Role of uterine stromal-epithelial crosstalk in embryo implantation

Hantak, Alison M.; Bagchi, Indrani C.; Bagchi, Milan K.

doi:10.1387/ijdb.130348mb

Cited by 86 publications

(72 citation statements)

References 67 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…For the embryo to attach to and implant into the uterus, the uterus must change from a nonreceptive to a receptive state. These changes are regulated by the hormones E2 and P4 and by an intricate series of downstream interactions between the stromal, luminal epithelium, and glandular epithelial layers of the uterus (26). In the uterine luminal epithelium, E2 signals support proliferation of the luminal epithelium, whereas P4 signals oppose proliferation and drive differentiation (27).…”

Section: Resultsmentioning

confidence: 99%

Follistatin is critical for mouse uterine receptivity and decidualization

Fullerton

Monsivais

Kommagani

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Embryo implantation remains a significant challenge for assisted reproductive technology, with implantation failure occurring in ∼50% of in vitro fertilization attempts. Understanding the molecular mechanisms underlying uterine receptivity will enable the development of new interventions and biomarkers. TGFβ family signaling in the uterus is critical for establishing and maintaining pregnancy. Follistatin (FST) regulates TGFβ family signaling by selectively binding TGFβ family ligands and sequestering them. In humans, FST is upregulated in the decidua during early pregnancy, and women with recurrent miscarriage have lower endometrial expression of FST during the luteal phase. Because global knockout of Fst is perinatal lethal in mice, we generated a conditional knockout (cKO) of Fst in the uterus using progesterone receptor-cre to study the roles of uterine Fst during pregnancy. Uterine Fst-cKO mice demonstrate severe fertility defects and deliver only 2% of the number of pups delivered by control females. In Fst-cKO mice, the uterine luminal epithelium does not respond properly to estrogen and progesterone signals and remains unreceptive to embryo attachment by continuing to proliferate and failing to differentiate. The uterine stroma of Fst-cKO mice also responds poorly to artificial decidualization, with lower levels of proliferation and differentiation. In the absence of uterine FST, activin B expression and signaling are up-regulated, and bone morphogenetic protein (BMP) signals are impaired. Our findings support a model in which repression of activin signaling by FST enables uterine receptivity by preserving critical BMP signaling.female infertility | implantation failure | TGFβ signaling | activin antagonism M ouse models are powerful tools for improving our understanding of uterine receptivity because mice can be easily manipulated with well-established genetic tools and experimental approaches (1). Studies using mice have shown that TGFβ family growth factors play critical roles in establishing uterine receptivity. The TGFβ family operates through a shared mechanism. The signaling cascade is initiated by binding of homodimeric or heterodimeric ligands to a cell-surface receptor complex composed of a type 2 receptor kinase and its partner type 1 receptor kinase. Once the ligand binds, the type 2 receptor phosphorylates and activates the type 1 receptor. The activated type 1 receptor kinase phosphorylates receptor SMADs, enabling them to form a complex with the co-SMAD, SMAD4. The resulting heterotrimeric SMAD complex concentrates in the nucleus where it regulates gene expression in conjunction with of a multitude of cofactors. Uterine conditional knockout (cKO) of TGFβ superfamily growth factors bone morphogenetic protein 2 (BMP2), type 1 receptors ALK2 and ALK3, and type 2 receptor bone morphogenetic protein receptor 2 (BMPR2) in mice have shown that local uterine TGFβ family signaling plays key roles in regulating embryo attachment and invasion as well as endometrial stromal cell decidualization (2-5)....

show abstract

Section: Resultsmentioning

confidence: 99%

Follistatin is critical for mouse uterine receptivity and decidualization

Fullerton

Monsivais

Kommagani

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…2B). In mice, blastocyst apposition and attachment occur on day 4 of pregnancy, at which point blastocysts can no longer be flushed from the uterus (33)(34)(35). We tested whether defective blastocyst attachment was occurring by mating Alk3 cKO females to males carrying a transgene of the EGFP to visualize GFP-expressing embryos (Fig.…”

Section: Resultsmentioning

confidence: 99%

Uterine ALK3 is essential during the window of implantation

Monsivais

Clementi

Jia

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

The window of implantation is defined by the inhibition of uterine epithelial proliferation, structural epithelial cell remodeling, and attenuated estrogen (E2) response. These changes occur via paracrine signaling between the uterine epithelium and stroma. Because implantation defects are a major cause of infertility in women, identifying these signaling pathways will improve infertility interventions. Bone morphogenetic proteins (BMPs) are TGF-β family members that regulate the postimplantation and midgestation stages of pregnancy. In this study, we discovered that signaling via activin-like kinase 3 (ALK3/BMPR1A), a BMP type 1 receptor, is necessary for blastocyst attachment. Conditional knockout (cKO) of ALK3 in the uterus was obtained by producing Alk3 flox/flox -Pgr-cre-positive females. Alk3 cKO mice are sterile and have defects in the luminal uterine epithelium, including increased microvilli density and maintenance of apical cell polarity. Moreover, Alk3 cKO mice exhibit an elevated uterine E2 response and unopposed epithelial cell proliferation during the window of implantation. We determined that dual transcriptional regulation of Kruppel-like factor 15 (Klf15), by both the transforming growth factor β (TGF-β) transcription factor SMAD family member 4 (SMAD4) and progesterone receptor (PR), is necessary to inhibit uterine epithelial cell proliferation, a key step for embryo implantation. Our findings present a convergence of BMP and steroid hormone signaling pathways in the regulation of uterine receptivity.BMP signaling pathway | endometrium | implantation failure | infertility | progesterone receptor D rastic structural and molecular changes are necessary for the luminal uterine epithelium to achieve a receptive status. Because it is the first site of contact between the mother and the invading blastocyst, remodeling of the luminal epithelium is crucial for establishing a successful pregnancy (1, 2). The steroid hormones, estrogen (E2) and progesterone (P4), coordinate many of these changes; however, many other growth factors and cytokines are involved (3, 4). The bone morphogenetic proteins (BMPs) are a class of growth factors that are important during pregnancy. BMPs are members of the transforming growth factor β (TGF-β) signaling pathway that regulate many cellular pathways, including processes related to normal reproductive function and pregnancy (5-13). BMPs transmit their signals by binding to a cell surface heterodimeric receptor complex that is composed of a combination of two type 1 receptors [activin-like kinase 2 (ALK2), ALK3, or ALK6] and two type 2 receptors [activin A receptor type II A (ACVR2A), ACVR2B, or BMP type 2 receptor (BMPR2)] (14-16). Upon ligand binding, the heterodimeric BMP receptor complex signals by phosphorylating and activating SMAD1/5/8, which associate with SMAD family member 4 (SMAD4) and translocate to the nucleus to regulate gene expression (17).BMPs are expressed in a temporal manner throughout early and late pregnancy (18), and conditional deletion of BMP2 resu...

show abstract

“…Ovarian dysfunction is not only related to low pregnancy rates but also to the increased risk of miscarriage. Some studies have reported that ovariectomy at any time during pregnancy of mice will lead to abortion [10,11]. Estrogen and progesterone, which are synthesized and secreted by the ovaries, are necessary to early pregnancy embryo implantation [12].…”

Section: Animal Model and Tissue Collectionmentioning

confidence: 99%

High insulin impaired ovarian function in early pregnant mice and the role of autophagy in this process

et al. 2017

Endocr J

View full text Add to dashboard Cite

METABOLIC DISORDERS, such as PCOS (polycystic ovary syndrome) and T2DM (type 2 diabetes mellitus), are reported to be associated with high miscarriage rates, decreased pregnancy rates, and low live birth rates [1]. PCOS and T2DM are characterized by hyperinsulinemia [2]. PCOS is an endocrine and metabolic disorder with a prevalence ranging from 5 to 13% in women of reproductive age. Moreover, PCOS is often accompanied by menstrual dysfunction, anovulaHigh insulin impaired ovarian function in early pregnant mice and the role of autophagy in this process Abstract. Metabolic disorders, such as PCOS (polycystic ovarian syndrome) and T2DM (type 2 diabetes mellitus), are associated with menstrual dysfunction, anovulation, infertility, and early pregnancy loss. Ovarian dysfunction is not only related to low pregnancy rates but also to the increased risk of miscarriage. Women with PCOS or T2DM, characterized by hyperinsulinemia, commonly experience ovarian dysfunction. In this study, we first explored whether high insulin levels directly affected ovarian functioning during embryo implantation. Mice in the insulin-treated group were given a subcutaneous injection of human recombinant insulin. After insulin treatment, serum levels of E2 (estrogen), PROG (progesterone), LH (luteinizing hormone), and FSH (follicle-stimulating hormone) were obviously lower, and there was a significant decrement of ovarian GDF9 (growth differentiation factor 9) mRNA. H&E (hematoxylin and eosin) staining showed a greater number of immature follicles and less luteinization in the insulin group. Further autophagy was studied in this process. A significant increase of P62 (SQSTM1/Sequestosome1) and a decrease of Cathepsin B, BECN1 (Beclin 1), and ULK1 (Unc-51-like kinase 1) mRNA in ovary was found in the insulin group. Western blot analysis showed that the expressions of LC3 (microtubule-associated protein 1 light chain 3), BECN1, and Cathepsin B proteins in ovaries from insulin group were obviously reduced, while P62 proteins were significantly increased. All these results illustrated that insulin could directly impair ovarian function during embryo implantation and the imbalance of ovarian autophagy due to insulin. Autophagy could enhance the impaired ovarian function results from insulin.

show abstract

Role of uterine stromal-epithelial crosstalk in embryo implantation

Cited by 86 publications

References 67 publications

Follistatin is critical for mouse uterine receptivity and decidualization

Follistatin is critical for mouse uterine receptivity and decidualization

Uterine ALK3 is essential during the window of implantation

High insulin impaired ovarian function in early pregnant mice and the role of autophagy in this process

Contact Info

Product

Resources

About