or medically induced abortions. The use of human fetal tissues was approved by the Regional Ethics Committee of Development and Reproduction. The tracheae were dissected in the hours after the abortions and maintained in RPMI 1640 culture medium (Seromed, Biochrom, Berlin, Germany) containing penicillin (100 U/ml) and streptomycin (100 µg/ml) before preparation of the explants.
Antibodies.
Monoclonal IgG1 clone P5D2 (9) raised against the
1-integrin subunit was used for immunocytochemistry.
Monoclonal blocking IgG1 clone Lia 1/2 (5) raised against
the
1-integrin subunit was used for the tubulogenesis
blocking assay, cell morphology, and the migration studies. They were,
respectively, provided by Dr. D. Sheppard (University of California,
San Francisco, CA) and purchased from Immunotech (Marseilles, France).
Monoclonal antibodies raised against cytokeratin 13 (CK13) were
purchased from Sigma (St. Louis, MO). Monoclonal antibodies raised
against the Ki67 antigen (MIB-1 clone) were purchased from Immunotech. Negative controls consisted of incubation with monoclonal nonimmune IgG2a,
fractions (Sigma).
Preparation of collagen gel matrix. The type I collagen used for explant cultures was extracted from rat tail tendons according to the method of Chambard et al. (6). Briefly, collagen was solubilized by stirring 1 g of Wistar rat tail tendons for 48 h at 4°C in 100 ml of a 0.1% acetic acid solution. The solution was then centrifuged at 16,000 g for 45 min at 4°C. Four volumes of supernatant containing 2 mg/ml of type I collagen without any other contaminant proteins (25) were mixed with 1.5 volumes of 5× concentrated RPMI 1640 medium and 0.15 volume of 1 N NaOH at 4°C; 2 ml of this collagen solution were then poured onto 35-mm culture dishes (Falcon, Becton Dickinson, Plymouth, UK) and allowed to polymerize at 37°C for 2 h.
Fetal tracheal explant cultures. The middle part of the trachea was cut into 1-mm2 explants and plated onto collagen gel in 35-mm culture dishes. The explants were incubated in RPMI 1640 medium supplemented with 50 µg/ml of L-ascorbic acid, 50 U/ml of catalase, 0.2 µg/ml of glucagon, 10 µg/ml of apo-transferrin, 0.6 ng/ml of 3,3',5-triiodo-L-thyronine, 4 ng/ml of epidermal growth factor, 4 ng/ml of sodium selenite, 1% of 100× MEM-nonessential amino acid solution, 15 ng/ml of retinoic acid, 4 ng/ml of hydrocortisone, 10 µg/ml of insulin, 200 U/ml of penicillin, and 200 µg/ml of streptomycin (Sigma-Aldrich Chemie, Steinheim, Germany) and incubated at 37°C in 95% air-5% CO2.
Collagen overlay to form a sandwich.
After 5-10 days of culture, an outgrowth of epithelial cells
developed around the explants. The cultures were then overlaid with
type I collagen at 4°C. The collagen sandwich was then incubated at
37°C in a 5% CO2 atmosphere and allowed to polymerize
for 30 min, and then culture medium was added. For
1-integrin-blocking assays, the explant cultures were
incubated with 100 µg/ml of Lia 1/2 antibodies for 1 h at 37°C
before the culture was covered with collagen. The cultures were
examined under an inverted phase-contrast microscope (Zeiss IM35,
Oberkochen, Germany).
Transmission electron microscopy. Collagen sandwich cultures were rinsed in 0.1 M, pH 7.2, phosphate-buffered saline (PBS; Sigma), fixed in 2.5% PBS-glutaraldehyde for 60 min, postfixed in 1% H2O-osmium tetraoxide for 2 h, dehydrated through graded concentrations of ethanol, and then embedded in agar resin 100 (Agar Scientific, Orsay, France). Semithin sections were stained with toluidine blue and observed under an Axiophot microscope (Zeiss). Ultrathin sections were stained with uranyl acetate and lead citrate and observed by using a Hitachi 300 transmission electron microscope operating at 75 kV.
Immunocytochemistry.
To determine the cellular localization of the 1-integrin
subunit, the distribution of proliferative cells (Ki67-positive staining) and the epithelial nature of the cells (CK13-positive staining), fetal tracheal explant cultures and collagen sandwich cultures were rinsed in PBS, embedded in optimum cutting temperature compound (Tissue Tek, Sakura Finetek, Zoeterwoude, The
Netherlands), and frozen in liquid nitrogen. Frozen sections (5 µm
thick) were fixed in precooled methanol (
20°C). To saturate
nonspecific sites, the sections were incubated with PBS containing 3%
bovine serum albumin (BSA). They were then sequentially treated as
follows: exposed to the monoclonal antibody P5D2 raised against the
1-integrin subunit (1:50 in 1% PBS-BSA), raised against
the Ki67 antigen (1:10 in 1% PBS-BSA) or raised against CK13
(1:400 in 1% PBS-BSA) for 90 min; washed; incubated with 3% PBS-BSA;
exposed to biotinylated goat anti-mouse IgG (1:50 in 1% PBS-BSA;
Boehringer Mannheim) for 60 min; washed; and incubated with 3%
PBS-BSA. The complexes formed were finally visualized with
streptavidin-coupled fluorescein isothiocyanate for the
1-integrin subunit and the Ki67 antigen or with
streptavidin-coupled Texas Red for CK13 (1:50 in 1% PBS-BSA; Amersham
Life Sciences, Poole, UK). The observations were made under an Axiophot
microscope with epifluorescence and Nomarski differential interference illumination.
Cell migration.
Cell migration was evaluated with a previously described technique
(36). Briefly, fetal tracheal explant cultures were
incubated for 30 min with Hoechst 33258 (0.1 mg/ml; Sigma) in culture
medium, allowing incorporation of the fluorescent dye into the nuclei of living cells. The cultures were then washed twice with culture medium to remove excess dye and overlaid with type I collagen at 4°C
or incubated with either fresh culture medium, an antibody raised
against 1-integrin (100 µg/ml of Lia 1/2 blocking
antibody), or nonimmune IgG2a,
for 1 h at 37°C. To measure
cell migration, the culture dishes were placed on the stage of an
inverted Zeiss IM35 microscope and enclosed in a transparent
environmental chamber with 5% CO2 in air at 37°C. The
microscope was equipped with epifluorescence illumination (mercury
lamp) through an excitation filter at 360 nm and an emission filter at
510 nm and with a low-level silicon-intensified target camera (Lhesa
4036, Cergy Pontoise, France). A shutter (Lambda 10-25) was placed in
the excitation light path to illuminate the culture for short periods
of time (1 s) and to simultaneously digitize the fluorescent images.
The images were digitized every 15 min as 512 × 512 pixels and an
8-bit array with a Sparc-Classic (Sun Microsystems, Mountain View, CA)
workstation equipped with an XVideo card (Parallax Graphics, Santa
Clara, CA). Specific software was used to quantify cell migration
through three main functions: the detection of individual cell nuclei,
the computation of their trajectories, and analysis of these
trajectories. From the latter, the computer calculated the cell
migration speed and the angular deviation (in degrees) from the
horizontal of each successive movement of the nucleus. The migration
speeds reported correspond to the mean migration speed of 12 HFTE cells
at the migration front. A small variation in the angular deviation is characteristic of a uniform direction of cell migration.
Morphogenesis and cell morphology.
To monitor the dynamics of cellular cord formation and the cell
morphology alterations according to the culture conditions, cultures
were placed in the environmental chamber on the stage of the Zeiss IM35
inverted microscope. To study the dynamics of cellular cord
morphogenesis, phase-contrast images of the collagen sandwich cultures
observed through a ×2.5 objective were recorded every 15 min for
24 h. Phase-contrast images of the cells located at the migrating
front of the epithelial outgrowth in collagen sandwich cultures were
digitized every minute for 2 h. To test the effect on cell
morphology of pouring cold collagen gel (4°C) onto the cell culture,
phase-contrast images of cell cultures on a collagen gel were digitized
every 30 s for 5 min after incubation with culture medium either
at 37°C or at 4°C. To analyze the effect of
anti-1-integrin subunit antibodies on cell morphology,
immediately after Lia 1/2 antibody addition (100 µg/ml in culture
medium) to the HFTE cell cultures, phase-contrast images were digitized every 15 s for 10 min.
Statistical analysis. The mean migration speeds of HFTE cells under the different experimental conditions were compared by unpaired Student's t-test. Data are expressed as means ± SD. Linear regression test was used to determine the influence of the fetal age on the mean migration speed of HFTE cells. A P value < 0.05 was considered to be significant.
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RESULTS |
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HFTE cells form differentiated tubular structures in type I
collagen gel sandwich cultures.
Whatever the age of the fetal trachea, cells of an epithelial nature,
as demonstrated by CK13-positive immunostaining (data not shown),
started to grow from the explants on the type I collagen gel after
2-7 days of culture, forming an outgrowth around the explants
(Fig. 1A). The cells located
at the advancing edge of the outgrowth had a migratory phenotype
characterized by a flattened aspect and the presence of lamellipodia
(Fig. 1B) and were nonproliferative as demonstrated by the
absence of Ki67 antigen immunostaining (data not shown).
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1-Integrin subunit is expressed by HFTE cells and
its distribution is altered during outgrowth development and tubular
morphogenesis.
During development of the epithelial cell outgrowth on the collagen
gel, the
1-integrin subunit was detected by
immunocytochemical staining on the entire plasma membrane of the cells
at the migrating edge of the culture (Fig.
4B), whereas an intense
immunoreactivity was mainly observed on the basal side of the
nonmigratory HFTE cells in contact with the collagen gel matrix (Fig.
4D). The plasma membranes of some cells located at basal
position were also weakly labeled (Fig. 4D). When the HFTE
cells were covered with collagen, the outgrowth retracted, the cells
became spherical, and the
1-integrin subunit was
detected in the cytoplasm of all the cells (Fig. 4F). After
2 days of sandwich culture, when the HFTE cells formed cords and
tubules, the
1-integrin subunit was localized at the
plasma membrane of all the tubule-forming cells, in the cytoplasm of the degenerative cells present around the tubule, and in the cytoplasm of the resting cells not involved in the tubule formation, which are
localized at the interface of the two collagen layers (Fig. 4H). All these alterations were similarly observed whatever
the age of the trachea and the degree of differentiation of the HFTE cells used for cultures.
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1-Integrins are involved in the tubular
morphogenesis of HFTE cells.
To determine the role of the
1-integrins in the
morphogenesis of HFTE cell branched cords and tubules, cultures of
tracheal explants were incubated with blocking antibodies directed
against the
1-integrin subunit before being overlaid
with collagen. Control cultures incubated with mouse nonimmune IgG
developed cellular branched cords and tubules (Fig.
5A) similar to those observed in control collagen-overlaid cultures without antibodies (Fig. 3A). In contrast, when exposed to
anti-
1-integrin subunit antibodies, HFTE cells came to a
standstill and failed to undergo cord formation. No further change
could be observed after a 10-day period. This result was obtained in
100% of human fetal tracheal explant cultures incubated with
anti-
1-integrin subunit antibodies (Fig. 5B).
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HFTE cell-matrix interactions lead to altered cell migration.
The speed and angular deviation of HFTE cell migration were studied
during outgrowth development when the cells were incubated with
nonimmune IgG or antibodies directed against the
1-integrin subunit and during the early phase of
cellular cord formation. The nuclei could be observed with Hoechst
fluorescent dye, and the study focused on the cells located at the
migratory edge of the outgrowth. The cells were tracked for 1 h.
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HFTE cell-matrix interactions lead to altered cell morphology.
The morphology of HFTE cells at the migrating forefront of the
outgrowth changed after the culture was covered with collagen (Fig.
7). During the first minute, the cells
extended lamellipodia (Fig. 7A), and thereafter they
progressively retracted these cytoplasmic extensions (lamellipodia).
This morphological change was accompanied by retraction of the overall
outgrowth, leaving some individual cells stranded (Fig. 7B).
After 10 min, the HFTE cells became spherical (Fig. 7C). The
collagen overlay was polymerized within 30 min, and 90 min later, the
cell morphology changed again with the extension of new visible
lamellipodia (Fig. 7D).
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DISCUSSION |
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1-Integrins play an important role in cell-cell and
cell-matrix interactions, acting as regulators of cell phenotype,
survival, migration, proliferation, and/or differentiation
(1, 12, 27, 33). In
the present study, we developed an in vitro human fetal model to assess
the role of the matrix environment via the
1-integrin
family receptor during epithelial cell migration leading to human
airway development. Our results show that matrix environment modification can act through
1-integrins to modulate the
epithelial cell migration and to induce cord and tubule formation by
HFTE cells. Until now, only a few studies have described in vitro
models for studying tubular morphogenesis of human respiratory
epithelial cells (4, 16). However, those
studies always used dissociated adult cells mixed with type I collagen,
and such a technique, which requires numerous cells, was not
appropriate for HFTE cells and does not permit an analysis of the
dynamic migratory process observed during in vivo fetal airway development.
In our model, the tubular morphogenesis phenomenon is obtained after
two steps of cell culture involving two steps of cell-matrix interactions. In the first step, the basal plasma membranes of all the
cell monolayers cultured on type I collagen interact with the matrix.
The HFTE cells grow out from the explant, and this outgrowth contains
two populations: at the leading edge, those with a migratory phenotype
characterized by flattening and lamellipodia and expressing the
1-integrin subunit on their entire plasma membrane; and
behind this migration front or near the explant, cells that do not
spread, do not have any lamellipodia, and express the
1-integrin subunit almost exclusively on their basal
plasma membranes. The
1-integrins detected in
basolateral plasma membranes were previously shown to be involved in
the stable attachment of stationary epithelial cells to the matrix and
in the maintenance of cell-cell interactions (30,
32). The pericellular distribution of
1-integrins was reported in processes involving
respiratory cell migration, such as wound repair, when epithelial cells
at the edge of the wound migrated to reepithelialize a denuded area (12). Coraux et al. (7) also
previously described this differential expression of the
1-integrins during the development of human fetal
airways in vivo. The
1-integrin subunit was expressed on the entire plasma membrane of cells at the tip of the bronchial epithelial buds growing and migrating into the mesenchyme of human fetal lungs, whereas it was localized at the basolateral plasma membrane of anchored and polarized epithelial cells along the proximal
branches. In our model, blocking antibodies directed against the
1-integrin subunit demonstrated the implication of these
glycoproteins in the migratory process because they altered cell
morphology by inducing retraction of the lamellipodia. The impaired
migration of respiratory and retinal pigment epithelial cells in the
presence of antibodies to
1-integrins was previously described (12, 13), but Hergott et al.
(13) did not observe any cell phenotype change. The
phenotype alteration that we described can explain the slowed speed and
angular deviation variations of the migration. Cell migration is known
to be a process involving cytoplasmic extensions at the leading edge of
migratory cells (lamellipodia), with cytoskeleton modifications and
cell-matrix interactions via integrins (21). During this
process, the cell nuclei seem to be passive and swept along by the
cytoplasmic movements. This postulate can explain the relatively
straight trajectories of the peripheral HFTE cell nuclei on collagen.
Adding blocking antibodies caused the lamellipodia to retract by
partially inhibiting the cell-matrix interactions, and the nuclear
trajectories became erratic.
Cell morphology and migration alterations could also be observed during
the second step of cell culture, i.e., the addition of a second layer
of collagen, so that the entire surface, not only the basal plasma
membrane of HFTE cells, came in contact with the collagen matrix. The
cell migratory phenotype was temporarily lost and associated with a
significant slowing of the mean migration speed of the advancing HFTE
cells, a disorientation of their migration direction, and a slightly
delayed cord and tubule formation. The second collagen layer caused a
depolarization and a redistribution of the 1-integrin
subunit from the basal side to the cytoplasm of HFTE cells. The
relationships between the cells and the matrix seem to be disturbed
because the cells redistributed part of their surface receptors.
Consequently, the cells became spherical, leading to altered migration.
Chambard et al. (6) described the same phenomenon of
disorganization of polarized thyroid epithelial cell monolayers and
alteration of cell migration that was triggered by contact of the
apical plasma membranes of the cells with collagen and led to the
complete reorganization of the cell population. This migration stopped
when a new apical pole was formed by the cells lining the collagen-free
lumen. In our model, unlike the observations made with
anti-
1-integrin subunit antibodies, perturbation of the
cell-matrix interactions by the second collagen layer was transient;
lamellipodia formation, migration, and ramifications proceeded after a
short delay. Studies using polarized Madin-Darby canine kidney cells
(24, 37) also showed that contact of the apical domain with a collagen matrix modified the
1-integrin expression pattern, demonstrating a polarity
reversion. In our culture model on a collagen matrix, nonmigratory HFTE
cells were polarized because
1-integrins were detected
in their basal plasma membrane. When coated with a second layer of
collagen, the cells were transiently depolarized. When epithelial
tubules were formed, the HFTE cells edging the lumen were polarized,
showing apical microvilli and cilia as reported during human fetal
airway development in vivo (11). The reorganization of
HFTE cell monolayers in tubular structures led to a new polarization of
the HFTE cells facing the lumen.
These different roles of 1-integrins can be explained by
their cellular localization but also by the
-chain involved in the
heterodimeric receptor formation. The
1-integrin subunit is known to form complexes with numerous
-subunits to form some extracellular matrix receptors differentially expressed during airway
development (7). Moreover, the contributions of integrin heterodimers to the morphogenesis of branched tubular organs have been
reported (10, 17, 20).
In conclusion, we demonstrated that the tubular morphogenesis of HFTE
cells in a collagen sandwich is dependent on cell-matrix interactions
and cell-migration regulation. According to their cellular
distributions, 1-integrins appear to be involved in the
cell migration and tubule formation of HFTE cells. Our assay could also
be used to examine the role of specific integrins using anti-
-subunit antibodies and to analyze whether other extracellular matrix components may assist or inhibit the process.
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ACKNOWLEDGEMENTS |
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This work was supported in part by European Community Network no. BIO-CT 95-0284 and by the Association Française de Lutte contre la Mucoviscidose (Paris, France).
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FOOTNOTES |
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C. Coraux is the recipient of a fellowship funded by the Ministère de L'Enseignement Supérieur et de la Recherche.
Address for reprint requests and other correspondence: D. Gaillard, INSERM U514, IFR 53, Université de Reims, CHU Maison Blanche, 45, rue Cognacq-Jay, 51092 Reims Cedex, France (E-mail: Dominique.Gaillard{at}univ-reims.fr).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Received 4 November 1999; accepted in final form 16 March 2000.
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