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Cell Adhesion to the Apical Pole of Epithelium: a Function of Ce 11 Polarity

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Cell Adhesion to the Apical Pole of Epithelium: a Function of Ce 11 Polarity 180 European Journal of Cell Biology 66, 180-191 (1995, February) © Wissenschaftliche Verlagsgesellschaft . Stuttgart Cell adhesion to the apical pole of epithelium: a function of ce 11 polarity Michael Thie1)a, Bärbel Harrach-Ruprechtb, Heinrich Sauere, Petra Fuchsa, Anja Albersa, Hans-Werner Denkera a Institute of Anatomy, University of Essen, Medical School, Essen/Germany b Institute für Arteriosclerosis Research, University of Münster, Münster/Germany C Max-Planck-Institute for Molecular Physiology, Dortmund/Germany ReceivedJuly 6, 1994 Accepted September 16, 1994 Uterine epithelium - epithelial phenotype - polarization • Introduction adhesiveness The epithelial cells lining the uterine cavity are structurally Human uterine epithelinm displays a distinct polarized organization with apical, lateral, and basal plasma membrane domains. Although and functionally polarized cells with distinct basal, lateral, and non-adhesive throughout most of the menstrual cyde, epithelial cells apical membrane domains. As is typical für simple epithelia, allow attachment of trophoblast cells to their apical pole during the apical surface of uterine epithelial cells (UECs) is free and embryo implantation. Arecent hypothesis postulates that epithelial non-adhesive for opposing UECs or embryonic cells such as cells turn off genes for apical-basal polarity and turn on genes for a trophoblast. Nevertheless, the uterine epithelium is not a pas• more mesenchyme-Iike phenotype allowing cell-cell interaction with sive surface, and UECs can be functionally reprogrammed to trophoblast. contribute actively to trophoblast adhesion. When appropri• Using an in vitro assay human uterine celllines (RL95-2, HEC-I-A, ately conditioned with steroid hormones, these epithelial cells AN3-CA) were selected on the basis of adhesiveness for trophoblast• enter astate of so-called receptivity and switch from a non• type cells (JAR). Subsequently, uterine cells were examined for epithelium-specific ultrastructure using transmission electron micros• adhesive state to a potentially adhesive state. When exhibiting copy, and for the expression of E-cadherin, «6-, ßl-, ß4-integrin sub• the adhesive state, the apical membrane domain of UECs units and cytokeratin using immunocytochemistry, confocallaser scan• allows the attachment of trophoblast (für review, see [22]). ning microscopy, and surface replication technique. HEC-I-A mono• The processes involved in modulating adhesiveness of UECs layers are non-adhesive for JAR cells and appear highly polarized für trophoblast, however, have not been identified so far. expressing E-cadherin, «6-, ßl-, ß4-integrin subunits, and cytokeratin. A mechanism to achieve UEC adhesiveness für trophoblast Both, integrins and E-cadherin, are present at the lateral membrane. is recently being discussed postulating that UECs modulate RL95-2 monolayers which are adhesive for JAR cells appear non• their apical-basal polarity [6, 7]. This plasticity in the pheno• polarized. Like HEC-I-A cells, RL95-2 cells express E-cadherin, «6-, ßl-, and ß4-integrin subunits, and cytokeratin. In contrast to HEC-I-A type of adult UECs may involve some of the elementary pro• cells, integrins and E-cadherin are distributed at the entire cell surface. cesses that playa rale in embryology during transformation of AN3-CA monolayers are non-adhesive for JAR cells and appear non• epithelium to mesenchyme. A characteristic of that latter pro• polarized. Cells lack epithelial-specific markers such as keratin and E• cess is, likewise, that apical-basal polarity is lost, and adhesion cadherin. They show only low expression of «6-, ßl-integrin subunits molecules are redistributed and/or newly acquired [12, 13]. In and lack ß4-integrin subunit. Conversely, they express vimentin. analogy, in UECs, part of the master gene pragram for the Thus, modulation of the epithelial phenotype of uterine cells, i. e. epithelial phenotype including genes for apical-basal polarity loss of apical-basal polarity, might prepare the apical cell pole for cell• may be turned off and, vice versa, certain genes for the cell interaction with trophoblast. However, loss of cell polarity would mesenchymal program may be turned on thus enhancing not lead to enhancement of adhesiveness for trophoblast if accom• adhesiveness of UECs for trophoblast. The activation of the panied by a loss of epithelium-specific adhesion molecules. mesenchymal pro gram in definitive epithelia occurs not only during development in vivo [13] but also in vitro, e. g. in lens epithelium [11] and Madin-Darby canine kidney cells [40]. Sig• nals such as tumor-promoting phorbol esters [21], oncoprote• ins [31], growth factors [26], and/or signals generated by cell• 1) Dr. Michael Thie, Institut für Anatomie, Universitätsklinikum, cell and cell-matrix interactions [30] appear to contral gene Hufelandstr. 55, D-45122Essen/Germany. activation in these systems. Loss of polarized epithelial phenotype 181 In this study we characterize parameters of the epithelial and spheroids were washed two times with RPMI 1640 medium prior phenotype of certain human endometrial ceIl lines (RL95-2, to the experiment. After 1 h, spheraid adhesion to the endometrial HEC-I-A, AN3-CA) and correlate these with adhesive or monolayers was quantified by cenrifuging coverslips with cell-spheroid non-adhesive behavior for trophoblast-type ceIls (JAR) in an surface facing down at 12g for 5 min. Attached spheroids were counted attempt to gain insight into the pro gram underlying UEC and expressed as the percentage of the nu mber of spheroids seeded. adhesiveness. We examine ultrastructural features as weIl as Immunofluorescence expression of markers associated to the epithelial phenotype, Cells grown on gJass coversJips were rinsed twice in phosphate• i. e. E-cadherin [35], a6-, ßl-, ß4-integrin subunits [33, 34], buffered saline (PBS), fixed and permeabilized by incubation in 96 % and keratin intermediate filaments [24]. methanol-water for 10 min at -20°C. After severaJ washings with PBS On the basis of our data we postulate that modulation of the and a finaJ wash in PBS supplemented with 0.5 % bovine serum albu• epithelial phenotype of UECs, specificaIly loss of apical-basal min (BSA) , cells were incubated for 1 h at room temperature with the polarity, prepares the apical ceIl pole for ceIl-ceIl interaction primary antibody. Thereafter, cells were rinsed in PBS/0.5 % BSA (4 x with trophoblast. Loss of ceIl polarity, however,' would not 10 min) and incubated with the corresponding fluorescein iso• lead to enhancement of UEC adhesiveness for trophoblast if thiocyanate-conjugated secondary antibody for 1 h at room temper• ature. In controJ experiments the primary antibody was omitted. After accompanied by a loss of epithelium-specific adhesion mole• rinsing with PBS, specimens were mounted with 90 % gJycerol-PBS, cules. This suggests that specific modulation of polarity• supplemented with 1.0 % p-phenyJenediamine as an antiquenching related parameters rather than down-regulation of the entire agent and examined with a Zeiss Axiophot microscope equipped with epithelial pro gram is a key event in this type of adhesive epi• epiillumination (450-490 nm excitation; fiJterset 487909). Photographs thelial interactions . were taken on Neopan 1600 film (Fuji, Tokyo/Japan). Antibodies Rat monocJonal antibody to a6-integrin subunit (GoH3; [32]) was pro• Materials and methods vided by Dr. A. Sonnenberg (The Netherlands Cancer Institute, Divi• sion of Cell Biology, Amsterdam/The Netherlands), and diJuted 1:3 Routine cell culture with PBS/0.5 % BSA before use. Rat monocJonal antibody to ßl• Human endometrial carcinoma cell lines were purchased from the integrin subunit (AllB2; [38]) was pravided by Dr. C. Damsky American Type Culture Collection (ATCC), Rockville, MDIUSA, i. e. (Department of Anatomy, University of California, San Francisco/ RL95-2 cells (CRL 1671; [37]), HEC-I-A cells (HTB 112; [19]), and USA), and was diJuted 1:3 with PBS/0.5 % BSA before use. Mouse AN3-CA cells (HTB 111; [5]). For routine culture, cell lines were monocJonal antibody to ß4-integrin subunit (3El) was purchased fram grown in plastic flasks in 5 % C02"95 % air at 37°C. In brief, RL95-2 BiomoJ, Hamburg/Germany, and was diluted 1: 100 with PBS/0.5 % cells were seeded out in a 1+1 mixture of Dulbecco's modification of BSA before use. Mouse monocJonal antibody to E-cadherin (6F9; [8]) Eagle's medium and Ham's F12 (Gibco-Life Technologies, Eggenstein/ was donated by Dr. J. Behrens (Max-DeJbrück-Centrum, Berlin/Ger• Germany) supplemented with 10% fetal calf serum (Gibco), 10 mM many), and was diJuted 1:5 with PBS/0.5% BSA before use. Mouse HEPES (Gibco), and 0.5 flg/ml insulin (Gibco), HEC-I-A cells in monocJonal antibody to cytokeratin No 8 (4.1.18) was purchased fram McCoy's 5A medium (Gibco) supplemented with 10 % fetal calf Boehringer Biochemica, Mannheim/Germany, and was diJuted 1:20 serum, and AN3-CA cells in Eagle's minimum essential medium with with PBS/0.5 % BSA before use. Mouse monocJonal antibody to Earle's salts and non-essential amino acids (Gibco) supplemented with vimentin (V9) was obtained fram Sigma-Aldrich, Deisenhofen/Ger• 10 % fetal calf serum. All media were additionally supplemented with many, and was diJuted 1:40 with PBS/0.5 % BSA before use. penicillin (100 lU/mi; Gibco) and streptomycin (100 flg/ml; Gibco). Fluorescein isothiocyanate (FITC)-conjugated rabbit anti-mouse The growth medium was changed every 2 to 3 days, and cells were sub• secondary antibodies (F232) and FITC-conjugated
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