How Mechanical Forces Change the Human Endometrium during the Menstrual Cycle in Preparation for Embryo Implantation

The human endometrium is characterized by exceptional plasticity, as evidenced by rapid growth and differentiation during the menstrual cycle and fast tissue remodeling during early pregnancy. Past work has rarely addressed the role of cellular mechanics in these processes. It is becoming increasingly clear that sensing and responding to mechanical forces are as significant for cell behavior as biochemical signaling. Here, we provide an overview of experimental evidence and concepts that illustrate how mechanical forces influence endometrial cell behavior during the hormone-driven menstrual cycle and prepare the endometrium for embryo implantation. Given the fundamental species differences during implantation, we restrict the review to the human situation. Novel technologies and devices such as 3D multifrequency magnetic resonance elastography, atomic force microscopy, organ-on-a-chip microfluidic systems, stem-cell-derived organoid formation, and complex 3D co-culture systems have propelled the understanding how endometrial receptivity and blastocyst implantation are regulated in the human uterus. Accumulating evidence has shown that junctional adhesion, cytoskeletal rearrangement, and extracellular matrix stiffness affect the local force balance that regulates endometrial differentiation and blastocyst invasion. A focus of this review is on the hormonal regulation of endometrial epithelial cell mechanics. We discuss potential implications for embryo implantation.

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Invited Review: Engineering approaches to cytoskeletal mechanics

Journal of Applied Physiology ◽

10.1152/jappl.2000.89.5.2085 ◽

2000 ◽

Vol 89 (5) ◽

pp. 2085-2090 ◽

Cited By ~ 69

Author(s):

Dimitrije Stamenović ◽

Ning Wang

Keyword(s):

Cell Biology ◽

Theoretical Models ◽

Force Balance ◽

Mechanical Forces ◽

Cellular Functions ◽

Cellular Mechanics ◽

Recent Developments ◽

Biochemical Mechanisms ◽

Underlying Mechanisms ◽

Biochemical Signals

An outstanding problem in cell biology is how cells sense mechanical forces and how those forces affect cellular functions. Various biophysical and biochemical mechanisms have been invoked to answer this question. A growing body of evidence indicates that the deformable cytoskeleton (CSK), an intracellular network of interconnected filamentous biopolymers, provides a physical basis for transducing mechanical signals into biochemical signals. Therefore, to understand how mechanical forces regulate cellular functions, it is important to know how cells respond to changes in the CSK force balance and to identify the underlying mechanisms that control transmission of mechanical forces throughout the CSK and bring it to equilibrium. Recent developments of new experimental techniques for measuring cell mechanical properties and novel theoretical models of cellular mechanics make it now possible to identify and quantitate the contributions of various CSK structures to the overall balance of mechanical forces in the cell. This review focuses on engineering approaches that have been used in the past two decades in studies of the mechanics of the CSK.

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Tripeptidyl peptidase I promotes human endometrial epithelial cell adhesive capacity implying a role in receptivity

Reproductive Biology and Endocrinology ◽

10.1186/s12958-020-00682-0 ◽

2020 ◽

Vol 18 (1) ◽

Author(s):

Leilani L. Santos ◽

Cheuk Kwan Ling ◽

Evdokia Dimitriadis

Keyword(s):

Menstrual Cycle ◽

Epithelial Cell ◽

Stromal Cells ◽

Embryo Implantation ◽

Unexplained Infertility ◽

Implantation Failure ◽

Secretory Phase ◽

Endometrial Epithelial Cell ◽

Tripeptidyl Peptidase ◽

Adhesive Capacity

AbstractThe endometrium undergoes cyclic remodelling throughout the menstrual cycle in preparation for embryo implantation which occurs in a short window during the mid-secretory phase. It is during this short ‘receptive window’ that the endometrial luminal epithelium acquires adhesive capacity permitting blastocysts firm adhesion to the endometrium to establish pregnancy. Dysregulation in any of these steps can compromise embryo implantation resulting in implantation failure and infertility. Many factors contribute to these processes including TGF-β, LIF, IL-11 and proteases. Tripeptidyl peptidase 1 (TPP1) is a is a lysosomal serine-type protease however the contribution of the TPP1 to receptivity is unknown. We aimed to investigate the role of TPP1 in receptivity in humans.In the current study, TPP1 was expressed in both epithelial and stromal compartments of the endometrium across the menstrual cycle. Expression was confined to the cytoplasm of luminal and glandular epithelial cells and stromal cells. Staining of mid-secretory endometrial tissues of women with normal fertility and primary unexplained infertility showed reduced immunostaining intensity of TPP1 in luminal epithelial cells of infertile tissues compared to fertile tissues. By contrast, TPP1 levels in glandular epithelial and stromal cells were comparable in both groups in the mid-secretory phase. Inhibition of TPP1 using siRNA compromised HTR8/SVneo (trophoblast cell line) spheroid adhesion on siRNA-transfected Ishikawa cells (endometrial epithelial cell line) in vitro. This impairment was associated with decreased sirtuin 1 (SIRT1), BCL2 and p53 mRNA and unaltered, CD44, CDH1, CDH2, ITGB3, VEGF A, OSTEOPONTIN, MDM2, CASP4, MCL1, MMP2, ARF6, SGK1, HOXA-10, LIF, and LIF receptor gene expression between treatment groups. siRNA knockdown of TPP1 in primary human endometrial stromal cells did not affect decidualization nor the expression of decidualization markers prolactin (PRL) and insulin-like growth factor-binding protein 1 (IGFBP1). Taken together, our data strongly suggests a role for TPP1 in endometrial receptivity via its effects on epithelial cell adhesion and suggests reduced levels associated with unexplained infertility may contribute to implantation failure.

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182 CALBINDIN-D28k IS PREDOMINANTLY EXPRESSED AND REGULATED BY ESTROGEN IN HUMAN ENDOMETRIUM DURING MENSTRUAL CYCLE

Reproduction Fertility and Development ◽

10.1071/rdv23n1ab182 ◽

2011 ◽

Vol 23 (1) ◽

pp. 192

Author(s):

K.-C. Choi ◽

H. Yang ◽

E.-B. Jeung

Keyword(s):

Menstrual Cycle ◽

Calcium Binding ◽

Potential Role ◽

Embryo Implantation ◽

Endometrial Receptivity ◽

Human Endometrium ◽

Ishikawa Cell ◽

Proliferative Phase ◽

Calbindin D28k ◽

The Brain

The human endometrium resists embryo implantation except during the window of receptivity. A change in endometrial gene expression is required for the development of receptivity. Uterine calbindin-D28k (CaBP-28k) has been shown to be involved in the regulation of endometrial receptivity by intracellular Ca2+. Nowadays, this protein has been mainly linked to the brain, kidneys, and pancreas, but potential role(s) of CaBP-28k remain to be clarified in the uterus of humans during the menstrual cycle. Thus, we demonstrated in this study that the expression of CaBP-28k in the human endometrium in more divided in the menstrual phases. During the menstrual cycle of humans, uterine expression levels of CaBP-28k mRNA and protein increased at the proliferative phase and fluctuated in these tissues, compared with other phases. We assessed the effects of the sex-steroid hormones E2 and P4 on the expression of CaBP-28k in the Ishikawa cell line. A significant increase in the expression of CaBP-9k mRNA was observed at the concentration of 17β-oestradiol (E2; 10–9 to 10–7 M). In addition, spatial expression of CaBP-28k was detected by immunohistochemistry. CaBP-28k is abundantly localised in the cytoplasm of the luminal and glandular epithelial cells during the menstrual cycle. Taken together, these results indicate that CaBP-28k, a uterine calcium-binding protein, is abundantly expressed in the human uterus, suggesting that uterine expression of CaBP-28k may be involved in reproductive functions during the menstrual cycle of humans.

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Expression and regulation of fucosyltransferase 4 in human endometrium

Reproduction ◽

10.1530/rep-07-0548 ◽

2008 ◽

Vol 136 (1) ◽

pp. 117-123 ◽

Cited By ~ 14

Author(s):

Anna P Ponnampalam ◽

Peter A W Rogers

Keyword(s):

Menstrual Cycle ◽

Protein Expression ◽

Real Time Pcr ◽

Hormonal Regulation ◽

Inductive Effect ◽

Human Endometrium ◽

Luminal Epithelium ◽

Selectin Ligands ◽

Initial Adhesion ◽

Endometrial Epithelium

It has been suggested that selectin ligands expressed by the endometrial epithelium are essential for the initial adhesion of the blastocyst to the luminal epithelium of human endometrium. One of the enzymes responsible for the production of selectin ligands is fucosyltransferase 4 (FUT4), a member of α1,3 fucosyltransferases. The aims of the present study were to characterize FUT4 mRNA and protein in human endometrium during the menstrual cycle and to investigate the hormonal regulation of FUT4 whose mRNA expression was quantified by real-time PCR in fresh endometrial tissue from cycling women and protein expression was analyzed by immunohistochemistry and Western blotting. Hormonal regulation of FUT4 transcription was investigated using an endometrial explant system. FUT4 mRNA was significantly upregulated in fresh tissues during early and mid-secretory phases when compared with other phases of the menstrual cycle. FUT4 protein was localized to glandular and luminal epithelium and the expression levels followed the same pattern as for FUT4 mRNA. Our data also show that, in proliferative explants, progesterone significantly increased FUT4 transcription and translation after 24 h in culture. The inductive effect of progesterone on FUT4 transcription was lost after 48 h of treatment. Estrogen did not have any significant effects. These data suggest that the upregulation of selectin ligands in the human endometrium at the time of implantation may be mediated, at least in part, by the regulation of FUT4 expression.

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