January 16, 2003
Researchers funded by the National Institutes of Health have discovered how an embryo initially attaches to the wall of the uterus-what appears to be one of the earliest steps needed to establish a successful pregnancy.
Specifically, the researchers found that 6 days after an egg is fertilized, the embryo uses specialized molecules on its surface and molecules on the surface of the uterus to attach itself to the wall of the uterus.
"This discovery opens up a promising new realm of research," said Duane Alexander, M.D., Director of the National Institute of Child Health and Human Development (NICHD). "It may lead to insight into infertility, early pregnancy loss, and perhaps to an understanding of the life-threatening complication of pregnancy known as preeclampsia." Part of the funding for the study was provided by the NICHD, the National Institute of General Medical Sciences (NIGMS), the National Heart, Lung, and Blood Institute (NHLBI), and the National Institute of Dental and Craniofacial Research (NIDCR), all part of the National Institutes of Health.
The finding appears in the January 17th Science. The research was conducted by scientists at the University of California at San Francisco (UCSF), the Nevada Center for Reproductive Medicine in Reno, the Lawrence Berkeley National Laboratory in Berkeley, California, and the University of Wisconsin, Madison.
About 6 days after fertilization, the embryo is shaped like a sphere. The surface of the sphere is made up of a layer of specialized cells called the trophoblast. At this phase of development, the embryo is called the blastocyst. The trophoblast later gives rise to the cells that will form the fetus' part of the placenta. (The placenta is made up of both maternal and fetal tissues.) The trophoblast is coated with a protein known as L-selectin. The wall of the uterus is coated with carbohydrate molecules. The researchers believe that as the blastocyst travels along the uterine wall, L-selectin on its surface binds to the carbohydrates on the uterine wall, until the blastocyst gradually slows to a complete stop. After this happens, the cells that later become the fetus' contribution to the placenta develop. The placental tissue from the fetus then invades the uterine wall by sending finger-like extensions into it. These projections make contact with the maternal blood supply, becoming the pipeline through which the fetus derives nutrients and oxygen, and rids itself of carbon dioxide and wastes.
"It's analogous to a tennis ball rolling over a table top covered with syrup," said the study's senior author, Susan Fisher, PhD., UCSF professor of stomatology, anatomy and pharmaceutical chemistry. "The embryo's journey is arrested by the sticky interaction with the uterine wall."
Dr. Fisher explained that learning about the molecular processes leading up to implantation may provide information useful for treating infertility. Some cases of unexplained infertility and early pregnancy loss are thought to derive from a failure of the trophoblast to properly attach to the uterine wall.
Findings from the study may also offer insight into preeclampsia. In this condition, pregnant women develop dangerously high blood pressure that may lead to convulsions and even death. With previous NICHD funding, Dr. Fisher and her colleagues learned that preeclampsia appears to result from a failure of placental cells to convert to blood vessel-like cells that perform their secondary function of conveying carbon dioxide, oxygen, nutrients, and wastes between the uterus and the fetus. Dr. Fisher said that if trophoblast cells fail to securely attach to the uterine wall, then it's possible they may not successfully convert to this secondary function.
To conduct the study, researchers at UCSF collected biopsies of the endometrium-the inner lining of the uterus-from volunteers. The tissue samples were taken during the women's monthly cycle both before the uterus is receptive to the blastocyst's implantation and at the time when the uterus is most receptive to implantation. The researchers found that the amount of carbohydrate on the uterine wall was greatest at the time when uterine receptivity to the blastocyst was greatest.
In separate, privately funded research conducted at his Nevada clinic, Russell Foulk, M.D. then demonstrated that at the time of implantation, the blastocyst expresses much larger amounts of L-selectin than it does before implantation. (Details of Dr. Foulk's work are described more fully in the Science article.)
Using the information developed by Dr. Foulk, the UCSF researchers then sought to determine how long after implantation the trophoblast retains its covering of L-selectin. To learn this, they exposed isolated trophoblasts to carbohydrate-covered beads under conditions resembling those found inside the uterus. The researchers found that the trophoblasts bonded to the carbohydrates on the beads. They also found that isolated trophoblasts bond more firmly to sections of uterine lining collected when the uterus is most receptive to implantation than to those collected when the uterine lining is least receptive. The researchers determined that the isolated trophoblasts were able to bond with the uterine carbohydrates for up to the 16th week of pregnancy.
The current study is an extension of earlier research by study author Steven Rosen, Ph.D., UCSF professor of anatomy. He had discovered that infection-fighting white blood cells known as leukocytes use the L-selectin on their surface to roll to a stop on the lining of blood vessels, which are coated with carbohydrate molecules.
"This study shows how basic research in one area can jump-start clinical studies in another," said Judith H. Greenberg, Ph.D., acting director of NIGMS, which funds Dr. Rosen's L-selectin research.
"The discovery of L-selectin's role in embryo implantation means that the wealth of knowledge scientists have amassed on this sticky molecule can now be applied to questions related to early pregnancy."
The NICHD, NIGMS, NHLBI, and NIDCR are part of the National Institutes of Health (NIH), the biomedical research arm of the federal government. NIH is part of the U.S. Department of Health and Human Services.