Biology subjects

McGovern, N.

Publications and source records attributed to McGovern, N..

9 recordsLinked to original sources

bioRxiv2026

A unified developmental framework of the human placenta in its uterine environment in vivo and in vitro

Despite advances in single-cell profiling of the human placenta, the genetic programs governing its physiological remodeling throughout gestation remain incompletely understood; this limits the interpretation of trophoblast organoid models. Here, we reconstruct the human placenta in its uterine environment across gestation by integrating public single-cell data into a unified developmental framework developed through a specialized computational strategy. We resolve 100 cell subtypes, expanding the known cellular repertoire and uncovering extensive gestational dynamics. In the placental mesenchymal core, we define a stromal-vascular niche comprising previously unresolved fibroblast heterogeneity and vascular hierarchies (capillary, arterial, and venous). This niche undergoes reprogramming from early angiogenesis to vascular maturation at term and engages signaling programs that support villous homeostasis. Within the trophoblast lineage, we uncover differential progenitor dynamics: bipotent cytotrophoblast (CTB) progenitors persist throughout gestation, whereas extravillous trophoblast (EVT)-biased progenitors are almost absent at term, coinciding with differentiation into specialized states. Benchmarking trophoblast organoids against this reference shows distinct regional identities and developmental biases. Tissue-derived models recapitulate villous CTB whilst trophoblast stem cell-derived organoids resemble smooth chorion CTB; all models capture early gestational syncytiotrophoblast and progressive EVT differentiation. Together, this work provides a resource for understanding placental remodeling across gestation and guiding the use of in vitro models.

cell biology↗

bioRxiv2026

Circulating pre-osteoclasts are primed for osteoclast fate and synovial tissue homing in psoriatic arthritis.

Psoriatic arthritis (PsA) is a complex immune-mediated inflammatory disease with heterogenous clinical features. Osteoclasts have a unique ability to destroy bone, playing key roles in both healthy bone turnover and pathological erosions in arthritis. They are believed to arise from monocytic precursors migrating to inflamed synovial tissue, though the identity of this precursor in humans has remained elusive. Here, we sought to determine whether monocytes home to psoriatic joints and their phenotype. We find that monocytes are recruited to inflamed joints in PsA but not uninvolved or healthy joints, and identify a pre-osteoclast (preOC) cell state derived from classical monocytes. PreOC are transcriptionally distinct from classical monocytes, are enriched for NFACT1, the master regulator of osteoclastogenesis, and form multinucleated osteoclasts in vitro without exogenous RANKL. They are expanded in the circulation of donors with active treatment naive PsA, compared to both healthy controls and those with cutaneous psoriasis only. Finally, using a customised spatial transcriptomics workflow, we identified these cells within human synovial tissue, and radiolabelling confirmed their recruitment from the circulation. These findings highlight the role of systemic immune priming in macrophage pathophysiology.

immunology↗

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↗

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

Human HLFneg placental erythro-myeloid progenitors give rise to HLA Class IIneg Hofbauer cells

The earliest macrophages are generated during embryonic development from erythro-myeloid progenitors (EMPs) via primitive haematopoiesis. This process is still poorly understood in humans but is generally thought to be spatially restricted to the yolk sac. Human fetal placental macrophages, Hofbauer cells (HBC), arise during the primitive haematopoietic wave, yet are unlikely to be yolk sac derived as they appear prior to placental vascularisation. Here we identify a population of placental erythro-myeloid progenitors (PEMPs) in the early human placenta that give rise to HBC. PEMP are fetal CD34+CD43+ progenitors found exclusively at early gestational timepoints. Transcriptomic analyses reveal that PEMP have a unique transcriptome with some conserved features of primitive yolk sac EMPs, including the lack of HLF expression. Using in vitro single-cell culture experiments we show that PEMP generate HBC-like cells which lack HLA-DR expression, a conserved feature of all fetal primitive macrophages in humans. These findings indicate that HBC are derived locally from PEMP and demonstrate that human primitive haematopoiesis is not restricted to the yolk sac, occurring also in the placenta.

immunology↗

bioRxiv2021

SARS-CoV-2 spike downregulates tetherin to enhance viral spread

The antiviral restriction factor, tetherin, blocks the release of several different families of enveloped viruses, including the Coronaviridae. Tetherin is an interferon-induced protein that forms parallel homodimers between the host cell and viral particles, linking viruses to the surface of infected cells and inhibiting their release. We demonstrated that SARS-CoV-2 infection causes tetherin downregulation, and that tetherin depletion from cells enhances SARS-CoV-2 viral titres. We investigated the potential viral proteins involved in abrogating tetherin function and found that SARS- CoV-2 ORF3a reduces tetherin localisation within biosynthetic organelles via reduced retrograde recycling and increases tetherin localisation to late endocytic organelles. By removing tetherin from the Coronavirus budding compartments, ORF3a enhances virus release. We also found expression of Spike protein caused a reduction in cellular tetherin levels. Our results confirm that tetherin acts as a host restriction factor for SARS-CoV-2 and highlight the multiple distinct mechanisms by which SARS-CoV-2 subverts tetherin function. Author SummarySince it was identified in 2019, SARS-CoV-2 has displayed voracious transmissibility which has resulted in rapid spread of the virus and a global pandemic. SARS-CoV-2 is a member of the Coronaviridae family whose members are encapsulated by a host-derived protective membrane shell. Whilst the viral envelope may provide protection for the virus, it also provides an opportunity for the host cell to restrict the virus and stop it spreading. The anti-viral restriction factor, tetherin, acts to crosslink viruses to the surface of infected cells and prevent their spread to uninfected cells. Here, we demonstrate that SARS-CoV-2 undergoes viral restriction by tetherin, and that SARS-CoV-2 moves tetherin away from the site of Coronavirus budding to enhance its ability to escape and infect naive cells. Tetherin depletion from cells enhanced SARS-CoV-2 viral release and increased propagation of the virus. We found that the SARS-CoV-2 protein, ORF3a, redirects tetherin away from the biosynthetic organelles where tetherin would become incorporated to newly forming SARS-CoV-2 virions - and instead relocalises tetherin to late endocytic organelles. We also found that SARS-CoV-2 Spike downregulates tetherin. These two mechanisms, in addition to the well described antagonism of interferon and subsequent ISGs highlight the multiple mechanisms by which SARS-CoV-2 abrogates tetherin function. Our study provides new insights into how SARS-CoV-2 subverts human antiviral responses and escapes from infected cells.

cell biology↗

bioRxiv2020

Phenotypic and functional characterisation of first trimester human placental macrophages, Hofbauer cells.

Hofbauer cells (HBC) are a population of macrophages found in high abundance within the stroma of the first trimester human placenta. HBC are the only fetal immune cell population within the stroma of healthy placenta. However, the functional properties of these cells are poorly described. Aligning with their predicted origin via primitive haematopoiesis, we find that HBC are transcriptionally similar to yolk sac macrophages. Phenotypically, HBC can be identified as HLA-DR-FOLR2+ macrophages. We identify a number of factors HBC secrete (including IL-8 and MMP-9) that could affect placental angiogenesis and remodelling. We determine that HBC have the capacity to play a defensive role, where they are responsive to Toll-like receptor stimulation and are microbicidal. Finally, we also identify a population of placenta-associated maternal macrophages (PAMM1a) that adhere to the placental surface and express factors, such as fibronectin, that may aid in repair. SummaryUsing transcriptomic and proteomic data, Thomas, J. et al, analyse human first trimester placental macrophages and delineate markers that identify them. They also reveal that Hofbauer cells have microbicidal capacity, providing the fetus with an additional layer of protection from certain microbes. One sentence summaryHofbauer cells are primitive placental macrophages with a unique phenotype and role in fetal defence. Non-standard abbreviationPlacental associated maternal monocytes/macrophages, PAMM.

immunology↗

bioRxiv2019

Trimester-specific Zika virus infection affects placental responses in women

Zika virus (ZIKV) infection during pregnancy is associated with neurologic birth defects, but the effects on placental development are unclear. Full-term placentas from three women, each infected with ZIKV during specific pregnancy trimesters, were harvested for anatomic, immunologic and transcriptomic analysis. In this study, each woman exhibited a unique immune response, but they collectively diverged from healthy controls with raised IL-1RA, IP-10, EGF and RANTES expression, and neutrophil numbers during the acute infection phase. Although ZIKV NS3 antigens co-localized to placental Hofbauer cells, the placentas showed no anatomical defects. Transcriptomic analysis of samples from the placentas revealed that infection during trimester 1 caused a disparate cellular response centered on differential eIF2 signaling, mitochondrial dysfunction and oxidative phosphorylation. These findings should translate to improve clinical prenatal screening procedures for virus-infected pregnant patients.

immunology↗

bioRxiv2017

Cellular reprogramming of human monocytes is regulated by time-dependent IL4 signalling and NCOR2

The clinical and therapeutic value of human in vitro generated monocyte-derived dendritic cell (moDC) and macrophages is well established. However, in line with recent findings regarding myeloid cell ontogeny and due to our limited understanding of their physiological counterparts, transcriptional regulation and heterogeneity, the full potential of these important cellular systems is still underestimated.\n\nIn this study, we use cutting edge high-dimensional analysis methods to better understand the transcriptional organization, phenotypic heterogeneity and functional differences between human ex vivo isolated and in vitro generated mononuclear phagocytes with the aim to better realize their full potential in the clinic.\n\nWe demonstrate that human monocytes activated by MCSF or GMCSF most closely resemble inflammatory macrophages identified in vivo, while IL4 signalling in the presence of GMCSF generates moDCs resembling inflammatory DCs in vivo, but not steady state cDC1 or cDC2. Moreover, these reprogramming regimes lead to activated monocytes that present with profoundly different transcriptomic, metabolic, phenotypic and functional profiles. Furthermore, we demonstrate that CD14+ monocytes are integrating multiple exogenous activation signals such as GMCSF and IL4 in a combinatorial and temporal fashion, resulting in a high-dimensional cellular continuum of reprogrammed monocytes dependent on the mode and timing of cytokine exposure. Utilizing nanostraw-based knockdown technology, we demonstrate that the IL4-dependent generation of moDCs relies on the induction, nuclear localization and function of the transcriptional regulator NCOR2.\n\nFinally, we unravel unappreciated heterogeneity within the clinically moDCs population and propose a novel high-dimensional phenotyping strategy to better tailor clinical quality control strategies for patient need and culture conditions to enhance therapeutic outcome.

immunology↗