Implantation and Placental Development

Implantation and Placental Development Research Group

Research Group Head

Before an embryo can implant and establish a pregnancy, the uterus must undergo a major remodelling process to provide “fertile soil” for embryo implantation. Our group investigates how the human uterus prepares for embryo implantation (known as “receptivity”) so that we can improve implantation success rates, especially in women undergoing IVF.

Our research focuses on the molecular mechanisms governing the fundamental cell biology of uterine remodelling for receptivity, as well as those governing the interactions between the uterus and the embryo at the time of implantation. This work is particularly relevant to patients who suffer from implantation failure during IVF treatent. This work is also important because preventing embryo implantation is an attractive strategy for non-hormonal contraception. Moreover, as many aspects of embryo implantation are similar to how cancers progress, a fundamental understanding of embryo implantation may lead to new ideas for cancer therapies.

After implantation, placental development is vital to support the growing fetus and is also important to maintain the mother’s health during pregnancy. Abnormal placentation will not only affect the developing fetus, but can also cause serious complications in the mother. Therefore, another major focus of our group is on how the placenta develops, so that we can better understand and manage pregnancy complications such as preeclampsia, intrauterine growth restriction and miscarriage.

We are particularly interested in a group of enzymes, the HtrA protease family, in placental development and pregnancy diseases. One of our major goals is to develop strategies for early detection and treatment of preeclampsia, a life-threatening disorder of human pregnancy. We are also interested in evaluating the long-term health consequences of placental insufficiency and pregnancy diseases.

We utilise a number of strategies including molecular biology, biochemistry, transcriptomics, proteomics, cell culture, gene manipulation using the latest technologies such as CRISPR/CAS9, and animal models. We collaborate closely with specialist clinicians, and a particular emphasis of our research is to translate our basic research discoveries into clinically-useful practices.

Research Projects

Research Group

Selected publications

  • Wang Y, Lim R and Nie G (2019). HtrA4 may play a major role in inhibiting endothelial repair in pregnancy complication preeclampsia. Scientific Reports Feb 25;9(1):2728.

  • Wang Y, La M, Pham T, Lovrecz GO, Nie G (2019) High levels of HtrA4 detected in preeclamptic circulation may disrupt endothelial cell function by cleaving the main VEGFA receptor KDR.  FASEB Jan 2: fj201802151RR.

  • Tseng E, Yee Teoh SS, Wang Y, Nie G (2019) Elevated protease HtrA4 in the maternal circulation of preeclampsia may contribute to endothelial barrier disruption by cleaving key junctional protein VE-cadherin.  Placenta Jan 2 pii:S0143-4004 (19)30001-3.

  • Nie G and Dimitriadis E (2018). Molecular and cellular basis of human embryo implantation. In How to Prepare the Endometrium to Maximize Implantation Rates and IVF Success. Kovacs G and Salamonsen L, eds. PA: Cambridge University Press, pp 10-18.

  • Mansilla M, Wang Y, Hyett J, da Silva Costa F, Nie G (2018) Serum podocalyxin for early detection of preeclampsia at 11-13 weeks of gestation.  Placenta 71:13-15.

  • Wang Y, Li Y, Hyett J, da Silva Costa F, Nie G (2018) HtrA3 isoform-specific ELISAs for early detection of preeclampsia. Slas Discovery 23:1092-1099.

  • Lv Q, Yang B, Ning C, Xie B, Nie G, Chen X and Chen Q (2018). Hypoxia is involved in the reduction of HtrA3 in patients with endometrial hyperplasia and cancer. Biochem Biophys Res Commun 503, 2918-2923.

  • Heng S, Evans J, Salamonsen LA, Jobling TW, Nie G (2017) The significance of post-translational removal of a-DG-N in early stage endometrial cancer development. Oncotarget 8:81942-81952.

  • Li Y, Salamonsen LA, Hyett J Costa FDS, Nie G (2017) Maternal HtrA3 optimizes placental development to influence offspring birth weight and subequent white fat gain in adulthood. Scientific Reports 7:4627.

  • Chen Q, Wang Y, Li Y, Zhao M, Nie G (2017) Serum podocalyxin is significantly increased in early-onset preeclampsia and may represent a novel marker of maternal endothelial cell dysfunction (2017) J Hypertens 35:2287-2294.

  • Wang Y, Chen Q, Zhao M, Walton K, Harrison C, Nie G (2017) Multiple soluble TGF-β receptors in addition to soluble endoglin are elevated in preeclamptic serum and they synergistically inhibit TGF-β signaling. J Clin Encodrinol Metab 102:3065-3074.

  • Evans J, Salamonsen L, Winship A, Menkhorst E, Nie G, Gargett C and Dimitriadis E (2016). Fertile ground: human endometrial programming and lessons in health and disease. Nat Reviews Endocrinology 12, 654-667.

  • Wang Y, Nie G (2016) High levels of HtrA4 observed in preeclamptic circulation drastically alter endothelial gene expression and induce inflammation in human umbilical vein endothelial cells. Placenta 47:46-55.

  • Heng S, Andrew N. Stephens AN, Jobling TW and Nie G (2016). Measuring PC activity in endocervical swab may provide a simple and non-invasive method to detect endometrial cancer in post-menopausal women. Oncotarget 7:46573-46578.

  • Chen Q, Wang Y, Zhao M, Hyett J, Costa FS, Nie G (2016) Serum levels of GDF15 are reduced in preeclampsia and the reduction is more profound in late-onset than early-onset cases. Cytokine 83:226-230.

  • Heng S, Vollenhoven B, Rombauts LJ and Nie G (2015) A high-throughput assay for the detection of a-dystroglycan N-terminus in human uterine fluid to determine uterine receptivity. J Biomol Screen 21:408-413.

  • Heng S, Paule SG, Li Y, Rombauts LJ, Vollenhoven B, Salamonsen LA, Nie G (2015) Post-translational removal of alpha-dystroglycan N-terminus by PC5/6 cleavage is important for uterine preparation for embryo implantation in women. FASEB 29:4011-4022.

  • Teoh SS, Zhao M, Wang Y, Chen Q Nie G (2015) Serum HtrA1 is differentially regulated between early-onset and late-onset preeclampsia. Placenta 36:990-995.

  • Singh H, Zhao M, Chen Qi, Wang Y, Li Y, Kaitu’u-Lino TJ, Tong S, Nie G (2015) Human HtrA4 expression is restricted to the placenta, is significantly up-regulated in early-onset preeclampsia, and high levels of HtrA4 cause endothelial dysfunction. JCEM 100:E936-E945.

  • Paule S, Nebl T, Webb AL, Vollenhoven B, Rombauts LJF, Nie G (2015) Proprotein convertase 5/6 cleaves platelet derived growth factor A in the human endometrium in preparation for embryo implantation. Mol Hum Reprod 21:262-270.

  • Singh H, Nero TL, Wang Y, Parker MW, Nie G (2014) Activity-modulating monoclonal antibodies to the human serine protease HtrA3 provide novel insights into regulating HtrA proteolytic activities. PLoS One 7:e45956.

  • Ho H, Li Y, Nie G (2014) Inhibition of embryo implantation in mice through vaginal administration of a proprotein convertase 6 inhibitor. Reproductive Biology 14:155-159.

  • Singh H, Li Y, Fuller PJ, Harrison C, Rao J, Stephens AN, Nie G (2013) HtrA3 is downregulated in cancer cell lines and significantly reduced in primary serous and granulosa cell ovarian tumors. J Cancer 4:152-164.

  • Ho H, Singh H, Aljofan M and Nie G (2012). A high-throughput in vitro model of human embryo attachment. Fertil Steril 97:974-978.

  • Heng S, Cervero A, Simon C, Stephens AN, Li Y,  Zhang J, Paule S, Rainczuk A, Singh H, Quinonero A, Tapia A, Velasquez L, Salamonsen L, Rombauts LJF and Nie G (2011). Proprotein convertase 5/6 is critical for embryo implantation in women: regulating receptivity by cleaving EBP50, modulating ezrin binding and membrane-cytoskeletal interactions. Endocrinology 52:5041-5052.

  • Heng S, Hannan NJ, Rombauts L, Salamonsen LA and Nie G (2011). PC6 levels in uterine lavage are closely associated with uterine receptivity and significantly lower in a sub-group of women with unexplained infertility. Human Reprod 26:840-846.

  • Singh H, Endo Y and Nie G (2011). Decidual HtrA3 negatively regulates trophoblast invasion during human placentation. Human Reprod 26:748-757.