Implantation initiation in eutherian mammals requires, at least in invasive types of implantation, that 1) the trophoblast or subpopulations of it have reached a state of "invasiveness" and, synchronously, 2) the endometrium has reached a state of "receptivity" ("implantation window"). The cell biological basis of "receptivity" as well as of "invasiveness" has long remained unknown, but recently it appears that the application of modern concepts of cell and developmental biology is opening new views of it, concentrating on cell adhesion and cell polarity phenomena. Implantation initiation requires that the trophoblast attaches via its apical plasma membrane to the apical plasma membrane of the uterine epithelium. Since apical plasma membranes of epithelia are normally non-adhesive, this represents a cell biological paradox. In development, cells can express two major phenotypes and switch between these: 1) the mesenchymal/fibroblastoid phenotype that is compatible with cells moving individually; 2) the epithelioid phenotype which is characterized by cells expressing apico-basal polarity and a strong association with neighbouring cells via various junctions, so that they can migrate as sheets but not as individual cells. Application of this concept to embryo implantation would seem to lead to the hypothesis that the trophoblast of blastocysts has to give up part of its typical epithelial organization when becoming invasive; it must express cell-cell adhesion molecules or matrix receptors non-typically at its apical plasma membrane, change the spectrum of expressed adhesion molecules, and alter its motility apparatus. This applies in a somewhat similar way to the uterine epithelium at "receptivity". Interestingly, recent data show that a substantial number of differentiation parameters of these cells change in addition. It appears that part of the epithelial differentiation program is down-regulated at this phase. This also suggests interesting new aspects of the basis of steroid hormone action at the endometrium, as well as of trophoblast invasiveness, possibly involving switches in the activity of regulatory "master" genes as are also involved in decision making during development.

Implantation: a cell biological paradox

Several transporting epithelia in vertebrates and invertebrates contain cells that are specialized for proton or bicarbonate secretion. These characteristic 'mitochondria-rich' (MR) cells have several typical features, the most important of which is an extremely high expression of a vacuolar-type proton-pumping ATPase (H+V-ATPase) both on intracellular vesicles and on specific domains of their plasma membrane. Physiological modulation of proton secretion is achieved by recycling the H+V-ATPase between the plasma membrane and the cytoplasm in a novel type of nonclathrin-coated vesicle. In the kidney, these cells are involved in urinary acidification, while in the epididymis and vas deferens they acidify the luminal environment to allow normal sperm development. Osteoclasts are non-epithelial MR cells that use H+V-ATPase activity for bone remodeling. In some insects, similar cells in the midgut energize K+ secretion by means of a plasma membrane H+V-ATPase. This review emphasizes important structural and functional features of proton-secreting cells, describes the tissue distribution of these cells and discusses the known functions of these cells in their respective epithelia.

Mitochondria-rich, proton-secreting epithelial cells.

This review begins with a brief commentary on the diversity of placentation mechanisms, and then goes on to examine the extensive alterations which occur in the plasma membrane of uterine epithelial cells during early pregnancy across species. Ultrastructural, biochemical and more general morphological data reveal that strikingly common phenomena occur in this plasma membrane during early pregnancy despite the diversity of placental types--from epitheliochorial to hemochorial, which ultimately form in different species. To encapsulate the concept that common morphological and molecular alterations occur across species, that they are found basolaterally as well as apically, and that moreover they are an ongoing process during much of early pregnancy, not just an event at the time attachment, the term 'plasma membrane transformation' is suggested which also emphasises that alterations in this plasma membrane during early pregnancy are key to uterine receptivity.

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Uterine receptivity and the plasma membrane transformation

The evolution of the reproductive process has resulted in the development of elaborate adaptive mechanisms to ensure the survival of the offspring. In viviparous animals such adaptations include the development of complex and diverse forms of implantation and placentation in order to support the attachment and development of embryos in utero. The implantation process exhibits remarkable diversity among species, most prominently in the extent of trophoblastic invasion into the uterus. Yet the general aim of implantation is accomplished in all species: to attach the embryo to the uterine wall and to establish an intimate union between maternal and fetal tissues so that an exchange of nutrients and waste products can occur. The details of the earliest interactions between the blastocyst and endometrium have been the focus of extensive study. It is our purpose to summarize some of the more important developments in this field since the publication of Finn’s fine review of the subject in the second edition of this book (Finn, 1977). In this chapter we have chosen to discuss four aspects of the implantation process: (1) adhesion of the trophoblast to the uterine epithelium; (2) increased vascular permeability at implantation sites; (3) the decidual cell reaction; and (4) loss of epithelial cells surrounding the implanting blastocyst. Our discussion is based primarily on the results of investigations using common laboratory animals, namely, the rat, mouse, and rabbit. In addition, other recent reviews and symposia may be of interest to the reader (Weitlauf, 1979; Glasser and McCormack, 1981; Finn, 1980; Leroy et al., 1980; Glasser and Bullock, 1981; Dey and Johnson, 1980; Kearns and Lala, 1983; Bell, 1983; Kennedy, 1983a; Chevez, 1984; Enders et al., 1983, 1985; Enders and Schlafke, 1986; Yoshinaga et al., 1986).

The Implantation Reaction

The Plasma Membrane of Uterine Epithelial Cells: Structure and Histochemistry

The ultrastructure of tight junctions between uterine luminal epithelial cells of the pregnant rat was studied by the freeze-fracture technique. On day 5 of pregnancy, the day of implantation, the region of tight junctions extended three times as far down the lateral cell membrane as on day 1 of pregnancy, and the strands of the complex interlinked more frequently. These observations suggest that tight junctions on day 5 may be more efficient in preserving the contents of the uterine lumen from dilution or escape than at earlier times of pregnancy.

The structure of tight junctions between uterine luminal epithelial cells at different stages of pregnancy in the rat

Freeze-fracture techniques have been used to study tight junctions on the lateral plasma membrane of cells of the luminal epithelium of the rat uterus under various hormonal regimes.

Effects of ovarian hormones on cell membranes in the rat uterus

In previous work we have shown that ovarian hormones, when injected into ovariectomized rats, alter the fine structure of the plasma membrane of endometrial epithelial cells. In this paper freeze-fractures have been used to study the apical plasma membrane of endometrial epithelial cells of rats during the period of blastocyst implantation of normal pregnancy. On day 1 of pregnancy there were 2354 +/− 114 intramembranous particles (IMPs) per micrometer2 of membrane. The particles were spherical and randomly distributed. On day 5 of pregnancy IMP density rose to 2899 +/− 289 per micrometer2 and some rod-shaped particles were also visible. By day 6 of pregnancy IMP density had risen to 4014 +/− 206 per micrometer2 and there were more rod-shaped IMPs than before. In addition, on day 6 IMPs were also present as rows of particles and some gap-junction-like arrays of particles were also seen. Our findings indicate that there are fine-structural alterations in the apical plasma membrane of endometrial epithelial cells, the site of first contact between maternal and embryonic cells, during the period of early pregnancy. The findings are discussed in the light of suggested mechanisms of blastocyst attachment to the uterine epithelium at implantation.

Changes in the fine structure of the apical plasma membrane of endometrial epithelial cells during implantation in the rat

Freeze fracture techniques have been used to study the apical membrane of cells of the luminal epithelium of the rat uterus under various hormonal regimes. In the ovariectomized but otherwise untreated rat, intramembranous particles (IMPs) occur at a density of 1395 +/- 122 per micron 2; they appeared spherical and uniformly distributed. After 3 days treatment with estrogen, no change in appearance or density was found, but 3 days of progesterone treatment produced a significant increase in IMP density to 1622 +/- 104. Treatment with progesterone, with an additional dose of estrogen on day 3, is known to produce an epithelium receptive to the implanting blastocyst. In these conditions, the IMP density rose to 3818 +/- 337: rod-shaped particles and aggregations of IMPs were seen, and some particle arrays resembling gap junctions, in addition to the isolated spherical particles.

Effects of ovarian hormones on cell membranes in the rat uterus. I. Freeze fracture studies of the apical membrane of the liminal epithelium.

Freeze-fracture electron microscopy has been used to study tight junctions of luminal epithelial cells of the human uterus. The junctions are deeper and more extensive in the middle of the menstrual cycle than they are later in the cycle. The results suggest that the contents of the uterine lumen may be more closely regulated at some times than at others.

J.G. Swift

Papers

The structure of tight junctions between uterine luminal epithelial cells at different stages of pregnancy in the rat

Effects of ovarian hormones on cell membranes in the rat uterus

Changes in the fine structure of the apical plasma membrane of endometrial epithelial cells during implantation in the rat

Effects of ovarian hormones on cell membranes in the rat uterus. I. Freeze fracture studies of the apical membrane of the liminal epithelium.

A freeze-fracture electron microscopic study of tight junctions of epithelial cells in the human uterus.