Uterine glands impact embryo survival and stromal cell decidualization in mice

Establishment of pregnancy is a critical event, and failure of embryo implantation and stromal decidualization in the uterus contribute to significant numbers of pregnancy losses in women. Glands of the uterus are essential for establishment of pregnancy in mice and likely in humans. Forkhead box a2 (FOXA2) is a transcription factor expressed specifically in the glands of the uterus and is a critical regulator of postnatal uterine gland differentiation in mice. In this study, we conditionally deleted FOXA2 in the adult mouse uterus using the lactotransferrin Cre (Ltf-Cre) model and in the neonatal mouse uterus using the progesterone receptor Cre (Pgr-Cre) model. The uteri of adult FOXA2-deleted mice were morphologically normal and contained glands, whereas the uteri of neonatal FOXA2-deleted mice were completely aglandular. Notably, adult FOXA2-deleted mice are completely infertile because of defects in blastocyst implantation and stromal cell decidualization. Leukemia inhibitory factor (LIF), a critical implantation factor of uterine gland origin, was not expressed during early pregnancy in adult FOXA2-deleted mice. Intriguingly, i.p. injections of LIF initiated blastocyst implantation in the uteri of both gland-containing and glandless adult FOXA2-deleted mice. Although pregnancy was rescued by LIF and was maintained to term in uterine gland-containing adult FOXA2-deleted mice, pregnancy failed by day 10 in neonatal FOXA2-deleted mice lacking uterine glands. These studies reveal a previously unrecognized role for FOXA2 in regulation of adult uterine function and fertility and provide original evidence that uterine glands and, by inference, their secretions play important roles in blastocyst implantation and stromal cell decidualization.

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Roles of WNT6 in Sheep Endometrial Epithelial Cell Cycle Progression and Uterine Glands Organogenesis

Veterinary Sciences ◽

10.3390/vetsci8120316 ◽

2021 ◽

Vol 8 (12) ◽

pp. 316

Author(s):

Xiaoxiao Gao ◽

Xiaolei Yao ◽

Xiaodan Li ◽

Yaxu Liang ◽

Zifei Liu ◽

...

Keyword(s):

Cell Cycle ◽

Litter Size ◽

Cell Cycle Progression ◽

Wnt Signaling Pathway ◽

Female Reproductive Tract ◽

Rna Seq ◽

Embryo Survival ◽

Cycle Progression ◽

Uterine Glands ◽

Hu Sheep

The uterus, as part of the female reproductive tract, is essential for embryo survival and in the maintenance of multiple pregnancies in domestic animals. This study was conducted to investigate the effects of WNT6 on Hu sheep endometrial epithelial cells (EECs) and uterine glands (UGs) in Hu sheep, with high prolificacy rates. In the present study, Hu sheep with different fecundity, over three consecutive pregnancies, were divided into two groups: high prolificacy rate group (HP, litter size = 3) and low prolificacy rate group (LP, litter size = 1). A comparative analysis of the endometrial morphology was performed by immunofluorescence. RNA-seq was used to analyze the gene’s expression in endometrium of HP and LP Hu sheep, providing a candidate gene, which was investigated in EECs and organoid culture. Firstly, higher density of UGs was found in the HP Hu sheep groups (p < 0.05). The RNA-seq data revealed the importance of the WNT signaling pathway and WNT6 gene in Hu sheep endometrium. Functionally, WNT6 could promote the cell cycle progression of EECs via WNT/β-catenin signal and enhance UGs organogenesis. Taken together, WNT6 is a crucial regulator for sheep endometrial development; this finding may offer a new insight into understanding the regulatory mechanism of sheep prolificacy.

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Biology of uterine glands : impact on reproductive function

10.32469/10355/69833 ◽

2018 ◽

Author(s):

◽

Andrew Michael Kelleher

Keyword(s):

Pregnancy Loss ◽

Stromal Cell ◽

Reproductive Function ◽

Embryo Viability ◽

University Of Missouri ◽

Uterine Gland ◽

Uterine Fluid ◽

Uterine Glands ◽

The Impact ◽

In Pregnancy

[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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Biology of uterine glands : impact on reproductive function

10.32469/10355/66310 ◽

2018 ◽

Author(s):

◽

Andrew Michael Kelleher

Keyword(s):

Pregnancy Loss ◽

Stromal Cell ◽

Reproductive Function ◽

Embryo Viability ◽

University Of Missouri ◽

Uterine Gland ◽

Uterine Fluid ◽

Uterine Glands ◽

The Impact ◽

In Pregnancy

[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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Indian Hedgehog, But Not Histidine Decarboxylase or Amphiregulin, Is a Progesterone-Regulated Uterine Gene in Hamsters

Endocrinology ◽

10.1210/en.2006-0231 ◽

2006 ◽

Vol 147 (9) ◽

pp. 4079-4092 ◽

Cited By ~ 15

Author(s):

Atanu Khatua ◽

Xiaohong Wang ◽

Tianbing Ding ◽

Qian Zhang ◽

Jeff Reese ◽

...

Keyword(s):

Cell Proliferation ◽

Expression Pattern ◽

Hormonal Regulation ◽

Stromal Cell ◽

Histidine Decarboxylase ◽

Expression Patterns ◽

Indian Hedgehog ◽

Uterine Receptivity ◽

Uterine Glands

Implantation occurs only in the progesterone (P4)-primed uterus in the majority of species, but little effort has been given to identify P4-mediated molecules in these species. Using hamsters as a model for P4-dependent implantation and three well-known uterine receptivity-associated P4-regulated genes, Indian hedgehog (Ihh), histidine decarboxylase (Hdc), and amphiregulin (Areg), in mice that require ovarian estrogen for uterine receptivity and implantation, our strategy aimed to determine whether P4 regulates uterine expression of these genes in hamsters and whether the event- and cell-specific uterine expression patterns of these genes during the periimplantation period in hamsters follow similarly with their patterns in mice. We report here that P4-mediated Ihh signaling is important for uterine receptivity and implantation in hamsters because uterine epithelial Ihh expression was regulated by P4 and its expression patterns during the periimplantation period of hamsters closely follow its pattern in mice. In contrast, we noted no hormonal regulation of Hdc and Areg in the hamster uterus. However, this did not diminish their importance in hamsters because their expression patterns and functions are event and cell specific during the periimplantation period: whereas Hdc was expressed exclusively in d 4 uterine glands and regulated by the blastocyst, Areg was expressed on the decidual area adjacent to the embryo from d 5 onward and involved in stromal cell proliferation. We conclude that similarities and dissimilarities exist in uterine expression pattern of implantation-related genes, including hormonal regulation and their event-specific importance.

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