Biology subjects

Turco, M. Y.

Publications and source records attributed to Turco, M. Y..

8 recordsLinked to original sources

bioRxiv2025

Low oxygen promotes extravillous trophoblast progenitor expansion but restrains maturation

Placental development occurs in a low oxygen environment, yet how oxygen tension instructs differentiation of progenitor cytotrophoblasts (CTB) along the extravillous versus villous pathways remains incompletely understood. In particular, the role of low oxygen in early extravillous trophoblast (EVT) progenitor expansion and subsequent maturation has been difficult to assess due to the lack of models allowing sequential, high-resolution characterization. Using human trophoblast organoids and single-cell transcriptomics, we examined the effects of ambient (21%) and physiological (2-3%, 8%) oxygen on EVT and SCT differentiation. We show that low oxygen promotes the initial expansion of column CTB-like progenitors but restricts terminal EVT maturation. Conversely, we show that ambient oxygen drives the formation of EVT and syncytiotrophoblast. Stabilization of HIF-1 partially recapitulates the EVT maturation block but does not contribute to EVT progenitor expansion, indicating HIF-dependent and-independent contributions. These findings clarify how oxygen shapes EVT lineage progression and define HIF-1s role in coordinating progenitor expansion versus maturation.

developmental biology↗

bioRxiv2025

A model of apical-out human first trimester trophoblast organoids to study regeneration after syncytial damage

The villous syncytiotrophoblast in humans is the interface between maternal blood and the placenta and its functions are essential for a successful pregnancy. The syncytium can be damaged in vivo focally by high-velocity and turbulent maternal blood flow, or more globally by oxidative stress. It then quickly regenerates, a process critical for the maintenance of placental functions including nutrient transfer and protection from infections. To investigate this process, we developed apical-out trophoblast organoids from first-trimester placentas and induced mechanical damage to the syncytium. We observed spontaneous regeneration of syncytiotrophoblast both morphologically and functionally. TNFRSF12A, the TWEAK receptor, was identified as a potential enhancer of syncytiotrophoblast regeneration. Supplementation with recombinant TWEAK in organoids increased the expression of cell proliferation and fusion markers, promoting syncytiotrophoblast formation. The source of TWEAK was found to be macrophages derived from maternal blood monocytes that adhere to sites of syncytiotrophoblast damage in vivo. This in vitro model that allows the exploration of syncytial biology has relevance for important pregnancy disorders including pre-eclampsia, where breaks occur more often, and vertical infections, where maternal monocytes could be a source of transmission.

developmental biology↗

bioRxiv2025

An organoid model of the menstrual cycle reveals the role of the luminal epithelium in regeneration of the human endometrium

Menstruation is an unusual physiological process whereby the human endometrium undergoes cyclical shedding yet scarless regeneration. Despite its pivotal role in reproductive health, the cellular states and interactions that coordinate this process are incompletely defined. Here, we establish an in vitro menstrual cycle (IVMC) protocol using human endometrial organoids that faithfully recapitulates the epithelium across the key phases of the menstrual cycle including differentiation, hormonal withdrawal, breakdown and regeneration. This IVMC protocol enables intricate study of the early phases of the cycle, which remain difficult to access in vivo. Using this system, we define transcriptional transitions in ciliated and non-ciliated epithelial cells during regeneration, revealing immediate stress-responsive states followed by wound-responsive ones that precede proliferation. We demonstrate that, in response to breakdown, organoids acquire a transcriptomic signature resembling the in vivo luminal epithelium in the menstrual and proliferative phases of the cycle. Luminal epithelial cells are crucial for this re-epithelialization and express factors such as WNT7A which we show to be required for long-term epithelial maintenance. Moreover, cell-cell communication analyses identify luminal epithelium as a signaling hub, interacting with endothelial and immune cells via pathways including CXCL8, consistent with promotion of angiogenesis and immune recruitment during the regenerative window. Taken together, our study establishes a physiologically relevant paradigm to dissect epithelial renewal and cell-cell interactions during menstruation with potential to extend towards modelling common and distressing conditions such as menstrual disorders and endometriosis.

cell biology↗

bioRxiv2023

Successful placentation in human pregnancy is regulated by reciprocal interactions between maternal uterine NK cells and fetal placental trophoblast

Fetal growth and development during human pregnancy depends on delivery of adequate maternal oxygen and nutrients to the fetus via the placenta. In humans, the balanced invasion of fetal placental trophoblast cells into the maternal uterine lining, where they interact with uterine natural killer cells (uNK), is thought to be critical for a successful pregnancy but exactly how this influences reproductive outcomes remains undefined. Here, we used our trophoblast organoid model and primary tissue samples to determine how uNK affect placentation. By locating potential interaction axes between primary trophoblast cells and uNK using single cell transcriptomics, and in vitro modelling of these interactions in trophoblast organoids, we identify a uNK-derived cytokine signal that promotes trophoblast differentiation by enhancing epithelial-mesenchymal transition and increasing trophoblast cells at the late stage of the invasive pathway. Moreover, it affects transcriptional programs involved in increasing blood flow, placental access to nutrients, and dampening inflammatory and adaptive immune responses, as well as gene signatures associated with disorders of pregnancy such as pre-eclampsia. Our findings shed new light on how optimal immunological interactions between maternal uNK cells and fetal trophoblast enhance reproductive success.

developmental biology↗

bioRxiv2022

Spatially resolved single-cell multiomics map of human trophoblast differentiation in early pregnancy

The relationship between the human placenta, the extraembryonic organ built by the fetus, and the decidua, the mucosal layer of the uterus, is essential to nurture and protect the fetus during pregnancy. Extravillous trophoblast cells (EVTs) anchor the placenta and infiltrate the decidua, transforming the maternal arteries into high conductance vessels. Defects in trophoblast invasion and arterial transformation established during early pregnancy underlie common pregnancy disorders such as pre-eclampsia. Despite its importance, how EVT invasion is regulated in humans is still unclear due the inaccessibility of the entire pregnant uterus and, until recently, a lack of reliable in vitro models. Here, we have generated a spatially-resolved multiomics single-cell atlas of the entire maternal-fetal interface including the myometrium, allowing us to resolve the full trajectory of trophoblast differentiation. We have used this cellular map to elucidate the main regulatory programmes mediating EVT invasion and show that they are preserved in trophoblast organoids. We define the transcriptomes of the final cell states of trophoblast invasion: placental bed giant cells (fused multinucleated EVTs) and endovascular EVTs (which form plugs inside the maternal arteries). We reconstruct the cell-cell communication events contributing to trophoblast invasion and GC formation, and define the dual role of interstitial EVTs and endovascular EVTs in mediating arterial transformation during early pregnancy. Together, our data provides a comprehensive analysis of postimplantation trophoblast differentiation in humans that can be used as a blueprint to design accurate multilineage placental in vitro models.

genomics↗

bioRxiv2021

Mapping the temporal and spatial dynamics of the human endometrium in vivo and in vitro

The endometrium, the mucosal lining of the uterus, undergoes dynamic changes throughout the menstrual cycle in response to ovarian hormones. We have generated single-cell and spatial reference maps of the human uterus and 3D endometrial organoid cultures. We dissect the signalling pathways that determine cell fate of the epithelial lineages in the lumenal and glandular microenvironments. Our benchmark of the endometrial organoids highlights common pathways regulating the differentiation of secretory and ciliated lineage in vivo and in vitro. We show in vitro that downregulation of WNT or NOTCH pathways increases the differentiation efficiency along the secretory and ciliated lineages, respectively. These mechanistic insights provide a platform for future development of treatments for a range of common endometrial disorders including endometriosis and carcinoma.

genomics↗

bioRxiv2020

BAP1/ASXL complex modulation regulates Epithelial-Mesenchymal Transition during trophoblast differentiation and invasion

Normal function of the placenta depends on the earliest developmental stages when trophoblast cells differentiate and invade into the endometrium to establish the definitive maternal-fetal interface. Previously, we identified the ubiquitously expressed tumour suppressor BRCA1-associated protein 1 (BAP1) as a central factor of a novel molecular node controlling early mouse placentation. However, functional insights into how BAP1 regulates trophoblast biology are still missing. Using CRISPR/Cas9 knockout and overexpression technology, here we demonstrate that the downregulation of BAP1 protein is essential to trigger epithelial-mesenchymal transition (EMT) during trophoblast differentiation associated with a gain of invasiveness. This function, which is conserved in mouse and humans, is dependent on the binding of BAP1 binding to Additional sex comb-like (ASXL1/2/3) proteins to form the Polycomb repressive deubiquitinase (PR-DUB) complex. Our results reveal that the physiological modulation of BAP1 determines the invasive properties of trophoblast, delineating a new role of the BAP1 PR-DUB complex in regulating early placentation.

developmental biology↗

bioRxiv2018

Reconstructing the human first trimester fetal-maternal interface using single cell transcriptomics

During the early weeks of human pregnancy, the fetal placenta implants into the uterine mucosa (decidua) where placental trophoblast cells intermingle and communicate with maternal cells. Here, we profile transcriptomes of [~]50,000 single cells from this unique microenvironment, sampling matched first trimester maternal blood and decidua, and fetal cells from the placenta itself. We define the cellular composition of human decidua, revealing five distinct subsets of decidual fibroblasts with differing growth factors and hormone production profiles, and show that fibroblast states define two distinct decidual layers. Among decidual NK cells, we resolve three subsets, each with a different immunomodulatory and chemokine profile. We develop a repository of ligand-receptor pairs (www.CellPhoneDB.org) and a statistical tool to predict the probability of cell-cell interactions via these pairs, highlighting specific interactions between decidual NK cells and invading fetal extravillous trophoblast cells, maternal immune and stromal cells. Our single cell atlas of the maternal-fetal interface reveals the cellular organization and interactions critical for placentation and reproductive success.

developmental biology↗