Human Endometrial Mucin MUC1 Is Up-Regulated by Progesterone and Down-Regulated In Vitro by the Human Blastocyst1

Abstract

Expression of MUC1 in endometrial epithelium has been suggested to create a barrier to embryo attachment that must be lifted at the time of implantation. In this study, we investigated the hormonal regulation of human endometrial MUC1 in hormone replacement therapy cycles and in the human blastocyst. We also analyzed the embryonic regulation of MUC1 in human endometrial epithelial cells (EECs) during the apposition and adhesion phases of human implantation using two different in vitro models. Our results indicate that endometrial MUC1 mRNA and immunoreactive protein increase in receptive endometrium compared to nonreceptive endometrium. Human blastocysts express MUC1, as demonstrated by reverse transcription-polymerase chain reaction and immunocytochemistry, localized at the trophectoderm. In vitro, MUC1 was present at the surface of primary cultures of human EEC, and presence of a human blastocyst (i.e., apposition phase) increases EEC MUC1 protein and mRNA compared to control EEC lacking embryos. Interestingly, when human blastocysts were allowed to attach to the EEC monolayer (i.e., adhesion phase), MUC1 was locally removed in a paracrine fashion on EEC at the implantation site. These results demonstrate a coordinated hormonal and embryonic regulation of EEC MUC1. Progesterone combined with estradiol priming induces an up-regulation of MUC1 at the receptive endometrium. During the apposition phase, presence of a human embryo increases EEC MUC1. However, at the adhesion phase, the embryo induces a paracrine cleavage of EEC MUC1 at the implantation site. These findings strongly suggest that MUC1 may act as an endometrial antiadhesive molecule that must be locally removed by the human blastocyst during the adhesion phase.

In vivo and in vitro studies of MUC1 regulation in sheep endometrium

“…These stages correspond to the period of high plasma 244 progesterone and its associated dominance in the endometrial LE. These results agree with previous 245 reports of increased MUC1 expression under progesterone-dominated endometrial epithelium in 246 rabbit [35] and human [1]. Interestingly, we could detect a significant drop in MUC1 mRNA 247 expression at post LH peak stage which was also confirmed by immunostaining.…”

“…In addition, our data has revealed a transient decline in 260 MUC1 mRNA and protein expression at the post-LH in both regions providing further evidence for 261 MUC1 dependency on steroid hormones [1]. This period coincides with the optimum insemination 262 time in sheep.…”

“…In the 26 reproductive system, MUC1 is expressed in the uterus [1] and in the testes [2]. MUC1 has been linked 27 to numerous functions [3] including antimicrobial effects by inhibiting microbial access to the cell 28 surface as well as inhibition of cell-cell adhesion.…”

“…Non-receptivity of 34 endometrium has been partly attributable to features characteristic of luminal epithelia expressing 35 glycocalyx, of which trans-membrane mucin 1 glycoprotein encoded by MUC1 gene is the most 36 widely expressed and distributed in the reproductive tract [3]. 37 MUC1 protein is expressed mainly in luminal epithelium (LE) and glandular epithelium (GE) of the 38 endometrium in many mammalian species including mice, rat, pig, sheep, horse and human during 39 various stages of a menstrual or estrous cycles [1,[8][9][10][11]. MUC1 is proposed to protect the 40 reproductive system by preventing entrance of pathogens through the LE into endometrium [12].…”

“…This hypothesis is supported by reduction of cellM A N U S C R I P T [10]. In contrast, MUC1 is upregulated in human endometrial at implantation [15] 58 however human embryos seems to locally down-regulate MUC1 as shown in maternal primary 59 endometrial cell culture in the region beneath embryo attachment points [1] suggesting regulatory 60 roles of embryo-produced factors. 61…”