Matrix Metalloproteinases in Human Decidualized Endometrial Stromal Cells.

Yoji Hisamatsu,Susumu Tanaka,Yoshiko Hashimoto,Hidetaka Okada,Masaaki Kitada,Hiromi Murata,Hiroaki Tsubokura

doi:10.3390/cimb43030146

Abstract

Cyclic changes, such as growth, decidualization, shedding, and regeneration, in the human endometrium are regulated by the reciprocal action of female hormones, such as estradiol (E2), and progesterone (P4). Matrix metalloproteases (MMPs) and tissue inhibitors of MMPs (TIMPs) control the invasion of extravillous trophoblast cells after implantation. Several MMPs and TIMPs function in the decidua and endometrial stromal cells (ESCs). Here, we aimed to systematically investigate the changes in MMPs and TIMPs associated with ESC decidualization. We evaluated the expression of 23 MMPs, four TIMPs, and four anti-sense non-coding RNAs from MMP loci. Primary ESC cultures treated with E2 + medroxyprogesterone acetate (MPA), a potent P4 receptor agonist, showed significant down-regulation of MMP3, MMP10, MMP11, MMP12, MMP20, and MMP27 in decidualized ESCs, as assessed by quantitative reverse transcription PCR. Further, MMP15 and MMP19 were significantly upregulated in decidualized ESCs. siRNA-mediated silencing of Heart and Neural Crest Derivatives Expressed 2 (HAND2), a master transcriptional regulator in ESC decidualization, significantly increased MMP15 expression in untreated human ESCs. These results collectively indicate the importance of MMP15 and MMP19 in ESC decidualization and highlight the role of HAND2 in repressing MMP15 transcription, thereby regulating decidualization.

Highlights

In the human endometrium, growth, decidualization, shedding, and regeneration occur repeatedly with each menstrual cycle, even without embryo implantation [1,2]
We examined the expression of 23 Matrix metalloproteases (MMPs), four non-coding RNAs from MMP loci (MMP2-AS1, MMP23A, MMP24OS, and MMP25-AS1), and four tissue inhibitors of MMPs (TIMPs) in control and decidualized human endometrial stromal cells (ESCs) induced by E2 + medroxyprogesterone acetate (MPA), a synthetic progestin that acts as a potent P4 receptor agonist [14]
Our analysis revealed that MMP3, MMP10, MMP11, MMP12, MMP20, and MMP27 were significantly downregulated in decidualized ESCs compared with those in the control (Figure 1)

Summary

Introduction

Growth, decidualization, shedding, and regeneration occur repeatedly with each menstrual cycle, even without embryo implantation [1,2]. These events are controlled by the reciprocal action of estradiol (E2) and progesterone (P4), the major ovarian steroid hormones [3]. Matrix metalloproteases (MMPs), controlled by tissue inhibitors of MMPs (TIMPs), play a notable role in regulating the invasion potential of EVTs by degrading ECM components. ESCs and decidualized ESCs undergo a cycle of endometrial breakdown and regeneration and decidua remodeling by secreting various MMPs that degrade ECM components and activate growth factors [10,11]. TIMPS regulate MMP activity by processing pro-zymogens and inhibiting active enzymes [13]

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