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The Transcriptional Cell Atlas of Testis Development in Sheep at Pre-Sexual Maturity.
Sheep testes undergo a dramatic rate of development with structural changes during pre-sexual maturity, including the proliferation and maturation of somatic niche cells and the initiation of spermatogenesis. To explore this complex process, 12,843 testicular cells from three males at pre-sexual maturity (three-month-old) were sequenced using the 10× Genomics ChromiumTM single-cell RNA-seq (scRNA-seq) technology. Nine testicular somatic cell types (Sertoli cells, myoid cells, monocytes, macrophages, Leydig cells, dendritic cells, endothelial cells, smooth muscle cells, and leukocytes) and an unknown cell cluster were observed. In particular, five male germ cell types (including two types of undifferentiated spermatogonia (Apale and Adark), primary spermatocytes, secondary spermatocytes, and sperm cells) were identified. Interestingly, Apale and Adark were found to be two distinct states of undifferentiated spermatogonia. Further analysis identified specific marker genes, including UCHL1, DDX4, SOHLH1, KITLG, and PCNA, in the germ cells at different states of differentiation. The study revealed significant changes in germline stem cells at pre-sexual maturation, paving the way to explore the candidate factors and pathways for the regulation of germ and somatic cells, and to provide us with opportunities for the establishment of livestock stem cell breeding programs.
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Cell Atlas of The Human Fovea and Peripheral Retina.
Most irreversible blindness results from retinal disease. To advance our understanding of the etiology of blinding diseases, we used single-cell RNA-sequencing (scRNA-seq) to analyze the transcriptomes of ~85,000 cells from the fovea and peripheral retina of seven adult human donors. Utilizing computational methods, we identified 58 cell types within 6 classes: photoreceptor, horizontal, bipolar, amacrine, retinal ganglion and non-neuronal cells. Nearly all types are shared between the two retinal regions, but there are notable differences in gene expression and proportions between foveal and peripheral cohorts of shared types. We then used the human retinal atlas to map expression of 636 genes implicated as causes of or risk factors for blinding diseases. Many are expressed in striking cell class-, type-, or region-specific patterns. Finally, we compared gene expression signatures of cell types between human and the cynomolgus macaque monkey, Macaca fascicularis. We show that over 90% of human types correspond transcriptomically to those previously identified in macaque, and that expression of disease-related genes is largely conserved between the two species. These results validate the use of the macaque for modeling blinding disease, and provide a foundation for investigating molecular mechanisms underlying visual processing.
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A single-cell transcriptomic atlas of the periventricular proliferative zone in the late gestation fetal brain in the pigtail macaque.
BACKGROUND: The fetal brain undergoes rapid changes in late gestation, when waves of neurogenesis and gliogenesis shape cortical circuitry. The periventricular proliferative region and adjacent white matter are enriched in neuroprogenitor cells, newborn neurons, and interneurons, which is challenging to study in the late gestation human fetal brain. The nonhuman primate (NHP) provides a powerful translational model to overcome this limitation, given its close similarity to human neurodevelopmental trajectories. The study objective was to construct a single-cell RNA-Seq (scRNA-Seq) atlas of the late-gestation fetal brain of the pigtail macaque (Macaca nemestrina), focused on the periventricular proliferative zone. METHODS: A sample of the lateral ventricular wall, subventricular zone, and overlying white/gray matter was dissociated into single cells and processed through the 10X Genomics pipeline, followed by SoupX removal of ambient RNA, and Seurat's pipeline to aggregate, cluster and annotate single-cell populations. Monocle3 was used to determine pseudotime and map lineage progression. RESULTS: This analysis captured diverse populations of neuroprogenitors, newborn neurons, developing lineages of excitatory and inhibitory neurons, oligodendrocyte and astrocyte lineages, and resident immune and endothelial cells. CONCLUSIONS: Single-cell populations from the third-trimester nonhuman primate fetal brain are highly similar to those in the human fetus. This late-gestation single-cell atlas of the periventricular proliferative zone provides a unique reference for progenitor, neuronal, glial, vascular, and immune cell states during a critical window of primate neurodevelopment, enabling mechanistic interrogation of how inflammatory, infectious, or hypoxic insults disrupt vulnerable neurogenic niches.
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High NLRC5 Expression Is Associated with an Immunosuppressive Tumor Microenvironment and Poor Prognosis in Esophageal Squamous Cell Carcinoma.
Background: Immunotherapy efficacy in esophageal squamous cell carcinoma (ESCC) is often limited by an immunosuppressive tumor microenvironment (TME). NLRC5, a key regulator of MHC-I antigen presentation, exhibits context-dependent roles in tumor immunity; however, its function in ESCC remains unclear. This study aimed to systematically investigate the expression pattern, prognostic value, and immunological role of NLRC5 in ESCC. Methods: An integrated analysis of bulk RNA sequencing and single-cell RNA sequencing (scRNA-seq) data was performed using multiple cohorts, including The Cancer Genome Atlas, Gene Expression Omnibus, and an in-house ESCC cohort. Differential expression, survival analysis, immune infiltration estimation, and functional enrichment analyses were conducted to elucidate the role of NLRC5 in the tumor microenvironment. Results: NLRC5 was significantly upregulated in ESCC and its high expression independently predicted poor patient survival. Although NLRC5 expression was associated with increased CD8+ T cell infiltration, it was paradoxically accompanied by features of T-cell exhaustion and elevated expression of multiple immune checkpoints. Moreover, NLRC5-high tumors were enriched in transcriptional programs related to PANoptosis, indicating an additional immunosuppressive mechanism within the TME. Conclusions: NLRC5 is not only a prognostic biomarker but also a key modulator of an immune-active yet functionally suppressed tumor microenvironment in ESCC. These findings highlight NLRC5 as a potential therapeutic target for restoring effective antitumor immunity.
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Universal prediction of cell-cycle position using transfer learning.
BACKGROUND: The cell cycle is a highly conserved, continuous process which controls faithful replication and division of cells. Single-cell technologies have enabled increasingly precise measurements of the cell cycle both as a biological process of interest and as a possible confounding factor. Despite its importance and conservation, there is no universally applicable approach to infer position in the cell cycle with high-resolution from single-cell RNA-seq data. RESULTS: Here, we present tricycle, an R/Bioconductor package, to address this challenge by leveraging key features of the biology of the cell cycle, the mathematical properties of principal component analysis of periodic functions, and the use of transfer learning. We estimate a cell-cycle embedding using a fixed reference dataset and project new data into this reference embedding, an approach that overcomes key limitations of learning a dataset-dependent embedding. Tricycle then predicts a cell-specific position in the cell cycle based on the data projection. The accuracy of tricycle compares favorably to gold-standard experimental assays, which generally require specialized measurements in specifically constructed in vitro systems. Using internal controls which are available for any dataset, we show that tricycle predictions generalize to datasets with multiple cell types, across tissues, species, and even sequencing assays. CONCLUSIONS: Tricycle generalizes across datasets and is highly scalable and applicable to atlas-level single-cell RNA-seq data.
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Rhaponticin inhibits the proliferation, migration, and invasion of head and neck squamous cell carcinoma (HNSCC) cells through modulation of the IL6/STAT3 signaling pathway.
BACKGROUND: Rhaponticin, a bioactive compound derived from rhubarb, has been demonstrated anti-tumor effects in various types of cancer. However, its impact on HNSCC remains unexplored. This study aims to investigate the specific molecular mechanisms by which Rhaponticin inhibits the invasion and metastasis of HNSCC cells. METHOD: The potential target genes that rhaponticin acts on in HNSCC were identified using online databases. The mechanisms by which rhaponticin influences the occurrence and progression of HNSCC were investigated through network pharmacology, molecular docking, bioinformatics analysis, and cellular experiments. RESULT: Using network pharmacology, we identified 40 hub genes from the collected gene set. Subsequently, by analyzing The Cancer Genome Atlas (TCGA) data with four machine learning algorithms, we identified IL-6 as a potential target associated with the occurrence and progression of HNSCC. Based on the average expression level of IL-6, we classified the samples into high-expression and low-expression groups and conducted survival analysis. Our results indicated that IL-6 expression was significantly correlated with patient survival. Gene Set Enrichment Analysis (GSEA) revealed that Rhaponticin might influence HNSCC via the IL6/STAT3 signaling pathway. Using the CIBERSORT algorithm, we assessed the differences in infiltration levels of 22 immune cell types between the high and low IL-6 expression groups. Our findings suggest that multiple immune cells may be involved in the pathogenesis of HNSCC. Additionally, we analyzed single-cell RNA sequencing (scRNA-seq) data from the GEO database to compare IL6 expression levels in tumor and normal tissues and evaluated its prognostic impact using Receiver Operating Characteristic (ROC) curve analysis. Molecular docking studies demonstrated that Rhaponticin binds stably to IL6. In the experimental section, we used two HNSCC cell lines (CAL 27 and SCC-9) to investigate the effects of Rhaponticin. Our results showed that Rhaponticin effectively inhibited cell proliferation, invasion, and migration, and reduced the expression of proteins in the IL6/STAT3 signaling pathway. CONCLUSION: Rhaponticin shows promise in treating HNSCC by inhibiting the IL6/STAT3 signaling pathway.
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Human Single-cell Atlas Analysis Reveals Heterogeneous Endothelial Signaling.
Endothelial cells (ECs) play complex roles across tissues and vessel types. Yet, systematic investigations of EC heterogeneity in the combined context of vessel type and tissue microenvironment are still largely lacking. We integrated over three million single cells from single-cell RNA-seq datasets in 15 human tissues. We found that ECs in some tissues (e.g., heart and kidney) exhibited greater tissue specificity, whereas others showed greater vessel specificity. We developed a computational pipeline to analyze cell-cell communications (CCC) mediated by metabolites or proteins to explore microenvironmental regulation. Interestingly, our results showed that CCC events involving ECs varied vastly across tissues, highlighting tissue-specific EC interactions. Using topic modeling, we identified CCC patterns, termed CCC topics, representing metabolite- and protein-mediated interactions between ECs and other tissue-resident cells. Most CCC topics showed high tissue specificity, potentially explaining the microenvironmental regulation of EC heterogeneity. The work systematically investigates EC heterogeneity and provides insights into its regulation across diverse tissue microenvironments. The script to reproduce all analyses in this study is available at https://github.com/zhuzimoo/EC_project.
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Spatial and functional dissection of cancer-associated fibroblasts-mediated immune modulation in H. pylori-associated gastric cancer.
BACKGROUND: Cancer-associated fibroblasts (CAFs) are key regulators of the tumor microenvironment, yet their spatial organization and immunomodulatory functions in H. pylori-associated gastric cancer (GC) remain incompletely understood. METHODS: We profiled formalin-fixed paraffin-embedded (FFPE) tumors from 71 GC patients using spatial transcriptomics and integrated single-cell RNA-seq from three independent cohorts (China, USA, and Singapore). CAF-immune cell colocalization was quantified by neighborhood enrichment and aggregation index score. Ligand-receptor inference and trajectory analysis resolved CAF signaling and state transitions. To delineate post-transcriptional control, ARE-motif scanning and expression correlations were combined with laser-assisted crosslinking and immunoprecipitation sequencing (LACE-seq) to nominate ZFP36 targets. Immune contexture and prognostic associations were evaluated using CIBERSORT-ABS and Kaplan-Meier analyses in The Cancer Genome Atlas (TCGA) and Asian Cancer Research Group (ACRG) cohorts. RESULTS: We first defined the spatial distributions of the four CAF subtypes reported in prior studies and found that their immune associations varied across histologic and infection-defined GC subtypes. In H. pylori-positive tumors, THBS1⁺ CAFs were spatially enriched near regulatory T cells (Tregs) and were associated with local immunosuppression through WNT5-FZD interactions. In parallel, ZFP36 bound AU-rich elements within the FN1 3' untranslated region (3'UTR), destabilizing FN1 mRNA and thereby diminishing FN1⁺ CAF-mediated cytotoxic T lymphocyte (CTL) activation. Together, these axes promoted Treg accumulation and suppression of CTL activation. CONCLUSIONS: These findings reveal infection-associated stromal programs that shape the immune landscape in GC and highlight CAF-directed pathways as potential therapeutic targets in H. pylori-associated GC.
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Landscape of epithelial cell subpopulations in the human esophageal squamous cell carcinoma microenvironment.
AIMS: We sought to reveal the landscape of epithelial cell subpopulations in the human esophageal squamous cell carcinoma microenvironment and investigate their parts on esophageal squamous carcinoma (ESCC) development. BACKGROUND: Epithelial cells play an important role in the occurrence and development of ESCC through multiple mechanisms. While the landscape of epithelial cell subpopulations in ESCC, remains unclear. OBJECTIVE: Exploring the role of epithelial cell subpopulations in ESCC progression. METHODS: Seurat R package was used for single-cell RNA sequencing (scRNA-seq) data filtering, dimensionality reduction, clustering and differentially expressed genes analysis. Cellmarker database was adopted for cell cluster annotation. Functional enrichment analysis was carried out by Gene Ontology (GO) analysis. InferCNV package was conducted for copy number variation (CNV) of epithelial cell subpopulations in all chromosomal regions. Pseudotime trajectory analysis was implemented for exploring differentiation trajectory of epithelial cells subgroups during the cancer progression. CellChat analysis was used for probing the interactions between epithelial cells and NK/T cells. cellular experiments were performed using Quantitative Real-Time Polymerase Chain Reaction (RT-qPCR), Wound-Healing Assay and transwell. RESULTS: 11 major cell subpopulations were identified in ESCC and adjunct tissues. Further reclassification of epithelial cells uncovered 4 subpopulations. Enrichment analysis revealed that highly expressed genes in 4 epithelial cell subpopulations were related to cell proliferation, immune response and angiogenesis. CNV analysis found that UBD + epithelial cells and GAS2L3+ epithelial cells had a higher proportion of CNV. Cell differentiation trajectories disclosed that KRT6C+ and GSTA1+ epithelial cells were in an intermediate state of differentiation, while UBD+ and GAS2L3+ epithelial cells are in an end state of differentiation during ESCC progression. Finally, we found that four epithelial cell subpopulations all inhibited NK/T cells through NECTIN2-TIGIT and CLEC2B-KLRB1. Low ATF3 and DDIT3 mRNA expression inhibited ESCC cell migration and invasion. CONCLUSION: Here, we obtained a through epithelial cell atlas of ESCC at single-cell resolution, explored the role of epithelial cell in ESCC progression, and unveiled immunosuppressive signals to NK/T cells in promoting ESCC. Our findings expand the comprehension of epithelial cells and offer a theoretical guidance for future anti-epithelial cell treatment of ESCC.
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Cancer-Specific Immune Prognostic Signature in Solid Tumors and Its Relation to Immune Checkpoint Therapies.
To elucidate the role of immune cell infiltration as a prognostic signature in solid tumors, we analyzed immune-function-related genes from four publicly available single-cell RNA-Seq data sets and twenty bulk tumor RNA-Seq data sets from The Cancer Genome Atlas (TCGA). Unsupervised clustering of pan-cancer transcriptomic signature showed two major immune function types: one related to NK-, T-, and B-cell functions and the other related to monocyte, macrophage, dendritic cell, and Toll-like receptor functions. Kaplan-Meier analysis showed differential prognosis of these two groups, dependent on the cancer type. Our analysis of TCGA solid tumors with an elastic net model identified 155 genes associated with disease-free survival in different tumor types with varied influence across different cancer types. With this gene set, we computed cancer-specific prognostic immune score models for individual cancer types that predicted disease-free and overall survival. Validation of our model on available published data of immune checkpoint blockade therapies on melanoma, kidney renal cell carcinoma, non-small cell lung cancer, gastric cancer and bladder cancer confirmed that cancer-specific higher immune scores are associated with response to immunotherapy. Our analysis provides a comprehensive map of cancer-specific immune-related prognostic gene sets that are associated with immunotherapy response.