Biology subjects

Winn, V. D.

Publications and source records attributed to Winn, V. D..

7 recordsLinked to original sources

bioRxiv2026

Spatial Logic and Evolutionary Innovation in Human Placentation

Human pregnancy unfolds in a unique mosaic tissue context. Embryonic/fetal placental and maternal uterine cells (decidua basalis) coalesce, forming the basal plate where immune tolerance is coordinated and the utero-placental circulation is initiated. The remaining approximately 70% of the maternal-fetal interface is comprised of the chorionic membranes, an epithelial-like layer of placental cells that lies adjacent to but does not coalesce with the overlying decidua capsularis and parietalis. It is unknown how these two regions of the maternal-fetal interface, which are comprised of seemingly similar cell types, diverge anatomically and functionally. Likewise, it is unknown whether the molecular characteristics of the maternal-fetal interface vary across human populations, potentially contributing to population disparities in pregnancy complications. Here, we generated large-scale paired single-nucleus RNA-seq and chromatin-accessibility profiles of the basal plate and chorionic membranes-associated decidual compartments from diverse-ancestry pregnancies, integrated with spatial transcriptomics and multiplexed protein imaging. We show that the two interfaces share a conserved cytotrophoblast differentiation hierarchy, which is deployed differently resulting in the observed distinct architectures. In the chorionic membranes, progenitor, early, and mature extravillous cytotrophoblast (EVT) states form an epithelial-like laminar shell. In the basal plate, this hierarchy is elaborated upon to enable deep placentation: EVTs that arise early in pregnancy invade the farthest into the uterus, while mature EVTs accumulate superficially to sculpt the local maternal immune microenvironment. Comparative analysis identified DSC4, a decidual stromal cell subtype, as an anti-invasive barrier that is densely enriched adjacent to the chorionic membranes but substantially reduced at the basal plate. Population-resolved analysis further identified the DSC4 marker NID2, which encodes the basement-membrane glycoprotein nidogen-2, as an ancestry-associated rheostat of EVT invasion. A specific NID2 promoter haplotype arose on the modern-human lineage, is absent from available archaic-human genomes, and shows evidence of positive selection in Eurasian populations. This haplotype is associated with reduced local chromatin accessibility and lower NID2 expression in DSC4 cells. Consistent with this genetic association, extracellular NID2 directly suppressed the invasion of primary human cytotrophoblasts in vitro. Together, these findings reveal how a shared developmental program is spatially reconfigured across distinct regions of the maternal-fetal interface and identify a recent modern-human regulatory innovation that modulates maternal decidual restraint of fetal trophoblast invasion across populations.

genomics↗

bioRxiv2025

Systemic immune dysregulation in hypertensive disorders of pregnancy persists years after delivery

BackgroundHypertensive disorders of pregnancy (HDP), including preeclampsia and gestational hypertension, are associated with an increased risk of cardiovascular disease (CVD) later in life. Mechanisms that link HDP to CVD, however, remain unclear. MethodsWe used a high-dimensional single-cell mass cytometry approach to profile the distribution and functional responses of maternal immune cells in three separate groups of HDP cases and normotensive controls, sampled antepartum, postpartum, and several years postpartum (midlife). We used multivariable sparse modeling to distinguish HDP cases from controls. ResultsWe accurately distinguished HDP cases from controls at all three study timepoints, with area under the receiver operator characteristic (AUROC) curve values of 0.814 for the antepartum group, 0.757 for the postpartum group, and 0.692 for the midlife group. Distinct immune signatures for each model underscore the dynamic dysregulation of the immune system throughout life. In addition, we identified a persistent immune dysregulation signal among HDP cases at all three timepoints, characterized by increased B cell frequency and decreased pSTAT3 response upon cytokine stimulation in classical monocytes. ConclusionsPersistent immune dysregulation among women with a history of an HDP may contribute to elevated long-term risk of CVD development.

immunology↗

bioRxiv2024

A Multiomics, Spatiotemporal, and Single Cell Atlas for Mapping Cell-Type-Specific Dysregulation at the Maternal-Fetal Interface

The placenta, the first organ to functionally mature, undergoes disordered development in many pregnancy complications. Molecular investigations have been hampered by the extreme cellular heterogeneity of the placenta, and this complexity is further exaggerated at the maternal-fetal interface where maternal and fetal cells co-mingle. We generated the paired single nucleus epigenomes and transcriptome for each of [~]200,000 cells at the human maternal-fetal interface from early pregnancy to term. These data identified cell-type-specific transcriptional regulatory programs and uncovered key transcription factors driving the lineage differentiation of placental cytotrophoblasts. Integrating spatial single cell proteomics profiling, we localized the observed cell types in situ, and characterized the dynamic stages and distinct features of endothelial cells of maternal spiral arteries remodeled by extravillous cytotrophoblasts. Integrative analyses of the single cell data across gestation enabled fine-mapping of the developmental trajectories of cytotrophoblasts and decidual stromal cells, and defining the signature molecular profiles of known and novel cell (sub)types. To demonstrate clinical value, we integrated the reference single cell data with large-scale population genomes from pregnancy complications and identified the most vulnerable maternal and fetal cell types in preeclampsia, preterm birth, and miscarriage. This study presents the most comprehensive placental and decidual single cell resource across gestation to date, reveals new insights into the drivers of normal human placentation, and uncovers the cellular basis of dysfunction associated with common pregnancy complications.

genomics↗

bioRxiv2022

Single cell transcriptomics of human prenatal anterior foregut-derived organs identifies distinct developmental signatures directing commitment and specialization of the thymic epithelial stroma

The thymus instructs T cell immunity and central tolerance, yet its therapeutic potential remains untapped. The quest to regenerate thymic function for clinical application is lagging while the signals that drive thymic epithelial cell differentiation remain incompletely understood. Here, we elucidate pathways instructing commitment and specialization of the human thymic epithelial stroma through complementary single cell transcriptomic approaches. First, we identify gene regulatory networks that define fetal thymic epithelium in the thus far unexplored context of other anterior foregut-derived organs; then, we characterize lineage trajectories within the thymic epithelial compartment across embryonic, fetal, and early postnatal stages. Activation of interferon response gene regulatory networks distinguished epithelial cells of the thymus from those of all other anterior foregut-derived organs. Interferon signals were processed differentially within thymic cortical and medullary lineages, reflected in distinct NF{kappa}B and IRF signatures, respectively. Our study reveals novel, translatable insights into the developmental programs underlying thymic epithelial cell differentiation that may advance the field of regenerative cell therapies. SUMMARYSingle cell transcriptomics of anterior foregut-derived organs identifies pathways governing thymic epithelial commitment and specialization.

developmental biology↗

bioRxiv2021

Coronary blood vessels from distinct origins converge to equivalent states during mouse and human development

Most cell fate trajectories during development follow a diverging, tree-like branching pattern, but the opposite can occur when distinct progenitors contribute to the same cell type. During this convergent differentiation, it is unknown if cells "remember" their origins transcriptionally or whether this influences cell behavior. Most coronary blood vessels of the heart develop from two different progenitor sources--the endocardium (Endo) and sinus venosus (SV)--but whether transcriptional or functional differences related to origin are retained is unknown. We addressed this by combining lineage tracing with single-cell RNA sequencing (scRNAseq) in embryonic and adult mouse hearts. Shortly after coronary development begins, capillary ECs transcriptionally segregated into two states that retained progenitor-specific gene expression. Later in development, when the coronary vasculature is well-established but still remodeling, capillary Ecs again segregated into two populations, but transcriptional differences were primarily related to tissue localization rather than lineage. Specifically, ECs in the heart septum expressed genes indicative of increased local hypoxia and decreased blood flow. Adult capillary ECs were more homogeneous with respect to both lineage and location. In agreement, SV- and Endo-derived ECs in adult hearts displayed similar responses to injury. Finally, scRNAseq of developing human coronary vessels indicated that the human heart followed similar principles. Thus, over the course of development, transcriptional heterogeneity in coronary ECs is first influenced by lineage, then by location, until heterogeneity declines in the homeostatic adult heart. These results highlight the plasticity of ECs during development, and the validity of the mouse as a model for human coronary development.

developmental biology↗

bioRxiv2020

Endocardial/endothelial angiocrines regulate cardiomyocyte development and maturation and induce features of ventricular non-compaction

Non-compaction cardiomyopathy is a devastating genetic disease caused by insufficient consolidation of ventricular wall muscle that can result in inadequate cardiac performance. Despite being the third most common cardiomyopathy, the mechanisms underlying the disease, including the cell types involved, are poorly understood. We have previously shown that endothelial cell-specific deletion of the chromatin remodeler gene Ino80 results in defective coronary vessel development that leads to ventricular noncompaction in embryonic mouse hearts. Here, we used single-cell RNA-sequencing to characterize endothelial and endocardial defects in Ino80-deficient hearts. We observed a pathological endocardial cell population in the non-compacted hearts, and identified multiple dysregulated angiocrine factors that dramatically affected cardiomyocyte behavior. We identified Col15A1 as a coronary vessel-secreted angiocrine factor, downregulated by Ino80-deficiency, that functioned to promote cardiomyocyte proliferation. Furthermore, mutant endocardial and endothelial cells (ECs) upregulated expression of secreted factors, such as Tgfbi, Igfbp3, Isg15, and Adm, which decreased cardiomyocyte proliferation and increased maturation. These findings support a model where coronary ECs normally promote myocardial compaction through secreted factors, but that endocardial and ECs can secrete factors that contribute to non-compaction under pathological conditions.

developmental biology↗

bioRxiv2018

Changes in pregnancy-related serum biomarkers early in gestation are associated with later development of preeclampsia

BackgroundPlacental protein expression plays a crucial biological role during normal and complicated pregnancies. We hypothesized that: (1) circulating pregnancy-associated, placenta-related protein levels throughout gestation reflect the uncomplicated, full-term temporal progression of human gestation, and effectively estimates gestational ages (GAs); (2) pregnancies with underlying placental pathology, such as preeclampsia (PE), are associated with disruptions in this GA estimation in early gestation; (3) malfunctions of this GA estimation can be employed to identify impending PE. In addition, to explore the underlying biology and PE etiology, we set to compare protein gestational patterns of human and mouse, using pregnant heme oxygenase-1 (HO-1) heterozygote (Het) mice, a mouse model reflecting PE-like symptoms.\n\nMethodsSerum levels of circulating placenta-related proteins - leptin (LEP), chorionic somatomammotropin hormone like 1 (CSHL1), elabela (ELA), activin A, soluble fms-like tyrosine kinase 1 (sFlt-1), and placental growth factor (PlGF)- were quantified by ELISA in blood serially collected throughout human pregnancies (20 normal subjects with 66 samples, and 20 PE subjects with 61 samples). Linear multivariate analysis of the targeted serological protein levels was performed to estimate the normal GA. Logarithmic transformed mean-squared errors of GA estimations were used to identify impending PE. Then the human gestational protein patterns were compared to those in the pregnant HO-1 mice.\n\nResultsAn elastic net (EN)-based gestational dating model was developed (R2 = 0.76) and validated (R2 = 0.61) using the serum levels of the 6 proteins at various GAs from women with normal uncomplicated pregnancies (n = 10 for training and n = 6 for validation). In pregnancies complicated by PE (n = 14), the EN model was not (R2 = -0.17) associated with GA at sampling in PE. Statistically significant deviations from the normal GA EN model estimations were observed in PE-associated pregnancies between GAs of 16-30 weeks (P = 0.01). The EN model developed with 5 proteins (ELA excluded due to the lack of robustness of the mouse ELA essay) performed similarly on normal human (R2 = 0.68) and WT mouse (R2 = 0.85) pregnancies. Disruptions of this model were observed in both human PE-associated (human: R2 = 0.27) and mouse HO-1 Het (mouse: R2 = 0.30) pregnancies. LEP out performed sFlt-1 and PlGF in differentiating impending PE at early human and late mouse gestations.\n\nConclusionsAs revealed in both human and mouse GA EN analyses, temporal serological placenta-related protein patterns are tightly regulated throughout normal human pregnancies and can be significantly disrupted in pathologic PE states. LEP changes earlier during gestation than the well-established late GA PE biomarkers (sFlt-1 and PlGF). Our HO-1 Het mouse analysis provides direct evidence of the causative action of HO-1 deficiency in LEP upregulation in a PE-like murine model. Therefore, longitudinal analyses of pregnancy-related protein patterns in sera, may not only help in the exploration of underlying PE pathophysiology but also provide better clinical utility in PE assessment.

molecular biology↗