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Embryo Transport and Implantation
Embryo Transport and Implantation Bruce M Carlson, University of Michigan ã 2014 Elsevier Inc. All rights reserved.
Transport Mechanisms by the Uterine Tube Zona Pellucida Implantation into the Uterine Lining
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Transport Mechanisms by the Uterine Tube The entire period of early cleavage occurs while the embryo is being transported from the place of fertilization to its implantation site in the uterus (Figure 1). At the beginning of cleavage, the zygote is still encased in the zona pellucida and the cells of the corona radiata. The corona radiata is lost within 2 days of the start of cleavage. The zona pellucida remains intact, however, until the embryo reaches the uterus. The embryo remains in the ampullary portion of the uterine tube for approximately 3 days. It then traverses the isthmic portion of the tube in as little as 8 h. Under the influence of progesterone, the uterotubal junction relaxes, thus allowing the embryo to enter the uterine cavity. A couple of days later (6–8 days after fertilization), the embryo implants into the midportion of the posterior wall of the uterus.
Zona Pellucida During the entire period from ovulation until entry into the uterine cavity, the ovum and the embryo are surrounded by the zona pellucida. During this time, the composition of the zona changes, through contributions from the blastomeres and the maternal reproductive tissues. These changes facilitate the transport and differentiation of the embryo. After the embryo reaches the uterine cavity, it begins to shed the zona pellucida in preparation for implantation. This is accomplished by a process called blastocyst hatching. A small region of the zona pellucida, usually directly over the inner cell mass in the primate, dissolves, and the blastocyst emerges from the hole. In rodents, blastocyst hatching is accomplished through the action of cysteine protease enzymes that are released from long microvillous extensions (trophectodermal projections) protruding from the surfaces of the trophoblastic cells. Over a narrow time window (4 h in rodents), the zona pellucida in this area is digested, and the embryo begins to protrude. In the uterus, the trophectodermal projections then make contact with the endometrial epithelial cells as the process of implantation begins. Enzymatic activity around the entire trophoblast soon begins to dissolve the rest of the zona pellucida. Only a few specimens of human embryos have been taken in vivo from the period just preceding implantation, but in vitro studies on human embryos suggest a similar mechanism, which probably occurs 1–2 days before implantation (Figure 2(c)).
Implantation into the Uterine Lining Approximately 6–7 days after fertilization, the embryo begins to make a firm attachment to the epithelial lining of the endometrium. Soon thereafter, it sinks into the endometrial stroma, and its original site of penetration into the endometrium becomes closed over by the epithelium, similar to a healing skin wound. The first stage in implantation consists of attachment of the expanded blastocyst to the endometrial epithelium. The apical surfaces of the hormonally conditioned endometrial epithelial cells express various adhesion molecules (e.g., integrins) that allow implantation to occur in the narrow window of 20–24 days in the ideal menstrual cycle. Correspondingly, the trophoblastic cells of the preimplantation blastocyst also express adhesion molecules on their surfaces. The blastocyst attaches to the endometrial epithelium through the mediation of bridging ligands. Some studies have stressed the importance of the cytokine leukemiainhibiting factor (LIF) on the endometrial surface and LIF receptors on the trophoblast during implantation. In vivo and in vitro studies have shown that attachment of the blastocyst occurs at the area above the inner cell mass (embryonic pole), a finding suggesting that the surfaces of the trophoblast are not all the same. The next stage of implantation is the penetration of the uterine epithelium. In primates, the cellular trophoblast undergoes a further stage in its differentiation just before it contacts the endometrium. In the area around the inner cell mass, cells derived from the cellular trophoblast (cytotrophoblast) fuse to form a multinucleated syncytiotrophoblast. Although only a small area of syncytiotrophoblast is evident at the start of implantation, this structure soon surrounds the entire embryo. Small projections of syncytiotrophoblast insert themselves between uterine epithelial cells. They spread along the epithelial surface of the basal lamina that underlies the endometrial epithelium to form a flattened trophoblastic plate. Within a day or so, syncytiotrophoblastic projections from the small trophoblastic plate begin to penetrate the basal lamina. The early syncytiotrophoblast is a highly invasive tissue, and it quickly expands and erodes its way into the endometrial stroma (Figure 3(a) and 3(b)). By 10–12 days after
Reference Module in Biomedical Research
http://dx.doi.org/10.1016/B978-0-12-801238-3.05431-3
1
Figure 1 Follicular development in the ovary, ovulation, fertilization, and transport of the early embryo down the uterine tube and into the uterus.
Figure 2 Human embryos resulting from in vitro fertilization. (a) Morula, showing the beginning of cavitation. (b) Blastocyst, showing a well-defined inner cell mass (arrow) and blastocoele. At this stage, the zona pellucida is very thin.(c) A hatching blastocyst beginning to protrude through the zona pellucida. Reproduced from Veeck, L. L. and Zaninovic, N. (2003). An atlas of blastocysts. Boca Raton, FL: Parthenon Publishing.
Embryo Transport and Implantation
3
Figure 3 Major stages in implantation of a human embryo. (a) The syncytiotrophoblast is just beginning to invade the endometrial stroma. (b) Most of the embryo is embedded in the endometrium; there is early formation of the trophoblastic lacunae. The amniotic cavity and yolk sac are beginning to form. (c) Implantation is almost complete, primary villi are forming, and the extraembryonic mesoderm is appearing. (d) Implantation is complete; secondary villi are forming.
fertilization, the embryo is completely embedded in the endometrium. The site of initial penetration is first marked by a bare area or a noncellular plug and is later sealed by migrating uterine epithelial cells (Figure 3(c) and 3(d)). As early implantation continues, projections from the invading syncytiotrophoblast envelop portions of the maternal endometrial blood vessels. They erode into the vessel walls, and maternal blood begins to fill the isolated lacunae that have been forming in the trophoblast (see Figure 3(c) and 3(d)). Trophoblastic processes enter the blood vessels and even share junctional complexes with the endothelial cells. By the time blood-filled lacunae have formed, the trophoblast changes character, and it is not as invasive as it was during the first few days of implantation. While the embryo burrows into the endometrium, and some cytotrophoblastic cells fuse into syncytiotrophoblast, the fibroblast-like stromal cells of the edematous endometrium swell, with the accumulation of glycogen and lipid droplets. These
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Embryo Transport and Implantation
cells, called decidual cells, are tightly adherent and form a massive cellular matrix that first surrounds the implanting embryo and later occupies most of the endometrium. Concurrent with the decidual reaction, as this transformation is called, the leukocytes that have infiltrated the endometrial stroma during the late progestational phase of the endometrial cycle secrete interleukin-2, which prevents maternal recognition of the embryo as a foreign body during the early stages of implantation.
Further Reading Dey SK, et al. (2004) Molecular cues to implantation. Endocrine Reviews 25: 341–373. Diedrich K, et al. (2007) The role of the endometrium and embryo in human implantation. Human Reproduction Update 13: 365–377. Dimitriadis E, et al. (2010) Local regulation of implantation at the human fetal–maternal interface. International Journal of Developmental Biology 54: 313–322. Weitlauf HM (1988) Biology of implantation. In: Knobil E and Neill J (eds.) The physiology of reproduction, pp. 231–262. New York: Raven.
Transport Mechanisms by the Uterine Tube Zona Pellucida Implantation into the Uterine Lining
1 1 1
Transport Mechanisms by the Uterine Tube The entire period of early cleavage occurs while the embryo is being transported from the place of fertilization to its implantation site in the uterus (Figure 1). At the beginning of cleavage, the zygote is still encased in the zona pellucida and the cells of the corona radiata. The corona radiata is lost within 2 days of the start of cleavage. The zona pellucida remains intact, however, until the embryo reaches the uterus. The embryo remains in the ampullary portion of the uterine tube for approximately 3 days. It then traverses the isthmic portion of the tube in as little as 8 h. Under the influence of progesterone, the uterotubal junction relaxes, thus allowing the embryo to enter the uterine cavity. A couple of days later (6–8 days after fertilization), the embryo implants into the midportion of the posterior wall of the uterus.
Zona Pellucida During the entire period from ovulation until entry into the uterine cavity, the ovum and the embryo are surrounded by the zona pellucida. During this time, the composition of the zona changes, through contributions from the blastomeres and the maternal reproductive tissues. These changes facilitate the transport and differentiation of the embryo. After the embryo reaches the uterine cavity, it begins to shed the zona pellucida in preparation for implantation. This is accomplished by a process called blastocyst hatching. A small region of the zona pellucida, usually directly over the inner cell mass in the primate, dissolves, and the blastocyst emerges from the hole. In rodents, blastocyst hatching is accomplished through the action of cysteine protease enzymes that are released from long microvillous extensions (trophectodermal projections) protruding from the surfaces of the trophoblastic cells. Over a narrow time window (4 h in rodents), the zona pellucida in this area is digested, and the embryo begins to protrude. In the uterus, the trophectodermal projections then make contact with the endometrial epithelial cells as the process of implantation begins. Enzymatic activity around the entire trophoblast soon begins to dissolve the rest of the zona pellucida. Only a few specimens of human embryos have been taken in vivo from the period just preceding implantation, but in vitro studies on human embryos suggest a similar mechanism, which probably occurs 1–2 days before implantation (Figure 2(c)).
Implantation into the Uterine Lining Approximately 6–7 days after fertilization, the embryo begins to make a firm attachment to the epithelial lining of the endometrium. Soon thereafter, it sinks into the endometrial stroma, and its original site of penetration into the endometrium becomes closed over by the epithelium, similar to a healing skin wound. The first stage in implantation consists of attachment of the expanded blastocyst to the endometrial epithelium. The apical surfaces of the hormonally conditioned endometrial epithelial cells express various adhesion molecules (e.g., integrins) that allow implantation to occur in the narrow window of 20–24 days in the ideal menstrual cycle. Correspondingly, the trophoblastic cells of the preimplantation blastocyst also express adhesion molecules on their surfaces. The blastocyst attaches to the endometrial epithelium through the mediation of bridging ligands. Some studies have stressed the importance of the cytokine leukemiainhibiting factor (LIF) on the endometrial surface and LIF receptors on the trophoblast during implantation. In vivo and in vitro studies have shown that attachment of the blastocyst occurs at the area above the inner cell mass (embryonic pole), a finding suggesting that the surfaces of the trophoblast are not all the same. The next stage of implantation is the penetration of the uterine epithelium. In primates, the cellular trophoblast undergoes a further stage in its differentiation just before it contacts the endometrium. In the area around the inner cell mass, cells derived from the cellular trophoblast (cytotrophoblast) fuse to form a multinucleated syncytiotrophoblast. Although only a small area of syncytiotrophoblast is evident at the start of implantation, this structure soon surrounds the entire embryo. Small projections of syncytiotrophoblast insert themselves between uterine epithelial cells. They spread along the epithelial surface of the basal lamina that underlies the endometrial epithelium to form a flattened trophoblastic plate. Within a day or so, syncytiotrophoblastic projections from the small trophoblastic plate begin to penetrate the basal lamina. The early syncytiotrophoblast is a highly invasive tissue, and it quickly expands and erodes its way into the endometrial stroma (Figure 3(a) and 3(b)). By 10–12 days after
Reference Module in Biomedical Research
http://dx.doi.org/10.1016/B978-0-12-801238-3.05431-3
1
Figure 1 Follicular development in the ovary, ovulation, fertilization, and transport of the early embryo down the uterine tube and into the uterus.
Figure 2 Human embryos resulting from in vitro fertilization. (a) Morula, showing the beginning of cavitation. (b) Blastocyst, showing a well-defined inner cell mass (arrow) and blastocoele. At this stage, the zona pellucida is very thin.(c) A hatching blastocyst beginning to protrude through the zona pellucida. Reproduced from Veeck, L. L. and Zaninovic, N. (2003). An atlas of blastocysts. Boca Raton, FL: Parthenon Publishing.
Embryo Transport and Implantation
3
Figure 3 Major stages in implantation of a human embryo. (a) The syncytiotrophoblast is just beginning to invade the endometrial stroma. (b) Most of the embryo is embedded in the endometrium; there is early formation of the trophoblastic lacunae. The amniotic cavity and yolk sac are beginning to form. (c) Implantation is almost complete, primary villi are forming, and the extraembryonic mesoderm is appearing. (d) Implantation is complete; secondary villi are forming.
fertilization, the embryo is completely embedded in the endometrium. The site of initial penetration is first marked by a bare area or a noncellular plug and is later sealed by migrating uterine epithelial cells (Figure 3(c) and 3(d)). As early implantation continues, projections from the invading syncytiotrophoblast envelop portions of the maternal endometrial blood vessels. They erode into the vessel walls, and maternal blood begins to fill the isolated lacunae that have been forming in the trophoblast (see Figure 3(c) and 3(d)). Trophoblastic processes enter the blood vessels and even share junctional complexes with the endothelial cells. By the time blood-filled lacunae have formed, the trophoblast changes character, and it is not as invasive as it was during the first few days of implantation. While the embryo burrows into the endometrium, and some cytotrophoblastic cells fuse into syncytiotrophoblast, the fibroblast-like stromal cells of the edematous endometrium swell, with the accumulation of glycogen and lipid droplets. These
4
Embryo Transport and Implantation
cells, called decidual cells, are tightly adherent and form a massive cellular matrix that first surrounds the implanting embryo and later occupies most of the endometrium. Concurrent with the decidual reaction, as this transformation is called, the leukocytes that have infiltrated the endometrial stroma during the late progestational phase of the endometrial cycle secrete interleukin-2, which prevents maternal recognition of the embryo as a foreign body during the early stages of implantation.
Further Reading Dey SK, et al. (2004) Molecular cues to implantation. Endocrine Reviews 25: 341–373. Diedrich K, et al. (2007) The role of the endometrium and embryo in human implantation. Human Reproduction Update 13: 365–377. Dimitriadis E, et al. (2010) Local regulation of implantation at the human fetal–maternal interface. International Journal of Developmental Biology 54: 313–322. Weitlauf HM (1988) Biology of implantation. In: Knobil E and Neill J (eds.) The physiology of reproduction, pp. 231–262. New York: Raven.