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Two distinct phenotypes of immunologically hot gastric cancer subtypes.
An in-depth understanding of the tumor microenvironment (TME) is required for the development of improved combination immunotherapies for gastric cancer. Recently, we classified these cancers into four main types defined by their immunological attributes, namely Hot 1, Hot 2, Intermediate and Cold. Of these, the T cell-inflamed "Hot" tumors were further divided into Hot 1 and Hot 2 with different clinical outcomes. Thus, overall survival and progression-free survival of patients with Hot 1 tumors were shorter than with Hot 2. In the present study, we re-evaluated RNA-Seq data of 6 Hot 1 and 6 Hot 2 gastric cancers to elucidate the underlying reason for the poor prognosis and T cell dysfunction in the former. In addition, 56 Hot 1 and 27 Hot 2 tumors in The Cancer Genome Atlas (TCGA) were analyzed. We report that single sample Gene Set Enrichment Analysis (ssGSEA) and differential gene expression analysis identified differences between Hot 1 and Hot 2 tumors involved in metabolism and cell adhesion pathways. Therefore, it is suggested that strategies to modulate active metabolism in Hot 1 tumors should be integrated into the treatment of these gastric cancers.
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The single-cell atlas of the epididymis in mice reveals the changes in epididymis function before and after sexual maturity.
Introduction: The epididymis is important for sperm transport, maturation, and storage. Methods: The head and tail of the epididymis of 5-week-old and 10-week-old C57 BL/6J male mice were used for single-cell sequencing. Results: 10 cell types including main, basal, and narrow/clear cells are identified. Next, we performed cell subgroup analysis, functional enrichment analysis, and differentiation potential prediction on principal cells, clear cells, and basal cells. Our study indicates that the principal cells are significantly involved in sperm maturation, as well as in antiviral and anti-tumor immune responses. Clear cells are likely to play a crucial role in safeguarding sperm and maintaining epididymal pH levels. Basal cells are implicated in the regulation of inflammatory and stress responses. The composition and functions of the various cell types within the epididymis undergo significant changes before and after sexual maturity. Furthermore, pseudo-temporal analysis elucidates the protective and supportive roles of epididymal cells in sperm maturation during sexual maturation. Discussion: This study offers a theoretical framework and forecasts for the investigation of epididymal sperm maturation and epididymal immunity.
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Integrative Multi-Omics Analysis Prioritizes Candidate Therapeutic Targets for Primary Open-Angle Glaucoma.
Primary open-angle glaucoma (POAG) is a leading cause of irreversible blindness driven by elevated intraocular pressure from compromised aqueous outflow. While genome-wide association studies have identified numerous risk loci, specific candidate proteins and their cellular mechanisms remain elusive. We employed a multi-omics framework integrating UK Biobank plasma proteomics (N = 53,022) and large-scale POAG GWAS summary statistics. We performed a Proteome-Wide Association Study, Mendelian Randomization, and Bayesian colocalization to infer causality. Identified candidates were mapped to human and mouse ocular scRNA-seq atlases to characterize cell-type specificity, followed by druggability assessments. We prioritized five putative causal proteins, with SEL1L and TFPI demonstrating the strongest evidence. Cross-species scRNA-seq revealed that SEL1L and SERPINF1 are robustly expressed in the trabecular meshwork (TM), particularly the juxtacanalicular tissue, implicating them in outflow resistance. Conversely, TFPI and SLC9A3R2 localize to Schlemm's canal endothelium, suggesting a role in modulating barrier function. Pathway analyses highlighted endoplasmic reticulum protein processing and coagulation cascades. This study maps putative causal POAG proteins to conventional outflow pathway cells, highlighting SEL1L as a novel target for TM homeostasis and TFPI for drug repurposing, thereby providing data-driven hypotheses to facilitate precision glaucoma therapeutics.
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Identifying Cell-Type Specific Genes and Expression Rules Based on Single-Cell Transcriptomic Atlas Data.
Single-cell sequencing technologies have emerged to address new and longstanding biological and biomedical questions. Previous studies focused on the analysis of bulk tissue samples composed of millions of cells. However, the genomes within the cells of an individual multicellular organism are not always the same. In this study, we aimed to identify the crucial and characteristically expressed genes that may play functional roles in tissue development and organogenesis, by analyzing a single-cell transcriptomic atlas of mice. We identified the most relevant gene features and decision rules classifying 18 cell categories, providing a list of genes that may perform important functions in the process of tissue development because of their tissue-specific expression patterns. These genes may serve as biomarkers to identify the origin of unknown cell subgroups so as to recognize specific cell stages/states during the dynamic process, and also be applied as potential therapy targets for developmental disorders.
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A single cell RNA sequence atlas of the early Drosophila larval eye.
The Drosophila eye has been an important model to understand principles of differentiation, proliferation, apoptosis and tissue morphogenesis. However, a single cell RNA sequence resource that captures gene expression dynamics from the initiation of differentiation to the specification of different cell types in the larval eye disc is lacking. Here, we report transcriptomic data from 13,000 cells that cover six developmental stages of the larval eye. Our data show cell clusters that correspond to all major cell types present in the eye disc ranging from the initiation of the morphogenetic furrow to the differentiation of each photoreceptor cell type as well as early cone cells. We identify dozens of cell type-specific genes whose function in different aspects of eye development have not been reported. These single cell data will greatly aid research groups studying different aspects of early eye development and will facilitate a deeper understanding of the larval eye as a model system.
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Comprehensive analysis of the papillary thyroid carcinoma identifies CSGALNACT1 as a proliferation driver and prognostic biomarker.
Papillary thyroid carcinoma (PTC) is the most prevalent form of thyroid cancer, yet its cellular heterogeneity and prognostic determinants remain poorly defined. Here, we integrate two single-cell RNA sequencing datasets comprising 20 human thyroid samples to construct a high-resolution cellular atlas of PTC. We identify 29 distinct cellular subpopulations and delineate their composition, dynamics, and interactions in healthy versus tumor tissues. Notably, epithelial and monocyte populations were markedly expanded in PTC, whereas adaptive immune subsets such as B and T cells were diminished. Cell-cell communication analysis revealed enhanced intercellular signaling in the tumor microenvironment, with epithelial and endothelial cells receiving the strongest inputs. Among monocyte-specific transcriptional signatures, we identified 65 prognostic genes via univariate Cox analysis. A LASSO-derived 14-gene risk score robustly stratified patient outcomes, with CSGALNACT1 emerging as a key epithelial-specific, independent prognostic gene. Pseudotime analysis further supported its role in epithelial cell differentiation. Functional validation demonstrated that CSGALNACT1 promotes proliferation in PTC cell lines, suggesting a potential oncogenic function. Immune deconvolution across risk groups revealed substantial divergence in innate and adaptive immune infiltration, indicating a close interplay between tumor-intrinsic transcriptional programs and immune microenvironment remodeling. Collectively, our study provides a comprehensive single-cell framework for PTC, identifies a clinically relevant risk model, and highlights CSGALNACT1 as a potential therapeutic target.
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A single-nucleus transcriptomic atlas reveals distinct cell identities and key regulators of cellular differentiation during early rice seed development.
The early morphogenesis of the embryo and endosperm sets the upper limit of rice grain yield; yet, the cellular dynamics and regulatory mechanisms underlying this critical stage remain largely elusive. Here, we present a single-cell atlas of developing rice seeds based on single-nucleus RNA sequencing of 67,922 high-quality nuclei from rice caryopses. Integration with bulk RNA-seq, in situ hybridization, and promoter-GUS staining enabled systematic cell-type annotation and revealed a distinct population of embryo-endosperm interface (EEI) cells occupying the boundary between the developing embryo and endosperm. Comparative analyses with maize data sets, together with trajectory inference, suggested that a subset of EEI cells shares molecular features with maize embryo-adjacent scutellum cells and shows transcriptional continuity with starchy endosperm cells. Embryo-endosperm interface cells were enriched in transport-related and developmental regulatory genes with known functions in seed development and embryogenesis. Focusing on the EEI-enriched regulator OsBZR4, we found that loss of OsBZR4 altered cellular composition and transcriptional programs during early seed development, disrupted embryonic developmental progression, and reduced the expression of embryonic genes, including OsCDP3.10 and RINO1. Together, our study provides a single-cell resolution framework for understanding early rice seed development, identifies the embryo-endosperm interface as an important cellular domain associated with embryogenesis, and offers a valuable resource for dissecting the molecular basis of seed formation in rice and related cereals.
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Zinc finger protein 296 promotes hepatocellular carcinoma progression via intervening interaction between macrophages and B cells.
OBJECTIVE: Hepatocellular carcinoma (HCC) is a prevalent malignancy with poor survival. Different cell types in the tumor microenvironment participate in the tumorigenesis and progression of HCC. This study aimed to analyze the immune microenvironment of HCC and its relationship with clinical outcomes. METHODS: We analyzed HCC RNA-seq for cell type identification and prognosis by estimating relative subsets of RNA transcripts using CIBERSORTx. The interaction between B cells and macrophages in HCC was analyzed using a Hepa1-6 orthotopic transplantation mouse model and flow cytometry. The effect of Zinc finger protein 296 (ZNF296) on the interaction of B cells and macrophages was verified using human HCC tissues analyzed through western blot, quantitative real-time polymerase chain reaction (qPCR), and multiplex immunofluorescence. A comparative analysis of immune cells associated with HCC prognosis was performed using RNA-seq data from The Cancer Genome Atlas (TCGA), bulk multimodal data, and single-cell transcriptomic data from existing HCC single-cell transcriptomic data employing the Single Cell Inferred Site Specific Omics Resource for Tumor Microenvironments (SCISSOR). RESULTS: Liver hepatocellular carcinoma (LIHC) RNA-seq analysis of TCGA showed that high eosinophil infiltration promoted HCC progression. The proportion of B cells correlated with that of macrophages (r=-0.24) and affected the infiltration and programmed death ligand 1 (PD-L1) expression of macrophages in HCC. ZNF296 may participate in the interaction between B cells and macrophages to accelerate the HCC progression by regulating PAFAH1B3 and H2AFX. Moreover, ZNF296 expression positively correlated with LAG3 (r=0.27) and CTLA4 (r=0.31) expression levels. Among the immune cell phenotypes related to survival and death identified by SCISSOR analysis, T cells correlated with an excellent prognosis of HCC. The normal function of liver and dendritic cells was also associated with a good prognosis in HCC. CONCLUSIONS: This study analyzed the interaction of the immune microenvironment with HCC prognosis, identifying ZNF296 as a promising diagnostic and therapeutic target for HCC.
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Integrating single-cell and spatial transcriptomics reveals the cellular heterogeneity of vestibular schwannoma.
Vestibular schwannoma (VS) is a benign tumor that can result in significant neurological and otological complications. The mechanisms underlying its development and spatial heterogeneity remain poorly understood. In this study, we analyzed single-cell RNA sequencing (scRNA-seq) data from three previously published vestibular schwannomas (VS1-3), along with spatial transcriptomics data from two additional specimens (VS_S1-2). Our results identified a VEGFA-enriched Schwann cell (SC) subtype in scRNA-seq data, which was validated by spatial transcriptomics. This subtype also exhibited a significant positive correlation with NOVhi SCs expression. These cells were centrally localized within tumor tissue. Furthermore, spatial analysis provided new insights into SC-stromal cell interactions, and we constructed a preliminary cellular atlas of VS tissues, enhancing our understanding of tumor growth dynamics.
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Human single-cell atlas of proliferative diabetic retinopathy reveals a SOX15-overexpressing stromal population driving retinal fibrosis through the endothelin-1 -EDNRB axis.
BACKGROUND: Proliferative diabetic retinopathy (PDR) is a leading cause of irreversible blindness worldwide, characterized by pathological neovascularization and progressive retinal fibrosis. Although anti-VEGF therapy effectively suppresses neovascularization, it does not address fibrovascular membranes (FVMs) formation and may paradoxically accelerate membrane contraction, increasing the risk of tractional retinal detachment. The lack of effective anti-fibrotic strategies highlights the importance to elucidate the key cellular mechanisms underlying retinal fibrosis in PDR. METHODS: We performed single-cell RNA sequencing (scRNA-seq) on primary retinal tissues from PDR organ donors and non-diabetic controls, generating a single-cell transcriptomic atlas of the human PDR retina. Critical findings were validated by immunofluorescence, in vivo and in vitro functional assays. Stromal-specific Sox15 conditional knockout mice in a two-stage laser-induced fibrosis model and siRNA-mediated knockdown in fibroblasts, and intravitreal administration of the EDNRB antagonist were performed. RESULTS: scRNA-seq of primary human PDR retinas generated the first comprehensive single-cell transcriptomic atlas of human PDR, revealing profound alterations in cellular composition including microglial expansion and Müller glia reprogramming as central neuroinflammatory features of PDR, and selective loss of metallothionein enriched rods subpopulation and S-cones. Notably, We identified a stromal cell population that was enriched in PDR retinas, localized in FVMs, and characterized by high SOX15 expression. Cell-cell communication analysis revealed that EDN1-EDNRB signaling between these stromal cells and Müller glia represented the most prominent intercellular interaction in PDR. Mechanistically, SOX15 regulates EDN1 transcription through binding to its promoter, driving EDN1 expression that activates EDNRB-expressing retinal macroglia to promote reactive gliosis and retinal fibrosis. Stromal-specific Sox15 conditional knockout significantly attenuated fibrotic lesion formation in vivo, and PDR-derived fibrocytes with elevated SOX15 exhibited enhanced fibroblast differentiation and EDN1 secretion, providing translational validation in human disease. Intravitreal EDNRB blockade with BQ-788 significantly reduced fibrotic area in a murine fibrosis model. CONCLUSIONS: This study identifies key pathological features of the human PDR retina, including pervasive neuroinflammation and selective loss of photoreceptor subpopulations, and delineates the SOX15-EDN1-EDNRB axis as a novel mechanism driving retinal fibrosis. Targeting this axis may represent a promising anti-fibrotic strategy for advanced PDR.