Not just a barrier : deciphering molecular and cellular signatures of placental villi in health and endocrine diseases

<p dir="ltr">Maternal obesity, intermediate hyperglycaemia, and PCOS can disrupt placental transport, endocrine, and immune functions, increasing the risk of adverse pregnancy outcomes. Yet these conditions are associated with divergent fetal growth trajectories, and the cell-type-specific placental mechanisms remain poorly characterised. This thesis addresses these questions using high-throughput sequencing with human subjects or mouse models across four studies.</p><p dir="ltr">Study I (Obesity) characterises placental signatures in maternal obesity using Single-nucleus RNA sequencing (snRNA-seq). Obese pregnancies with either Appropriate for gestational age (AGA) or Large for gestational age (LGA) outcomes were compared with healthy controls. Regardless of birth weight, maternal obesity was associated with hypoxia signalling in Syncytiotrophoblast (STB), disrupted STB secretome, and reduced growth factor receptor signalling in Cytotrophoblast (CTB). Overlap between obesity-altered genes and adipose co-culture-responsive genes implicated adipose-derived signals in STB dysfunction. In LGA pregnancies specifically, growth-promoting ligands including PAPP-A and Human placental lactogen (hPL) were downregulated, and inflammatory activation of Hofbauer cell (HBC) and fibroblasts through TNF-a signalling was observed, identifying stromal inflammation as a candidate mechanism for obesity-associated fetal overgrowth.</p><p dir="ltr">Study II (Hyperglycaemic mice) employed a Streptozotocin (STZ)-induced mouse model to study intermediate hyperglycaemia. In contrast to the LGA in Study I, fetal growth restriction and increased resorption were observed, driven by placental hypoxia and dysfunctional compensatory angiogenesis rather than structural malformation. Oocyte transcriptomic and chromatin accessibility profiles were preserved under intermediate hyperglycemia, with vulnerability emerging only above a glucose threshold, as corroborated by human oocytes in vitro. This positions the placenta, rather than the germline, as a likely mediator of adverse fetal outcomes in intermediate hyperglycaemia.</p><p dir="ltr">Study III (PCOS-mice) turns to PCOS, using a continuous androgen-exposed mouse model. PCOS increases the risk of small-for-gestational-age outcomes. In PCOS-mice, trophoblast precursor maintenance and differentiation were disrupted through both transcriptional and epigenetic mechanisms, leading to malformation of the placental labyrinth zone and mid-gestation embryo loss. Co-exposure with the androgen receptor antagonist flutamide prevented all identified phenotypes, implicating androgen receptor signalling as the mechanistic driver. Human trophoblast organoids exposed to androgen recapitulated impaired differentiation, which was similarly rescued by flutamide.</p><p dir="ltr">Study IV (PCOS patients) characterises placental signatures in human PCOS pregnancies, and tests whether ameliorating the metabolic side of the pathology using metformin could prevent these signatures. Using snRNA-seq and histological analyses, trophoblast proportion was reduced, and broad suppression of gene expression was identified across trophoblast and stromal cell types in PCOS pregnancies, consistent with Study III. Previously characterised PCOS-related genes as well as genes associated with preeclampsia and growth factors relevant in small-for-gestational-age were detected. Placental fibroblasts and STB were identified as a likely source of circulating Plasminogen activator inhibitor-1 (PAI-1), potentially contributing to the pro-thrombotic state in PCOS. Metformin treatment during pregnancy failed to prevent the vast majority (95.77%) of PCOS-associated placental changes and introduced its own molecular perturbations.</p><p dir="ltr">Together, these studies show that the placenta mounts distinct cell-type-specific responses to different systemic insults, that these responses account for the divergent fetal outcomes observed across conditions and species, and that the identified molecular signatures may represent targets for improving pregnancy outcomes.</p><h3 dir="ltr">List of scientific papers</h3><p dir="ltr">I. <b>Hong Jiang</b>^#, Emilie Derisoud^#, Denise Parreira, Nayere Taebnia, Paulo R Jannig, Reza Zandi Shafagh, Allan Zhao, Congru Li, Macarena Ortiz, Manuel Alejandro Maliqueo, Elisabet Stener-Victorin, Volker M Lauschke, Qiaolin Deng. (2025). Decoding human placental cellular and molecular responses to obesity and fetal growth. Advanced Science, e09691. <a href="https://doi.org/10.1002/advs.202509691" target="_blank">https://doi.org/10.1002/advs.202509691</a></p><p dir="ltr">II. Allan Zhao, <b>Hong Jiang</b>, Arturo Reyes Palomares, Alice Larsson, Wenteng He, Jacob Grünler, Xiaowei Zheng, Kenny A Rodriguez Wallberg, Sergiu-Bogdan Catrina, Qiaolin Deng. (2024). Appropriate glycemic management protects the germline but not the uterine environment in hyperglycemia. EMBO reports, 25(4), 1752. <a href="https://doi.org/10.1038/s44319-024-00097-7" rel="noreferrer" target="_blank">https://doi.org/10.1038/s44319-024-00097-7</a></p><p dir="ltr">III. Haojiang Lu^#, <b>Hong Jiang</b>^#, Congru Li, Emilie Derisoud, Allan Zhao, Gustaw Eriksson, Eva Lindgren, Han-Pin Pui, Sanjiv Risal, Yu Pei, Theresa Maxian, Claes Ohlsson, Anna Benrick, Sandra Haider, Elisabet Stener-Victorin, Qiaolin Deng. (2024). Dissecting the impact of maternal androgen exposure on developmental programming through targeting the androgen receptor. Advanced Science, 11(36), 2309429. <a href="https://doi.org/10.1002/advs.202309429" target="_blank">https://doi.org/10.1002/advs.202309429</a></p><p dir="ltr">IV. <b>Hong Jiang</b>^#, Xuelei Wang^#, Eszter Vanky, Denise Parreira, Emilie Derisoud, Paulo R Jannig, Emelie Nordenhok, Allan Zhao, Solhild Stridsklev, Malin Holzmann, Xinmin Li, Charlotte Millde Luthander, Elisabet Stener-Victorin, Qiaolin Deng. Spatial cellular expression landscape of placentas from women with polycystic ovary syndrome with and without gestational metformin treatment. [Manuscript]</p><p dir="ltr">^# Equal contribution</p>