Biology subjects

Hoo, R.

Publications and source records attributed to Hoo, R..

6 recordsLinked to original sources

bioRxiv2023

Automatic cell type harmonization and integration across Human Cell Atlas datasets

Harmonizing cell types across the single-cell community and assembling them into a common framework is central to building a standardized Human Cell Atlas. Here we present CellHint, a predictive clustering tree-based tool to resolve cell type differences in annotation resolution and technical biases across datasets. CellHint accurately quantifies cell-cell transcriptomic similarities and places cell types into a relationship graph that hierarchically defines shared and unique cell subtypes. Application to multiple immune datasets recapitulates expert-curated annotations. CellHint also reveals underexplored relationships between healthy and diseased lung cell states in eight diseases. Furthermore, we present a workflow for fast cross-dataset integration guided by harmonized cell types and cell hierarchy, which uncovers underappreciated cell types in adult human hippocampus. Finally, we apply CellHint to 12 tissues from 38 datasets, providing a deeply curated cross-tissue database with [~]3.7 million cells and various machine learning models for automatic cell annotation across human tissues.

bioinformatics↗

bioRxiv2023

Early infection response of the first trimester human placenta at single-cell scale

Placental infections are a major worldwide burden, particularly in developing countries. The placenta is a transient tissue located at the interface between the mother and the fetus. Some pathogens can access the placental barrier resulting in pathological transmission from mother to fetus, which may have a profound impact on the health of the developing fetus. Limited tissue accessibility, critical differences between humans and mice, and, until recently, lack of proper in vitro models, have hampered our understanding of the early placental response to pathogens. Here we use single-cell transcriptomics to describe the placental primary defence mechanisms against three pathogens that are known to cause fetal and maternal complications during pregnancy - Plasmodium falciparum, Listeria monocytogenes and Toxoplasma gondii. We optimise ex vivo placental explants of the first-trimester human placenta and show that trophoblasts (the epithelial-like cells of the placenta), and Hofbauer cells (placental macrophages) orchestrate a coordinated inflammatory response after 24 hours of infection. We show that hormone biosynthesis and transport are downregulated in the trophoblasts, suggesting that protective responses are promoted at the expense of decreasing other critical functions of the placenta, such as the endocrine production and the nourishment of the fetus. In addition, we pinpoint pathogen-specific effects in some placental lineages, including a strong mitochondrial alteration in the Hofbauer cells in response to T. gondii. Finally, we identify adaptive strategies and validate nutrient acquisition employed by the P. falciparum during placental malaria infection. This study provides the first detailed cellular map of the first-trimester placenta upon infection and describes the early events that may lead to fetal and placental disorders if left unchecked.

genomics↗

bioRxiv2022

X-inactivation states of single cell transcriptomes reveal cellular phylogenies in human females

Human females undergo X-inactivation (Xi), whereby one copy of X is randomly inactivated early in development, then propagated through cell division. Because Xi state is inherited, its measurement in populations of cells encodes information about the phylogeny that created them and their relationships to other cells. We present a method, inactiveXX, to determine the Xi state of single cell transcriptomes, and demonstrate its accuracy using cancer and gold standard reference data. We apply inactiveXX to single cell transcriptomes from 190 human females, revealing that Xi in humans likely occurs around the 16 cell blastocyst stage and affects both embryonic and extra-embryonic tissues. We further find significant cell type specific variability in Xi skew, only detectable with cell type specific resolution, with certain cell types exhibiting strong population bottlenecks across tissues and disease state.

genomics↗

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

Selective expression of variant surface antigens enables Plasmodium falciparum to evade immune clearance in vivo

Plasmodium falciparum has developed extensive mechanisms to evade host immune clearance. Currently, most of our understanding is based on in vitro studies of individual parasite variant surface antigens and how this relates to the processes in vivo is not well-understood. Here, we have used a humanized mouse model to identify parasite factors important for in vivo growth. We show that upregulation of the specific PfEMP1, VAR2CSA and the RIFIN PF3D7_1254800 provides the parasite with protection from macrophage phagocytosis and natural killer cell mediated killing. Taken together, these findings reveal new insights on the molecular and cellular mechanisms that coordinate the immune escape process the parasite utilizes in vivo. As immune evasion may be particularly important during the establishment of the blood stage infection when parasite numbers are still relatively small, identification of specific parasite variant surface antigens provides targets for developing more effective vaccines by targeting parasite immune evasion.

microbiology↗