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Egg must signal the uterus in order to implant
Using 3D imaging and molecular testing, researchers uncover the earliest stage of mammalian pregnancy, offering clues to implantation errors.
Investigators in the Division of Reproductive Sciences at Cincinnati Children's published their data in Nature Communications. They demonstrate in mice that glands in the uterus must communicate directly with the embryo in order for it to implant properly and begin a pregnancy. Specifically, they followed the Vangl2 gene found in epithelial cells lining the uterus and its glands.
"[Uterine] gland secretions produce molecules essential to embryo development. Without the gene Vangl2, the glands do not extend and connect to an embryo, and the embryo does not properly implant."
Researchers are particularly interested in preterm birth and infant mortality, both persistent pregnancy challenges. Their study is just one piece of the puzzle in an expanding body of research attempting to unravel possible genetic, molecular and lifestyle causes for these outcomes. The study was able to reproduce visual and molecular details comparing normal mouse pregnancy with abnormal mouse pregnancy — as when the Vangl2 is deleted in uterine tissues. Highly conserved across both the mouse and human species, the Vangl2 gene produces Van Gogh-Like protein 2 which helps control cell movement and cell spatial arrangement in many developing tissues.
In a normal mouse pregnancy, researchers found maternal glands extend away from the uterine lining to connect directly to an embryo. These connection chambers are now called "crypts." Crypts remain connected to embryos throughout the early stages of pregnancy. They also found that a growth factor protein called HB-EGF (heparin-binding EGF like growth factor) coordinates with Vangl2 to continue the attachment process. HB-EGF is normally expressed in both embryo and crypt. To simulate what occurs in pregnancy, the researchers transferred embryo-sized beads soaked with HB-EGF into mice uteri. Even in the absence of implanting embryos, the HB-EGF-carrying beads stimulated implantation-like responses in the mothers with gland-crypt formations. Earlier studies by Dey and his colleagues had confirmed HB-EGF is one of the earliest molecular markers of embryo-uterine implantation.
The current study adds important insight into the field of reproductive science by showing what takes place when HB-EGF is expressed by a competent early embryo. HB-EGF expression induces genetic activity in the crypt epithelia cells to collaborate with Vangl2 and foster direct communication between glands and the implanting embryo.
Researchers then tested what happened when they administered HB-EGF to mice with deleted Vangl2. Genetic deletion of Vangl2 caused mice uterine glands to form improperly and wither. Although each gland connected to a blastocyst, the connection was insufficient to support full embryo implantation. But when researchers administered HB-EGF to the mice externally, injections rescued the mouse pregnancy by restoring the crypt — and the molecular links between the embryo and the crypt. Still unclear at this point is how the current study's findings apply to human pregnancy. Though the study does open doors to future research possibilities in other animal models more closely approximating human pregnancy.
Ethical concerns limit future investigations of these findings in human pregnancy. But, Dey noted that advanced imaging technologies today, including some forms of magnetic resonance imaging, might allow observation of human pregnancy displaying uterus-gland interaction in normal as well as abnormal pregnancy. And with more research, there may eventually be potential for HB-EGF as a therapy for implantation problems in pregnancy.
Embryo implantation is central to pregnancy success. Our previous understanding is limited by studying this phenomenon primarily in two dimensions. Here we employ 3D visualization, revealing that epithelial evaginations that form implantation chambers (crypts) consistently arise with preexisting glands, suggesting direct access of glands to embryos within the chamber. While the lobular domains of the glands become more developed, the ductal regions continue to elongate and progressively stretch following implantation. Using diapausing mice and mice with deletion of the planar cell polarity gene Vangl2 in uterine epithelial cells, we show that dynamic changes in gland topography depend on implantation-competent blastocysts and planar cell polarity. By transferring blastocyst-size beads preloaded with HB-EGF in pseudopregnant mice, we found that HB-EGF is a trigger for the communication between embryos and glands. Glands directly connecting the crypt encasing the embryo during implantation are therefore fundamental to pregnancy success.
Authors: Jia Yuan, Wenbo Deng, Jeeyeon Cha, Xiaofei Sun, Jean-Paul Borg and Sudhansu K. Dey
Funding support for the research came in part from the National Institutes of Health (R01HD068524, DA006668, P01CA77839), the March of Dimes, a National Research Service Award (F30AG040858); the University of Cincinnati Medical Scientist Training Program and La Ligue Nationale Contre le Cancer SIRIC (INCa-DGOS735-Inserm 6038).
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Confocal microscopic image (LEFT) Uterine crypt extending from the uterine wall of a mouse with a gene that expresses the protein — Vangl2. (RIGHT) Uterus of a mouse without the gene and protein, showing abnormal crypt formation, withered glands obstructing egg implantation. Image credit: Sudhansu Dey.