A UCSF-led research team has identified the first molecular step that allows a week-old human embryo to attach to the uterus. The finding is expected to provide a new tool to diagnose and treat infertility and early pregnancy loss, the scientists report.
The researchers found convincing evidence that a molecular sticking process stops the embryo’s journey along the uterine wall and starts attaching it to the wall—the first stage of implantation. Failure of the embryo to implant causes about three-fourths of lost pregnancies.
The research is published in the January 17 issue of the journal SCIENCE. A perspective article on the research also appears in the issue.
The team found that about six days after fertilization, molecules on the embryo’s surface interact with molecules on the mother’s uterine wall to create the sticky environment - the same combination of molecules known to stop the movement of disease-fighting leukocytes migrating through blood vessels, and allow them to attach to the blood vessel walls in areas of inflammation.
“It’s like a tennis ball rolling across a surface covered in syrup,” said Susan Fisher, PhD, UCSF professor of stomatology, anatomy and pharmaceutical chemistry and senior author of the SCIENCE report. “The embryo’s journey along the uterine wall is arrested by the sticky interaction.”
Human embryo implantation is poorly understood, and the causes of many implantation-related disorders are not known. Discovering the molecular basis of the first step in implantation may prove useful to treat infertility and provide insights into common pregnancy problems, Fisher said.
UCSF has filed for a patent for the use of L-selectin to diagnose if a woman is capable of becoming pregnant and to pinpoint causes of infertility.
Fisher and her colleagues discovered that when the time is right for implantation, the outer cells of the early embryo, or blastocyst, express a protein known as L-selectin while the uterus becomes enriched with carbohydrates. L-selectin normally binds briefly to such carbohydrates, so a continual sticking and unsticking interplay between the protein and carbohydrates can progressively slow the embryo’s progress along the uterine wall. When the embryo comes to rest, the stage is set for it to adhere to the uterine wall where it establishes a nourishing blood supply from the mother through the placenta.
About ten years ago, such a protein-carbohydrate sticking mechanism was found to allow leukocytes to roll to a stop and start attaching to blood vessel walls when they reach an area of inflammation.
In their research, the scientists collected endometrial biopsies taken before and after the period when the uterus is most receptive to implantation. Using antibodies that recognize a part of the key carbohydrate, they found a dramatic increase in the amount of carbohydrate that interacts with L-selectin when the uterus is receptive to implantation.
A researcher at a private in vitro fertilization clinic, a collaborator on the study, found that at the time of implantation, the outer layer of the blastocyst - known as the trophoblast - expresses L-selectin. The trophoblast normally becomes the “baby part” of the placenta, Fisher explained. Trophoblast cells invade the arterial walls of the uterus, displacing the mother’s own cells.
The research done at the private clinic was conducted with private funds.
To confirm the link between the sticking process and the embryo’s preparation for implantation, the scientists coated latex beads with carbohydrates that normally bind L-selectin, and demonstrated that the beads bound to trophoblast cells in placental tissue under conditions found in the uterus.
They also showed that isolated placental trophoblast cells expressing L-selectin stuck much more strongly to carbohydrates on uterine epithelial cells collected when the uterus is receptive to implantation than during non-receptive times - strong confirmation of the L-selectin-carbohydrate interaction, since it is known that implantation normally occurs when these uterine cells interact with trophoblast cells.
The research may contribute to understanding preeclampsia, the most common cause of maternal death in the industrialized world, Fisher said. In this condition, which occurs in nearly one in ten first pregnancies, the placenta does not attach adequately to the uterine wall, starving the fetus of oxygen and threatening the mother’s life, she said. Since it is the outer layer of the embryo—the trophoblast—that gives rise to the placenta, this process, like the slowing of the early embryo along the uterine wall, probably involves the interaction of L-selectin and carbohydrates, Fisher said.
Lead author on the paper is Olga D. Genbacev, PhD, research cell biologist in stomatology at UCSF. Co-authors are Akraporn Prakobphol, DDS and PhD, research oral biologist, and Dusko Ilic, MD, PhD, research cell biologist, both in stomatology, UCSF; Russell A. Foulk, MD, director of the Nevada Center for Reproductive Medicine, Reno; Ana R. Krtolica, PhD, postdoctoral fellow at Lawrence Berkeley National Laboratory; Zhi-Qiang Yang, a graduate student, and Laura L. Kiessling, PhD, professor of chemistry and biology, both at the University of Wisconsin-Madison; Mark S. Singer, research specialist in anatomy, and Steven D. Rosen, PhD, professor of anatomy, both at UCSF.
Support for the research includes grants from the National Institutes of Health.