Biology of uterine glands : impact on reproductive function
[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT AUTHOR'S REQUEST.] Pregnancy loss is the most common complication of human gestation, and roughly one-half of conceptions result in pregnancy loss, most frequently in the first two weeks of gestation. In humans, uterine gland dysfunction is thought to result in pregnancy loss and complications, such as preeclampsia, and fetal growth restriction. Available studies in mice support the hypothesis that uterine glands and forkhead box A2 (FOXA2), a uterine gland specific transcription factor, have important biological roles in blastocyst attachment, implantation, and stromal cell decidualization. Thus, aims of this dissertation included: (1) interrogation of the uterine transcriptome and secretome with and without uterine glands during the periimplantation period of pregnancy; and (2) elucidation of the impact of uterine glands and FOXA2 on endometrial receptivity, blastocyst implantation, and stromal cell decidualization. Those objectives were addressed by utilizing mouse models lacking uterine glands and/or FOXA2 in conjunction with in-depth histomorphological, transcriptomic and proteomic analysis. Results of these studies established: (1) uterine glands substantially impact homeostasis of the uterine environment; (2) leukemia inhibitory factor (LIF), and other gland-derived products, are not present within the uterine fluid during the periimplantation period; (3) FOXA2 regulates uterine expression of Lif; (4) LIF-repletion is sufficient for pregnancy establishment but not maintenance in glandless mice; (5) FOXA2- independent uterine gland-derived factors are required for a successful pregnancy. Collectively, these studies provide original evidence that uterine glands are critical for synchronous embryo-endometrial interactions and coordinate on-time implantation and stromal cell decidualization, thereby impacting embryo viability and pregnancy success. These studies also identified novel glandular factors that may be of significance to implantation and post-implantation processes in mice and humans.
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