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

Leilani L Santos,Evdokia Dimitriadis,Cheuk Kwan Ling

doi:10.1186/s12958-020-00682-0

Leilani L Santos, Evdokia Dimitriadis + Show 1 more

Open Access

https://doi.org/10.1186/s12958-020-00682-0

Copy DOI

Abstract

The 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.

Highlights

The endometrium undergoes a coordinated cyclic remodelling during the menstrual cycle in preparation for embryo implantation
Our study suggests Tripeptidyl peptidase 1 (TPP1) promotes endometrial receptivity and embryo implantation via effects on endometrial epithelial cell adhesion and sirtuin 1 (SIRT1), B-cell lymphoma 2 (Bcl-2) and p53 stimulation and likely not via effects on endometrial stromal cell decidualization
Treatment of primary human endometrial stromal cells with estrogen and methoxyprogesterone acetate (MPA) for 12 days resulted in decidualization as indicated by a change from characteristic elongated fibroblast-shaped stromal cells (Fig. 4a) into a more rounded morphology characteristic of decidualized stromal cells (Fig. 4b)

Summary

Introduction

The endometrium undergoes a coordinated cyclic remodelling during the menstrual cycle in preparation for embryo implantation. During a short ‘receptive period’ or ‘implantation window’ which occurs within the midsecretory phase, the endometrium transforms from a non-receptive to an embryo-responsive state to allow for embryo implantation [1]. The natural fate of the receptive endometrium, in the absence of implantation, is development of a second set of changes that lead to menstruation [2, 3]. The endometrial surface or luminal epithelium undergoes extensive changes to become adhesive to blastocysts [1] the midsecretory phase or the implantation window thought to occur between ~days 19–23 of the cycle [1]. The endometrial stromal cells which maximally express steroid hormone receptors differentiate to transform into decidualized stromal cells [1]. Information on lesser known proteases such as tripeptidyl peptidase I (TPP1) are lacking

Objectives

Methods

Results

Conclusion