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A single-cell atlas of the Culex tarsalis midgut during West Nile virus infection.
The mosquito midgut functions as a key interface between pathogen and vector. However, studies of midgut physiology and virus infection dynamics are scarce, and in Culex tarsalis-an extremely efficient vector of West Nile virus (WNV)-nonexistent. We performed single-cell RNA sequencing on Cx. tarsalis midguts, defined multiple cell types, and determined whether specific cell types are more permissive to WNV infection. We identified 20 cell states comprising 8 distinct cell types, consistent with existing descriptions of Drosophila and Aedes aegypti midgut physiology. Most midgut cell populations were permissive to WNV infection. However, there were higher levels of WNV RNA (vRNA) in enteroendocrine cells (EE), suggesting enhanced replication in this population. In contrast, proliferating intestinal stem cells (ISC) had the lowest levels of vRNA, a finding consistent with studies suggesting ISC proliferation in the midgut is involved in infection control. ISCs were also found to have a strong transcriptional response to WNV infection; genes involved in ribosome structure and biogenesis, and translation were significantly downregulated in WNV-infected ISC populations. Notably, we did not detect significant WNV-infection induced upregulation of canonical mosquito antiviral immune genes (e.g., AGO2, R2D2, etc.) at the whole-midgut level. Rather, we observed a significant positive correlation between immune gene expression levels and vRNA load in individual cells, suggesting that within midgut cells, high levels of vRNA may trigger antiviral responses. Our findings establish a Cx. tarsalis midgut cell atlas, and provide insight into midgut infection dynamics of WNV by characterizing cell-type specific enhancement/restriction of, and immune response to, infection at the single-cell level.
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A multi-omics atlas of CAF subtypes reveals apCAF-M2 macrophage interactions driving immune resistance in glioma.
Cancer-associated fibroblasts (CAFs) are a critical component of the glioma microenvi-ronment and play essential roles in tumor progression and resistance to immunotherapy. To comprehensively characterize CAF heterogeneity and their interactions with immune cells, we conducted an integrative multi-omics analysis incorporating single-cell and bulk RNA sequencing, spatial transcriptomics, and multiplex immunofluorescence. This approach identified nine distinct CAF subtypes with phenotypic and functional diversity, including tumor-like CAFs (tCAFs), myofibroblast-like CAFs (myCAFs), vascular CAFs (vCAFs), metabolic CAFs (meCAFs), proliferative CAFs (pCAFs), antigen-presenting CAFs (apCAFs), interferon-responsive CAFs (infCAFs), inflammatory CAFs (iCAFs), and a group of CAFs with unknown identity. Several subtypes were significantly associated with poor clinical outcomes. Notably, apCAFs engaged in extensive crosstalk with M2-polarized macrophages via TGF-β signaling pathways. Spatial transcriptomic pro-filing and immunofluorescence imaging revealed the co-localization of apCAFs and M2 macrophages at the tumor periphery, indicating the formation of an immunosuppressive niche. Moreover, AQP4 was identified as a specific marker of apCAFs, and its expression was significantly correlated with poor prognosis and resistance to immunotherapy. These findings offer a comprehensive atlas of CAF heterogeneity in glioma and highlight the therapeutic promise of targeting apCAF-M2 macrophage interactions or AQP4 to over-come immune resistance and improve clinical outcomes.
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Cytotoxic lymphocyte heterogeneity in glioblastoma: insights from single-cell and spatial multiomics toward precision immunotherapeutic reprogramming.
Glioblastoma (GBM) represents the most aggressive primary brain tumor in adults, characterized by a profoundly immunosuppressive tumor microenvironment (TME) that systematically disables cytotoxic lymphocyte function and renders conventional immunotherapy largely ineffective. While exhaustion of CD8+ T cells and natural killer (NK) cells within solid tumors has been extensively studied in other cancer types, the CNS-specific architectural, metabolic, and molecular constraints that shape cytotoxic lymphocyte heterogeneity in GBM remain insufficiently characterized. Recent advances in single-cell RNA sequencing (scRNA-seq) and spatial multiomics have begun to reveal a rich landscape of cytotoxic lymphocyte subpopulations in GBM. These include TCF-1+ progenitor-exhausted T cells (Tpex), terminally exhausted CD8+ T cells (Tex), and dysfunctional natural killer (NK) cell subsets, each distributed across anatomically distinct immune niches. This review synthesizes current knowledge across three interconnected areas: the single-cell atlas of GBM-infiltrating cytotoxic lymphocytes; the spatial organization of their dysfunction within perinecrotic, perivascular, and infiltrative-edge niches; and the epigenetic and transcriptional programs that underlie GBM-specific cytotoxic failure, including dysregulation of the TOX/TCF-1 axis and IDH-mutation-driven silencing of NKG2D ligands. Critically, we compare CD8+ T cell and NK cell exhaustion mechanisms, highlighting their mechanistic divergence and therapeutic implications. We further discuss how these multiomics insights can be translated into neurosurgically relevant strategies, including intraoperative tumor profiling, progenitor T cell expansion via epigenetic priming, NKG2A/TIGIT dual blockade, and intracavitary delivery of engineered NK cells. Together, this review proposes a spatially and cellularly resolved framework for understanding cytotoxic immune failure in GBM and outlines precision immunotherapy approaches tailored to the unique immunobiology of the CNS tumor microenvironment.
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Single-cell transcriptome profiling of sepsis identifies HLA-DRlowS100Ahigh monocytes with immunosuppressive function.
BACKGROUND: Sustained yet intractable immunosuppression is commonly observed in septic patients, resulting in aggravated clinical outcomes. However, due to the substantial heterogeneity within septic patients, precise indicators in deciphering clinical trajectories and immunological alterations for septic patients remain largely lacking. METHODS: We adopted cross-species, single-cell RNA sequencing (scRNA-seq) analysis based on two published datasets containing circulating immune cell profile of septic patients as well as immune cell atlas of murine model of sepsis. Flow cytometry, laser scanning confocal microscopy (LSCM) imaging and Western blotting were applied to identify the presence of S100A9+ monocytes at protein level. To interrogate the immunosuppressive function of this subset, splenic monocytes isolated from septic wild-type or S100a9-/- mice were co-cultured with naïve CD4+ T cells, followed by proliferative assay. Pharmacological inhibition of S100A9 was implemented using Paquinimod via oral gavage. RESULTS: ScRNA-seq analysis of human sepsis revealed substantial heterogeneity in monocyte compartments following the onset of sepsis, for which distinct monocyte subsets were enriched in disparate subclusters of septic patients. We identified a unique monocyte subset characterized by high expression of S100A family genes and low expression of human leukocyte antigen DR (HLA-DR), which were prominently enriched in septic patients and might exert immunosuppressive function. By combining single-cell transcriptomics of murine model of sepsis with in vivo experiments, we uncovered a similar subtype of monocyte significantly associated with late sepsis and immunocompromised status of septic mice, corresponding to HLA-DRlowS100Ahigh monocytes in human sepsis. Moreover, we found that S100A9+ monocytes exhibited profound immunosuppressive function on CD4+ T cell immune response and blockade of S100A9 using Paquinimod could partially reverse sepsis-induced immunosuppression. CONCLUSIONS: This study identifies HLA-DRlowS100Ahigh monocytes correlated with immunosuppressive state upon septic challenge, inhibition of which can markedly mitigate sepsis-induced immune depression, thereby providing a novel therapeutic strategy for the management of sepsis.
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The prognostic value and immunological role of CD44 in pan-cancer study.
To investigate the correlation between cluster of differentiation-44 (CD44) expression and immunotherapy response and identify its possible predictive value in pan-cancer. Datasets of 33 cancer types from The Cancer Genome Atlas (TCGA) database were applied to investigate the relationship of CD44 expression with prognosis, tumor mutational burden (TMB), and microsatellite instability (MSI), and determine its potential prognostic value in pan-cancer. Patients were split into high-risk and low-risk cancer groups based on the survival outcomes of various cancer types. Additionally, the underlying mechanisms of CD44 in the tumor microenvironment (TME) were analyzed using ESTIMATE and CIBERSORT algorithms and Gene Set Enrichment Analysis (GSEA). Subsequently, the biological role of CD44 at single-cell level was investigated using CancerSEA database. Variable expression levels of CD44 between tumor and adjacent normal tissues were identified in pan-cancer datasets, further survival analysis revealed that CD44 expression was associated with multiple clinical annotations and survival indicators. Besides, the expression of CD44 was significantly associated with TMB and MSI in 10 types and 6 types of cancer, respectively, indicating it could be exploited as a potential biomarker predicting immunotherapy outcomes. Meanwhile, CD44 could influence several crucial immune cell-related pathways. and the results revealed by CancerSEA database denoted the correlation of CD44 with malignant phenotype and functional states, further indicating it can serve as a potential therapeutic target in cancer management. Our study demonstrated that CD44 shows great promise as a prognostic biomarker in numerous cancers, which will assist in developing new strategies in cancer management.
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A spatiotemporal atlas of cerebrovascular development in zebrafish.
The vertebrate brain requires precisely patterned vasculature, yet the molecular and cellular dynamics of cerebrovascular development remain incompletely understood. While single-cell studies have profiled brain vasculature, integrating these data across molecular, cellular, and architectural scales remains challenging. We combine in situ sequencing, single-cell transcriptomics, and 3D vascular reconstruction to map zebrafish brain endothelial development (3-11 dpf). Quantitative 3D analysis reveals a developmental shift from lateral vascularization to intraparenchymal angiogenesis, coinciding with blood-brain barrier (BBB) maturation. We identify 6 endothelial subtypes with conserved mammalian signatures, showing capillary endothelial cells (CapECs), the predominant intracranial subtype exhibiting stage-specific enrichment of transporter and tight junction modules. Spatial transcriptomics show progressive CapEC enrichment in mesencephalic/metencephalic regions versus arterial EC accumulation in prosencephalic vessels. Functional assays confirm BBB competency by 11 dpf, while genetic perturbation of three uncharacterized CapEC-enriched genes (slc16a1a, zgc:158423, cldc1) disrupts vascular patterning and BBB integrity. This multidimensional atlas provides an evolutionary perspective on cerebrovascular development, bridges molecular profiles with vascular architecture, and offers insights into developmental dynamics across scales.
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High-Resolution Spatial Profiling of Microglia Reveals Proximity Associated Immunometabolic Reprogramming in Alzheimer's Disease.
Single-cell RNA sequencing has demonstrated that the presence of parenchymal amyloid plaques and intracellular hyperphosphorylated tau pathology is associated with distinctive (and possibly disease-driving) microglial heterogeneity. However, our understanding of how proximity to these Alzheimer's disease (AD) pathological hallmarks in situ relates to microglial gene expression remains obscure. Here, we utilized high-resolution spatial transcriptomics (ST) via the Xenium platform with a fully customized gene panel to elucidate disease-associated microglial subtypes in tandem with examining metabolic signatures across AD-relevant mouse models and well-characterized human postmortem tissue. Three mouse models were evaluated: PS19, APP/PS1, and 5xFAD. Analyzing anatomical features across entire hemisections, our approach resolved the distribution of five disease-associated microglial subtypes, while deciphering how proximity to cerebral amyloid plaques influenced transcriptional mediators governing metabolic pathways. We observed robust alterations in glycolytic and cholesterol/lipid processing pathways in plaque-associated microglia, consistent with a specific switch to glycolysis and lipid-fueled metabolism in the plaque niche. Extending our analysis to human postmortem dorsolateral prefrontal cortex (dlPFC), we identified conserved disease-reactive microglial states, i.e., similar proximity-dependent metabolic shifts around amyloid plaques. Further, integrating spatial transcriptomics with machine-learning approaches revealed novel anatomic domain-specific cellular gene expression profiling features, highlighting differential vulnerabilities of neuronal, glial, and vascular populations near specific microglial subtypes. Together, our findings provide one of the first comprehensive and high-resolution atlas of microglial immunometabolic states across species, anatomical regions, and AD pathological burden.
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Transient Receptor Potential Melastatin 4 (TRPM4) is associated with an immuno-stimulatory TME and better prognosis in BLCA.
OBJECTIVE: Bladder cancer (BLCA) is one of the most invasive and malignant tumors in the world, thus leading to the urgent need of an accurate and recognizable biomarker. Several previous research has shown that Transient Receptor Potential Melastatin 4 (TRPM4) plays an important role in measuring vascular fragility and endothelial function. However, the role of TRPM4 in tumor hasn't been explored. METHODS: We obtained the clinical data and gene expression profiles of The Cancer Genome Atlas (TCGA) datasets via UCSC Xena. The tumor microenvironment (TME) was also evaluated by the amount of immunomodulators. The role of TRPM4 was demonstrated using the dataset GSE130001 via the website ( http://tisch.comp-genomics.org/ ). We also validated the results of the pathway analysis through the Polymerase Chain Reaction (PCR). RESULTS: Patients with higher TRPM4 expression showed better prognosis. We found out that high TRPM4 tended to shape an immuno-stimulatory TME with less T cell exhaustion and lower level of immune overdrive. We demonstrated that TRPM4 could predict the molecular subtype and different therapy options in BLCA. We also found the important influence of TRPM4 in P53 pathway and TNF-a pathway. Last but not least, we developed a prognostic model centered on TRPM4 using ten machine learning algorithms, which showed excellent predictive ability. CONCLUSION: High TRPM4 shapes a more immuno-stimulatory tumor microenvironment and can not only predict the immune phenotypes but also predict the clinical phenotypes in BLCA. High TRPM4 predicts better prognosis. TRPM4 is a potential biomarker in the future for identifying the immunogenicity and immune-therapy probability of BLCA.
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A high-definition spatiotemporal transcriptomic atlas of mammalian kidney development.
The structural composition of organs undergoes significant transformations during organogenesis, laying the foundation for their eventual functional architecture. In contrast, adult organs maintain structural homeostasis. However, the dynamics of organ structure during the organogenesis and homeostasis stages remain poorly understood. Here, we present a spatially resolved transcriptome atlas at single-cell resolution to explore the establishment and maintenance of kidney structure in mice. Our analysis reveals 40 migration-related cell-cell communication events during kidney organogenesis. Contrary to the traditional two-layer model (cortex and medulla), we demonstrate that the kidney develops a five-layer structure over time. Mechanistically, migration-related cell-cell communication drives this structural formation, with ephrin-A5 (Efna5) playing a key role in forming three distinct layers within the medulla. The spatial distribution of specific cell types and their gene expression patterns within these five layers likely enhances renal adaptation to hypoxic and hyperosmotic environments. Furthermore, Frizzled 4 receptor (Fzd4) is critical for the morphogenesis of the U-shaped loop of Henle (LoH). In the adult stage, when structural homeostasis prevails, only three migration-related ligand-receptor pairs are observed, and a stable four-layer structure is maintained due to the absence of progenitor cells. Overall, our findings illustrate the role of intercellular communication in driving the transition from structural establishment during organogenesis to stable maintenance in homeostasis. These insights provide new avenues for advancing organ regeneration strategies.
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Single-Cell Transcriptomics Reveals Rora-Associated Aberrant Granulosa Cell Differentiation in Polycystic Ovary Syndrome.
INTRODUCTION: Polycystic ovary syndrome (PCOS) is characterized by follicular developmental arrest, yet the molecular basis underlying impaired granulosa cell (GC) differentiation remains incompletely understood. METHODS: We constructed a single-cell transcriptomic atlas of ovaries from DHEA-induced PCOS-like mice and matched vehicle controls, and leveraged spatial transcriptomics as an orthogonal reference for major cell-type annotation, followed by in-depth profiling of GC heterogeneity. Pseudotime inference, co-expression networks, and regulon activity analysis were integrated, and findings were validated in independent human GC datasets. In silico Rora perturbation, cell-cell communication analysis, and drug repositioning were additionally performed. RESULTS: We identified a subset of luteinized mural GCs with robust Rora regulon activation, termed Rora-regulon-active GCs. This subset was markedly enriched in PCOS and was reproducibly observed in independent human GC datasets. Rora-regulon-active GCs exhibited an incomplete luteinization phenotype coupled with lipid-metabolic reprogramming. In silico Rora knockdown partially reconfigured GC differentiation trajectories and shifted the PCOS-skewed subset composition toward control, with concordant changes in metabolic transcriptional programs. Cell-cell communication analyses implicated stromal-derived Mdk-Sdc1 signaling and suggested additional crosstalk with macrophages potentially mediated by ligands such as Vegfa. In silico drug repositioning prioritized betaine hydrochloride and bempedoic acid as candidate therapeutics. DISCUSSION: Our study delineates a Rora-associated aberrant GC differentiation program linked to PCOS, nominating this aberrant program as a potential cellular basis of PCOS-associated follicular arrest and providing mechanistic and translational leads for precision-targeted therapy.