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Intercellular Junctions Between Decidual Cells in the Growing BIOLOGY OF REPRODUCTION 15, 593-603 (1976) Intercellular Junctions Between Decidual Cells in the Growing Deciduoma of the Pseudopregnant Rat Uterus’ RUTH G. KLEINFELD, HENRY A. MORROW and VINCENT J. DeFEO Department of Anatomy and Reproductive Biology, The John A Burns School of Medicine, University of Hawaii, Honolulu, Hawaii 96822 Downloaded from https://academic.oup.com/biolreprod/article/15/5/593/2768190 by guest on 01 October 2021 ABSTRACT The appearance of gap junctions between decidual cells and the restructuring of the intercellular matrix of the endometrium was studied by electron microscopy in the developing primary deciduoma of the pseudopregnant rat uterus. Decidualization was induced by intraluminal injection of Hanks balanced salt solution at the time of peak sensitivity (Day 4). The progression of decidualization was followed through Day 9 of pseudopregnancy. At the time of sensitivity the periluminal stromal cells of the antimesometrial region are surrounded by an abundant collagenous matrix and there are relatively few contacts between processes of neighboring cells. When junctions exist they are of the maculae adherentes type. On the day following the deciduogenic stimulus (Day 5) contacts between cells are numerous and gap junctions are present. The presence of gap junctions between the early differentiating decidual cells suggests that cell to cell communication may be involved in the spread of decidualization. As decidualization progresses a rapid reduction in the amount of intercellular matrix occurs. With continued growth extensive infoldin and interdigitations of the plasma membranes develop between adjoining decidual cells forming a complex membranous labyrinth. Numerous gap junctions are present involving extensive areas of the cell surfaces. By Day 9 the antimesometrial region consists of large, polyploid, glycogen-rich decidual cells with extensive surface info!din that are joined by gap junctions. INTRODUCTION h later. This is a transitory state lasting only a Preparation of the rat uterus for ovum few hours. In normal pregnancy and pseudo- implantation involves specific interactions of pregnancy this occurs on Day 4 (DeFeo, 1967; the two ovarian hormones, progesterone and Psychoyos, 1973). At this time the uterus is estrogen (for reviews see: DeFeo, 1967; Psy- capable of responding to a variety of stimuli choyos, 1973; Glasser and Clark, 1975). The which elicit the decidual response. uterus of the rat and of many other mammals is Decidualization, a specific response of the normally not receptive to ovum implantation progestational endometrium, involves an exten- and must undergo specific hormone dependent sive reorganization of the endometrial cell changes before it develops a sensitive or recep- populations, analogous in many ways to em- tive state. Experiments with ovariectomized bryonic organogenesis. A period of rapid rats have established that uterine sensitivity growth transforms the mesenchymal-like stro- (the ability to decidualize in response to an mal cells into a densely confluent population of implanting blastocyst) depends on the comple- epithelioid cells. RNA and protein synthesis tion of a basic hormone sequence: daily expo- increase, DNA replication and mitosis are great- sure to progesterone for at least 48 h and the ly stimulated, cell migrations occur and the presence of minute amounts of estrogen at the stromal cells differentiate into large polyploid end of this period (Tachi et al., 1972; Psy- cells filled with glycogen and lipid. Within five choyos, 1973). When this sequence is com- days the uterine weight may increase more than pleted, a state of peak sensitivity occurs 20-24 10-fold (DeFeo, 1967; Finn, 1971). Decidualization involves an orderly coordi- nated progression of stromal cell differentiation Accepted July 29, 1976. starting with a population of periluminal stro- Received June11, 1976. ma! cells at the antimesometrial pole, then ‘This work was supported in part by National spreading toward the peripheral regions and the Institutes of Health grant HD 02399, a grant from the Ford Foundation 660-0202A and a research grant mesometrial pole as more stromal cells divide from the University of Hawaii. and differentiate. In each zone, cell division 593 594 KLEINFELD ET AL. precedes cell differentiation. When fully differ- tion on the day of estrus, Day 0 (DeFeo, 1%6). The entiated, the decidual cells stop dividing and decidual response was induced between 12 noon and 1 pm on Day 4 of pseudopregnancy by injection of eventually degenerate. The sequential pattern 0.1 ml of Hanks balanced salt solution (Cibco) into of cellular changes suggests that cell to cell the tubal end of the uterine lumen of each cornu interactions are involved. under ether anesthesia. The uterus of anesthetized rats A consistent feature of decidual tissue, was perfused via the dorsal aorta on Days 4, 5, 7 or 9 of pseudopregnancy with 3 percent glutaraldehyde in demonstrated by electron microscopy, is the 0.1 M phosphate buffer at pH 7.2. The uterine horns presence of junctional complexes between de- were removed and cross sectional slices (0.5-1 mm cidual cells (Jollie and Bencosme, 1965; Enders thick) were immersed in the buffered glutaraldehyde Downloaded from https://academic.oup.com/biolreprod/article/15/5/593/2768190 by guest on 01 October 2021 and Schlafke, 1967; Finn and Lawn, 1967; solution for 24 h at 4#{176}C.The tissue samples were Lawn et al., 1971; Kleinfeld and DeFeo, 1971). washed several times in the same buffer and postfixed for 4-6 h in 1 percent 0s04 in 0.1 M phosphate Gap junctions between decidual cells (earlier buffer pH 7.2, dehydrated in a graded series of ethanol referred to as tight junctions) have been noted solutions and embedded in Epon 812. in the pregnant mouse uterus (Finn and Lawn, Lanthanum was used according to the procedure of 1967; Finn, 1971), in the pseudopregnant rat Revel and Karnovsky (1967) to outline the extracellu- lar space and delineate the specialized gap junctions. deciduoma (Kleinfeld and DeFeo, 1971), and The uterus was perfused with 3 percent glutaraldehyde between predecidual cells in the human endo- buffered with s-collidine containing a final concentra- metrium during the late luteal phase of the tion of 1 percent lanthanum nitrate. The tissue was menstrual cycle (Lawn et a!., 1971). Gap then processed in a manner similar to that of uterine junctions are regions of membrane specializa- tissue not treated with lanthanum except that 1 percent lanthanum nitrate was added to all solutions tion where adjacent cell membranes are closely up until dehydration. apposed (2-3 nm) and are believed to be the To select specific areas of the uterus semithin structural basis of a form of communication sections (1 Mm) were stained with toluidine blue (0.5 between cells allowing free passage of ions, percent toluidene blue in 2.5 percent sodium car- metabolites and other low molecular weight bonate) and blocks were trimmed accordingly. Thin sections (silver to gold) cut with a diamond knife were substances (Lowenstein, 1968; Bennett, 1973). mounted on 200 mesh grids and stained with 3 There is currently much interest in the role percent aqueous uranyl acetate followed by lead such communicating junctions play in facilitat- citrate (leynolds, 1963). The sections prepared from ing synchronous responses to hormonal signals the lanthanum experiments were lightly stained with lead citrate (Venable and Coggeshall, 1965). Sections (Bergman, 1968; Merck et a!., 1972, 1973; were scanned in a Phillips EM 300 electron microscope Albertini and Anderson, 1974) or the coordina- at 60KV. tion of growth and differentiation (Gilula et al., 1972; Lowenstein, 1973). RESULTS The fine structure of decidual cells in the pseudopregnant rat was previously described by The cells of the antimesometrial region of Jollie and Bencosme (1965). This report de- the uterus are the first to respond to a scribes the fine structural features of intercellu- deciduogenic stimulus. There is a wave-like lar contacts that exist between stromal cells and progression of mitotic activity and differentia- decidual cells in the developing deciduoma of tion starting with the periluminal stromal cells the rat from Days 4 to 9 of pseudopregnancy. then spreading toward the peripheral region as Particular attention is focused on 1) the time of more cells become involved. The antimesome- appearance of gap junctions and 2) the exten- trial region reaches peak development and sive increase in cell surface area of decidual cells growth by Day 9, at which time cells in the in relation to the reduction of the intercellular inner region start to degenerate. Mesometrial matrix and free space. decidualization starts on Day 7 and reaches peak development by Days 11-13. MATERIALS AND METHODS The endometrial stromal cells resemble em- Three month old Holtzmann virgin female rats bryonic mesenchyme, consisting of irregular were made pseudopregnant by vaginal-cervical stimula- stellate cells with large ovoid nuclei and rela- All electron micrographs are taken from the antimesometrial pole of the endometrium. FIGS. 1-5. Day 4 of pseudopregnancy prior to administration of the deciduogenic stimulus. FIG. 1. Stromal cells from the periluminal area are larger, more rounded with lobate processes which extend out in all directions. X5,100. INTERCELLULAR JUNCTIONS BETWEEN DECIDUAL CELLS 595 Downloaded from https://academic.oup.com/biolreprod/article/15/5/593/2768190 by guest on 01 October 2021 .4 ‘0 I 4: rr ; .‘ A -. .,, - 4 :‘ 7 #{149}.. 0 W .L. _;--L, FIG. 2. A contact of the macula adherens type junction between two periluminal stromal cells. X 38,200. FIG. 3. An elongated area of contact between two periluminal stromal cells resembling the zonula adherens type junction. X40,200. FIG. 4. Stromal cells just below the periluminal area resemble active fibroblasts and are surrounded by an abundant collagenous matrix. X 5,300. FIG. 5. A portion of a stromal cell showing a newly polymerized collagen fibril at the surface of a small recess. X35,500.
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