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A complete Sigmodon hispidus genome and dynamic single-cell transcriptomics reveal evolutionarily conserved responses to RSV infection.
The cotton rat (Sigmodon hispidus) has emerged as a preclinical model for human respiratory syncytial virus (RSV) research because of its ability to support effective viral replication and recapitulate disease; however, the mechanisms supporting this evolutionarily conserved phenotype remain unclear. Here, we report both the chromosomal genome and respiratory single-cell transcriptomic atlas of the cotton rat throughout the course of RSV infection. Phylogenetic analysis showed that cotton rats are in different evolutionary branches from common mouse and rat models and exhibit substantial conservation of tissue profiles with humans. The respiratory cell atlas, alveolar cell trajectory, and distribution of potential viral receptors are also similar to those of humans, explaining the superiority of cotton rats as an RSV infection model. The target cells of RSV, including club cells, secretory2 cells, mesothelial cells, and nerve-associated astrocytes, were expanded after infection. We also identified differential transcriptional regulators, specific antiviral proteins, and cytokines that could be translated into potential clinical markers in humans. Candidate host factors were also identified, which will enable the exploration of host-RSV interactions and offer a source of therapeutic targets.
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An integrated transcriptomic cell atlas of human endoderm-derived organoids.
Human pluripotent stem cells and tissue-resident fetal and adult stem cells can generate epithelial tissues of endodermal origin in vitro that recapitulate aspects of developing and adult human physiology. Here, we integrate single-cell transcriptomes from 218 samples covering organoids and other models of diverse endoderm-derived tissues to establish an initial version of a human endoderm-derived organoid cell atlas. The integration includes nearly one million cells across diverse conditions, data sources and protocols. We compare cell types and states between organoid models and harmonize cell annotations through mapping to primary tissue counterparts. Focusing on the intestine and lung, we provide examples of mapping data from new protocols and show how the atlas can be used as a diverse cohort to assess perturbations and disease models. The human endoderm-derived organoid cell atlas makes diverse datasets centrally available and will be valuable to assess fidelity, characterize perturbed and diseased states, and streamline protocol development.
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Identification and validation of RNA-binding protein-related gene signature revealed potential associations with immunosuppression and drug sensitivity in glioma.
BACKGROUND: Glioma is the most common central nervous system tumor in adults, and a considerable part of them are high-degree ones with high malignancy and poor prognosis. At present, the classification and treatment of glioma are mainly based on its histological characteristics, so studies at the molecular level are needed. METHODS: RNA-seq data from The Cancer Genome Atlas (TCGA) datasets (n = 703) and Chinese Glioma Genome Atlas (CGGA) were utilized to find out the differentially expressed RNA-binding proteins (RBPs) between normal cerebral tissue and glioma. A prediction system for the prognosis of glioma patients based on 11 RBPs was established and validated using uni- and multi-variate Cox regression analyses. STITCH and CMap databases were exploited to identify putative drugs and their targets. Single sample gene set enrichment analysis (ssGSEA) was used to calculate scores of specific immune-related gene sets. IC50 of over 20,000 compounds in 60 cancer cell lines was collected from the CellMiner database to test the drug sensitivity prediction value of the RBP-based signature. RESULTS: We established a reliable prediction system for the prognosis of glioma patients based on 11 RBPs including THOC3, LSM11, SARNP, PABPC1L2B, SMN1, BRCA1, ZC3H8, DZIP1L, HEXIM2, LARP4B, and ZC3H12B. These RBPs were primarily associated with ribosome and post-transcriptional regulation. RBP-based risk scores were closely related to immune cells and immune function. We also confirmed the potential of the signature to predict the drug sensitivity of currently approved or evaluated drugs. CONCLUSIONS: Differentially expressed RBPs in glioma can be used as a basis for prognosis prediction, new drugs screening and drug sensitivity prediction. As RBP-based glioma risk scores were associated with immunity, immunotherapy may become an important treatment for glioma in the future.
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Single-cell transcriptomics of the developing lateral geniculate nucleus reveals insights into circuit assembly and refinement.
Coordinated changes in gene expression underlie the early patterning and cell-type specification of the central nervous system. However, much less is known about how such changes contribute to later stages of circuit assembly and refinement. In this study, we employ single-cell RNA sequencing to develop a detailed, whole-transcriptome resource of gene expression across four time points in the developing dorsal lateral geniculate nucleus (LGN), a visual structure in the brain that undergoes a well-characterized program of postnatal circuit development. This approach identifies markers defining the major LGN cell types, including excitatory relay neurons, oligodendrocytes, astrocytes, microglia, and endothelial cells. Most cell types exhibit significant transcriptional changes across development, dynamically expressing genes involved in distinct processes including retinotopic mapping, synaptogenesis, myelination, and synaptic refinement. Our data suggest that genes associated with synapse and circuit development are expressed in a larger proportion of nonneuronal cell types than previously appreciated. Furthermore, we used this single-cell expression atlas to identify the Prkcd-Cre mouse line as a tool for selective manipulation of relay neurons during a late stage of sensory-driven synaptic refinement. This transcriptomic resource provides a cellular map of gene expression across several cell types of the LGN, and offers insight into the molecular mechanisms of circuit development in the postnatal brain.
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Single-cell transcriptomics reveals that human milk feeding shapes neonatal immune cell interleukin signaling pathways in a nonrandomized clinical trial.
BACKGROUND: Several studies have indicated the benefits of human milk feeding to infants however, mechanisms behind positive health outcomes have not been investigated. OBJECTIVES: The study aimed to characterize circulating immune cell subpopulation gene expression in human milk-fed (HMF) compared with cow milk formula-fed (FF) infants using single-cell transcriptomics. METHODS: Peripheral blood mononuclear cells (PBMCs) were isolated from healthy HMF (n = 6), and FF (n = 3) infants who were 3-3.5 mo old and enrolled in a nonrandomized clinical trial. Single-cell RNA sequencing was used to generate a PBMC atlas and evaluate gene expression in immune cell subsets. Differential expression analysis was performed on each cell type independently after clustering the cells by similar marker gene expression using the scGEAToolbox. Differentially expressed genes were subjected to pathway analyses using an online functional enrichment analysis program. RESULTS: The relative abundance (%) of T and B lymphocytes, natural killer (NK) cells, and plasmacytoid dendritic cells were similar, whereas monocytes were higher in FF infants than in HMF infants (22.6 ± 10.7 compared with 8.3 ± 5.6; P = 0.0314). In addition, innate and adaptive immune cells from FF infants exhibited a higher activation state compared with HMF infants. We identified 16 distinct cell subsets from the major immune cell types: 3 monocyte subsets, 4 NK subsets, 2 B cell subsets, and 7 T cell subsets. Transcriptional profiles of each peripheral innate and adaptive immune cell subtype varied between HMF and FF infants. Pathway enrichment analysis of cell-specific transcriptional changes within subsets of major cell types revealed that the interleukin (IL)-4/IL-13 signaling pathways were upregulated in FF infants relative to HMF infants. CONCLUSIONS: These findings suggest that human milk downregulates peripheral immune cell cytokine transcriptional signatures linked to allergic inflammation and infection relative to formula feeding.
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A prenatal skin atlas reveals immune regulation of human skin morphogenesis.
Human prenatal skin is populated by innate immune cells, including macrophages, but whether they act solely in immunity or have additional functions in morphogenesis is unclear. Here we assembled a comprehensive multi-omics reference atlas of prenatal human skin (7-17 post-conception weeks), combining single-cell and spatial transcriptomics data, to characterize the microanatomical tissue niches of the skin. This atlas revealed that crosstalk between non-immune and immune cells underpins the formation of hair follicles, is implicated in scarless wound healing and is crucial for skin angiogenesis. We systematically compared a hair-bearing skin organoid (SkO) model derived from human embryonic stem cells and induced pluripotent stem cells to prenatal and adult skin1. The SkO model closely recapitulated in vivo skin epidermal and dermal cell types during hair follicle development and expression of genes implicated in the pathogenesis of genetic hair and skin disorders. However, the SkO model lacked immune cells and had markedly reduced endothelial cell heterogeneity and quantity. Our in vivo prenatal skin cell atlas indicated that macrophages and macrophage-derived growth factors have a role in driving endothelial development. Indeed, vascular network remodelling was enhanced following transfer of autologous macrophages derived from induced pluripotent stem cells into SkO cultures. Innate immune cells are therefore key players in skin morphogenesis beyond their conventional role in immunity, a function they achieve through crosstalk with non-immune cells.
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A Cellular atlas of the human fallopian tube reveals the metamorphosis of secretory epithelial cells during the menstrual cycle and menopause.
UNLABELLED: The fallopian tube, connecting the uterus with the ovary, is a dynamic organ that undergoes cyclical changes and is the site of several diseases, including serous cancer. Here, we use single-cell technologies to construct a comprehensive cell map of healthy pre-menopausal fallopian tubes, capturing the impact of the menstrual cycle and menopause on different fallopian tube cells at the molecular level. The comparative analysis between pre- and post-menopausal fallopian tubes reveals substantial shifts in cellular abundance and gene expression patterns, highlighting the physiological changes associated with menopause. Further investigations into menstrual cycle phases illuminate distinct molecular states in secretory epithelial cells caused by hormonal fluctuations. The markers we identified characterizing secretory epithelial cells provide a valuable tool for classifying ovarian cancer subtypes. GRAPHICAL SUMMARY: Graphical summary of results. During the proliferative phase (estrogen high ) of the menstrual cycle, SE2 cells (OVGP1 + ) dominate the fallopian tube (FT) epithelium, while SE1 cells (OVGP1 - ) dominate the epithelium during the secretory phase. Though estrogen levels decrease during menopause, SE post-cells (OVGP1 + , CXCL2 + ) make up most of the FT epithelium.
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Mapping gene activity of Arabidopsis root hairs.
BACKGROUND: Quantitative information on gene activity at single cell-type resolution is essential for the understanding of how cells work and interact. Root hairs, or trichoblasts, tubular-shaped outgrowths of specialized cells in the epidermis, represent an ideal model for cell fate acquisition and differentiation in plants. RESULTS: Here, we provide an atlas of gene and protein expression in Arabidopsis root hair cells, generated by paired-end RNA sequencing and LC/MS-MS analysis of protoplasts from plants containing a pEXP7-GFP reporter construct. In total, transcripts of 23,034 genes were detected in root hairs. High-resolution proteome analysis led to the reliable identification of 2,447 proteins, 129 of which were differentially expressed between root hairs and non-root hair tissue. Dissection of pre-mRNA splicing patterns showed that all types of alternative splicing were cell type-dependent, and less complex in EXP7-expressing cells when compared to non-root hair cells. Intron retention was repressed in several transcripts functionally related to root hair morphogenesis, indicative of a cell type-specific control of gene expression by alternative splicing of pre-mRNA. Concordance between mRNA and protein expression was generally high, but in many cases mRNA expression was not predictive for protein abundance. CONCLUSIONS: The integrated analysis shows that gene activity in root hairs is dictated by orchestrated, multilayered regulatory mechanisms that allow for a cell type-specific composition of functional components.
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Single-cell transcriptomic atlas reveals distinct immunological responses between COVID-19 vaccine and natural SARS-CoV-2 infection.
To control the ongoing coronavirus disease-2019 (COVID-19) pandemic, CoronaVac (Sinovac), an inactivated vaccine, has been granted emergency use authorization by many countries. However, the underlying mechanisms of the inactivated COVID-19 vaccine-induced immune response remain unclear, and little is known about its features compared to (Severe acute respiratory syndrome coronavirus 2) SARS-CoV-2 infection. Here, we implemented single-cell RNA sequencing (scRNA-seq) to profile longitudinally collected PBMCs (peripheral blood mononuclear cells) in six individuals immunized with CoronaVac and compared these to the profiles of COVID-19 infected patients from a Single Cell Consortium. Both inactivated vaccines and SARS-CoV-2 infection altered the proportion of different immune cell types, caused B cell activation and differentiation, and induced the expression of genes associated with antibody production in the plasma. The inactivated vaccine and SARS-COV-2 infection also caused alterations in peripheral immune activity such as interferon response, inflammatory cytokine expression, innate immune cell apoptosis and migration, effector T cell exhaustion and cytotoxicity, however, the magnitude of change was greater in COVID-19 patients, especially those with severe disease, than in immunized individuals. Further analyses revealed a distinct peripheral immune cell phenotype associated with CoronaVac immunization (HLA class II upregulation and IL21R upregulation in naïve B cells) versus SARS-CoV-2 infection (HLA class II downregulation and IL21R downregulation in naïve B cells from severe disease individuals). There were also differences in the expression of important genes associated with proinflammatory cytokines and thrombosis. In conclusion, this study provides a single-cell atlas of the systemic immune response to CoronaVac immunization and revealed distinct immune responses between inactivated vaccines and SARS-CoV-2 infection.
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Multi-omic profiling of follicular lymphoma reveals changes in tissue architecture and enhanced stromal remodeling in high-risk patients.
Follicular lymphoma (FL) is a generally incurable malignancy that evolves from developmentally blocked germinal center (GC) B cells. To promote survival and immune escape, tumor B cells undergo significant genetic changes and extensively remodel the lymphoid microenvironment. Dynamic interactions between tumor B cells and the tumor microenvironment (TME) are hypothesized to contribute to the broad spectrum of clinical behaviors observed among FL patients. Despite the urgent need, existing clinical tools do not reliably predict disease behavior. Using a multi-modal strategy, we examined cell-intrinsic and -extrinsic factors governing progression and therapeutic outcomes in FL patients enrolled onto a prospective clinical trial. By leveraging the strengths of each platform, we identify several tumor-specific features and microenvironmental patterns enriched in individuals who experience early relapse, the most high-risk FL patients. These features include stromal desmoplasia and changes to the follicular growth pattern present 20 months before first progression and first relapse.