Placental tissues contain a heterogeneous population of cells, including villous cytotrophoblasts, syncytiotrophoblasts and extravillous trophoblasts (EVTs). EVTs are mainly uninuclear cells comprising all the trophoblastic elements located outside the villi. EVTs have two distinct phenotypes: proliferative and invasive. The activity of the invasive EVTs is dependent on their apoptotic capacity and less on their proliferative potential. Apoptosis is an important determinant in regulating placental growth. Actually, apoptosis is more evident in the invasive EVTs than their proliferative counterparts, and the extent of apoptosis is associated with augmented Fas and Fas ligand expression and reduced Bcl-2 protein expression [Citation1].
The human early placenta is characterised by the invasion of EVTs to the decidua, leading to direct contact between EVTs and maternal blood. During the invasion process, EVTs express matrix metalloproteinases (MMPs), which are proteolytic enzymes that cleave all the constituents of the extracellular matrix. Although the controlled invasion of EVTs into the decidua is an essential process for early placental development and the maintenance of early pregnancy, the molecular mechanisms involved in EVT invasion to the decidua has been poorly understood. In this editorial, the vital roles of progesterone, thyroid hormone and relaxin in the regulation of invasive potential of EVTs in early placental development are summarised on the basis of our recent studies.
Progesterone in the regulation of the invasion of EVTs
Clinically, progesterone (P4) is used in the treatment of threatened abortion, prevention of recurrent miscarriage and in the luteal support in assisted reproduction programme. However, little is known about the molecular mechanism of P4 in the regulation of EVTs' function. P4 mediates its physiological effects through interaction with the progesterone receptor (PR), a transcription factor and a member of a large family of structurally related gene products known as the nuclear receptor superfamily. PR is expressed in multiple tissues as two isoforms: PR-A and PR-B. Our recent study revealed that PR-A and PR-B are present in HTR-8/SV neo cell line, which is a possible model of human EVTs [Citation2]. P4 inhibits apoptosis in the EVT cells by down-regulating Fas, Fas-ligand, caspase-3 and poly (ADP-ribose) polymerase (PARP) expression as well as up-regulating Bcl-2 expression in those cells. It seems that P4 may promote the invasion of EVTs to the decidua by inhibiting apoptosis of EVTs. This may explain the mechanism of P4 treatment on threatened abortion.
Thyroid hormone in the regulation of the invasion of EVTs
In clinical practice, maternal thyroid hormone deficiency has been implicated in early pregnancy loss, indicating that thyroid hormone is vital for the maintenance of early pregnancy. Actually, it became evident that T3 receptor mRNA (a 212-bp c-erbAβ1 transcript) and protein are present in early placental EVTs [Citation3]. In cultured early placental EVTs, treatment with 3,5,3′-triiodothyronine (T3) reduced the expression of Fas and Fas-ligand as well as the cleavage of caspase-3 and PARP and suppressed apoptosis in those cells. Matrigel invasion assay revealed that T3 treatment remarkably increased the number of cell projections of EVTs over the membrane of Matrigel. Consistently, T3 treatment increased the expression of MMP-2, MMP-3, fibronectin (FN) and integrin α5β1 mRNA in the cultured EVTs [Citation4]. These findings suggest that T3 promotes the invasion of EVTs to the decidua by suppressing apoptosis and by up-regulating the expression of MMPs and integrin in early placental EVTs. This may explain the mechanism of thyroid hormone for the vital role in maintaining early pregnancy.
Relaxin in the regulation of the invasion of EVTs
Although relaxin is known to promote softening of the uterine cervix and inhibits uterine contractility in rats, mice and pigs, little information is available about the role of relaxin in humans. In 2002, LGR7 and LGR8 were discovered to be the receptors for relaxin. Actually, we have demonstrated for the first time the presence of relaxin receptors (LGR7 and LGR8) in the human early placental EVTs [Citation5]. In humans, three forms of relaxin have been identified: H1, H2 and H3 relaxin. H1 relaxin is present in the human decidua, placenta and prostate but not in the ovaries, whereas H2 relaxin is present in the corpus luteum, placenta and decidua. H3 relaxin is mainly present in the brain. It seems that in humans, relaxin is both a systemic hormone secreted by the corpus luteum and an autocrine/paracrine hormone at the maternal–foetal interface formed by the decidua, placenta and foetal membranes. In our recent study to investigate the effects of recombinant H2 (rH2) relaxin on cultured early placental EVTs, treatment with rH2 relaxin increased MMP-2 and MMP-9 mRNA levels and decreased TIMP-1 mRNA levels in those cells (5). These results suggest that relaxin may promote the invasive potential of early placental EVTs by up-regulating MMP-2 and MMP-9 expression and down-regulating TIMP-1 expression through the interaction with relaxin receptors (LGR7 and LGR8) in EVTs.
References
- Murakoshi H, Matsuo H, Laoag-Fernandez JB, Samoto T, Maruo T. Expression of Fas/Fas ligand, Bcl-2 protein and apoptosis in extravillous trophoblast along invasion to the deciduas in human term placenta. Endocr J 2003;50:199–207.
- Liu J, Matsuo H, Laoag-Fernandez JB, Xu Q, Maruo T. The effects of progesterone on apoptosis in the human trophoblast-derived HTR-8/SV neo cells. Mol Hum Reprod 2007;13:869–874.
- Laoag-Fernandez JB, Matsuo H, Murakoshi H, Hamada AL, Tsang BK, Maruo T. 3,5,3′-Triiodothyronine down-regulates Fas and Fas ligand expression and suppresses caspase-3 and poly (adenosine 5′-diphosphate-ribose) polymerase cleavage and apoptosis in early placental extravillous trophoblasts in vitro. J Clin Endocrinol Metab 2004;89:4069–4077.
- Oki N, Matsuo H Nakago S, Murakoshi H, Laoag-Fernandez JB, Maruo T. Effects of 3,5,3′-triiodothyronine on the invasive potential and the expression of integrins and matrix metalloproteinases in cultured early placental extravillous trophoblasts. J Clin Endocrinol Metab 2004;89:5213–5221.
- Maruo N, Nakabayashi K, Wakahashi S, Yata A, Maruo T. Effects of recombinant H2 relaxin on the expression of matrix metalloproteinases and tissue inhibitor metalloproteinase in cultured early placental extravillous trophoblasts. Endocrine 2007;32:303–310.