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Found: 4 934
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Single-cell transcriptomic atlas reveals the underlying mechanism of indole-3-acetic acid in protecting against acute cholestatic liver injury.
Cholestasis resulting from disorders of bile secretion and excretion is a serious manifestation of hepatopathy. Indole-3-acetic acid (3-IAA), a biologically active indole derivative from the tryptophan metabolic pathway, has recently attracted considerable attention. However, the therapeutic potential of 3-IAA in acute cholestatic liver injury (ACLI) remains unclear. By integrating transcriptomics and metabolomics, our study revealed that endogenous 3-IAA was downregulated in bile duct ligation induced ACLI rats. Further in vivo animal experiments demonstrated that exogenous 3-IAA administration effectively attenuated the progression of ACLI. Through single-cell RNA sequencing, our study comprehensively mapped the single-cell atlas relating to 3-IAA alleviating ACLI. Mechanistically, 3-IAA may inhibit hepatocyte inflammatory response and promote hepatocyte regeneration by regulating GZMA+GZMK+ effector NK cell and expanding hepatic anti-inflammatory CD59+ macrophages. Taken together, our study revealed the liver protective effect and potential immune mechanism of 3-IAA in ACLI, positioning it as a promising therapeutic candidate for cholestatic liver injury.
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Identification of renal cyst cells of type I Nephronophthisis by single-nucleus RNA sequencing.
Background: Nephronophthisis (NPH) is the most common genetic cause of end-stage renal disease (ESRD) in childhood, and NPHP1 is the major pathogenic gene. Cyst formation at the corticomedullary junction is a pathological feature of NPH, but the mechanism underlying cystogenesis is not well understood. The isolation and identification of cystic cell subpopulation could help to identify their origins and provide vital clues to the mechanisms underlying cystogenesis in NPH. Methods: Single-nucleus RNA sequencing (snRNA-seq) was performed to produce an atlas of NPHP1 renal cells. Kidney samples were collected from WT (Nphp1 +/+) mice and NPHP1 (Nphp1 del2-20/del2-20) model mice. Results: A comprehensive atlas of the renal cellular landscape in NPHP1 was generated, consisting of 14 basic renal cell types as well as a subpopulation of DCT cells that was overrepresented in NPHP1 kidneys compared to WT kidneys. GO analysis revealed significant downregulation of genes associated with tubular development and kidney morphogenesis in this subpopulation. Furthermore, the reconstruction of differentiation trajectories of individual cells within this subpopulation confirmed that a specific group of cells in NPHP1 mice become arrested at an early stage of differentiation and proliferate to form cysts. We demonstrate that Niban1 is a specific molecular marker of cystic cells in both mice and human NPHP1. Conclusion: In summary, we report a novel subpopulation of DCT cells, marked by Niban1, that are classified as cystic cells in the NPHP1 mice kidney. These results offer fresh insights into the cellular and molecular basis of cystogenesis in NPH.
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Identification of a differentiation-related prognostic nomogram based on single-cell RNA sequencing in clear cell renal cell carcinoma.
Renal cell carcinoma (RCC) is a kidney cancer that is originated from the lined proximal convoluted tubule, and its major histological subtype is clear cell RCC (ccRCC). This study aimed to retrospectively analyze single-cell RNA sequencing (scRNA-seq) data from the Gene Expression Omnibus (GEO) database, to explore the correlation among the evolution of tumor microenvironment (TME), clinical outcomes, and potential immunotherapeutic responses in combination with bulk RNA-seq data from The Cancer Genome Atlas (TCGA) database, and to construct a differentiation-related genes (DRG)-based prognostic risk signature (PRS) and a nomogram to predict the prognosis of ccRCC patients. First, scRNA-seq data of ccRCC samples were systematically analyzed, and three subsets with distinct differentiation trajectories were identified. Then, ccRCC samples from TCGA database were divided into four DRG-based molecular subtypes, and it was revealed that the molecular subtypes were significantly correlated with prognosis, clinicopathological features, TME, and the expression levels of immune checkpoint genes (ICGs). A DRG-based PRS was constructed, and it was an independent prognostic factor, which could well predict the prognosis of ccRCC patients. Finally, we constructed a prognostic nomogram based on the PRS and clinicopathological characteristics, which exhibited a high accuracy and a robust predictive performance. This study highlighted the significance of trajectory differentiation of ccRCC cells and TME evolution in predicting clinical outcomes and potential immunotherapeutic responses of ccRCC patients, and the nomogram provided an intuitive and accurate method for predicting the prognosis of such patients.
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A single-cell gene expression atlas of human follicular aspirates: Identification of leukocyte subpopulations and their paracrine factors.
Leukocytes are in situ regulators critical for ovarian function. However, little is known about leukocyte subpopulations and their interaction with follicular cells in ovulatory follicles, especially in humans. Single-cell RNA sequencing (scRNA-seq) was performed using follicular aspirates obtained from four IVF patients and identified 13 cell groups: one granulosa cell group, one thecal cell group, 10 subsets of leukocytes, and one group of RBC/platelet. RNA velocity analyses on five granulosa cell populations predicted developmental dynamics denoting two projections of differentiation states. The cell type-specific transcriptomic profiling analyses revealed the presence of a diverse array of leukocyte-derived factors that can directly impact granulosa cell function by activating their receptors (e.g., cytokines and secretory ligands) and are involved in tissue remodeling (e.g., MMPs, ADAMs, ADAMTSs, and TIMPs) and angiogenesis (e.g., VEGFs, PGF, FGF, IGF, and THBS1) in ovulatory follicles. Consistent with the findings from the scRNA-seq data, the leukocyte-specific expression of CD68, IL1B, and MMP9 was verified in follicle tissues collected before and at defined hours after hCG administration from regularly cycling women. Collectively, this study demonstrates that this data can be used as an invaluable resource for identifying important leukocyte-derived factors that promote follicular cell function, thereby facilitating ovulation and luteinization in women.
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Single-cell and Bulk RNA-Seq Analyses Reveal TOMM7-mediated Multi-cell Death Mechanisms Driving Muscle-invasive Bladder Cancer Progression.
INTRODUCTION: Muscle-invasive bladder cancer (MIBC) is characterized by high malignancy and poor prognosis. Advances in single-cell RNA sequencing (scRNA-seq) have provided new insights into the molecular heterogeneity and progression of MIBC. METHODS: A single-cell atlas of bladder cancer (BCa) was constructed, and MIBC-related epithelial subclusters (Epi_MIBC) were identified. Key transcription factors and dysregulated cell death pathways were characterized. A prognostic model based on MIBC-related cell death genes (MIBC.CDGs) was developed using machine learning algorithms and validated across multiple cohorts. The functional role and druggability of TOMM7, a core gene, were evaluated through in vitro experiments and molecular docking analysis. RESULTS: The MIBC-related cell death score (MIBC.CDS) was shown to effectively stratify patient prognosis and predict immunotherapy response. Multiple cell death pathways were found to be activated in MIBC. Knockdown of TOMM7 suppressed proliferation, invasion, and migration in T24 cells, while modulating apoptosis, autophagy, mitophagy, cuproptosis, and ferroptosis. Molecular docking analysis identified sorafenib as a potential TOMM7-targeted therapeutic agent. DISCUSSION: The findings highlighted the critical role of cell death dysregulation in MIBC progression and underscored TOMM7 as a novel oncogenic regulator. The integration of multiomics data and machine learning enhanced our understanding of tumor biology and provided a foundation for developing personalized treatment strategies. CONCLUSION: TOMM7 was found to drive MIBC progression by regulating multiple cell death pathways. The MIBC.CDS may serve as a promising tool for prognostic evaluation and therapeutic stratification. Sorafenib was identified as a potential candidate for TOMM7-targeted therapy in MIBC.
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Tracing colonic embryonic transcriptional profiles and their reactivation upon intestinal damage.
We lack a holistic understanding of the genetic programs orchestrating embryonic colon morphogenesis and governing damage response in the adult. A window into these programs is the transcriptomes of the epithelial and mesenchymal cell populations in the colon. Performing unbiased single-cell transcriptomic analyses of the developing mouse colon at different embryonic stages (embryonic day 14.5 [E14.5], E15.5, and E18.5), we capture cellular and molecular profiles of the stages before, during, and after the appearance of crypt structures, as well as in a model of adult colitis. The data suggest most adult lineages are established by E18.5. We find embryonic-specific gene expression profiles and cell populations that reappear in response to tissue damage. Comparison of the datasets from mice and human colitis suggests the processes are conserved. In this study, we provide a comprehensive single-cell atlas of the developing mouse colon and evidence for the reactivation of embryonic genes in disease.
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A cell atlas of human thymic development defines T cell repertoire formation.
The thymus provides a nurturing environment for the differentiation and selection of T cells, a process orchestrated by their interaction with multiple thymic cell types. We used single-cell RNA sequencing to create a cell census of the human thymus across the life span and to reconstruct T cell differentiation trajectories and T cell receptor (TCR) recombination kinetics. Using this approach, we identified and located in situ CD8αα+ T cell populations, thymic fibroblast subtypes, and activated dendritic cell states. In addition, we reveal a bias in TCR recombination and selection, which is attributed to genomic position and the kinetics of lineage commitment. Taken together, our data provide a comprehensive atlas of the human thymus across the life span with new insights into human T cell development.
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Construction and Validation of a Ferroptosis-Related Prognostic Signature for Melanoma Based on Single-Cell RNA Sequencing.
Melanoma, the deadliest type of skin cancer, is on the rise globally. The generally poor prognosis makes melanoma still an enormous public health problem. Ferroptosis is a newly emerging form of iron-dependent regulated cell death, which has been implicated in the development and treatment of several tumors. However, whether there is a connection between ferroptosis-related genes and the prognosis of melanoma patients remains an enigma. In the present study, we identified a ferroptosis-related genes signature to predict the prognosis of melanoma patients by analyzing single-cell RNA-sequencing data from the Gene Expression Omnibus (GEO). Single-cell trajectory analysis was performed to explore malignant differentiation. CellChat was used to investigate intercellular communications in melanoma. Collectively, a novel four-gene signature (CP, MAP1LC3A, transferrin, and TP53) was constructed for prognosis prediction. COX proportional hazards regression analysis showed that the established ferroptosis-associated risk model was an independent prognostic predictor for melanoma patients (HR = 2.3293; 95%CI 1.1528-4.706) (p < 0.018). Patients with low-risk scores had significantly better overall survival (OS) than those with high-risk scores in The Cancer Genome Atlas, GSE59455, and GSE22153 dataset (p = 0.0015, p = 0.031, p = 0.077). Furthermore, the gene expression level of the four genes were verified in multistrain melanoma cell lines and normal human epidermal melanocytes (NHEM). The protein expression level of the four genes in clinical samples were further verified in the Human Protein Atlas (HPA) databases. Taken together, our study identified the prognostic significance of the ferroptosis-related genes in melanoma and developed a novel four-gene prognostic signature, which may shed light on the prognostic assessment and clinical decision making for melanoma patients.
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A multimodal atlas of COVID-19 severity identifies hallmarks of dysregulated immunity.
The alpha-variant wave of the COVID-19 pandemic provided a unique opportunity to study, at single-cell resolution, how near-universal exposure to the same pathogen can lead to either effective or dysfunctional immune responses in humans. Although single-cell RNA-sequencing studies have characterized immune cellular features of COVID-19, they have not shown how tocilizumab treatment changes these features at single-cell resolution, or which features might persist into convalescence. In this study, we analyzed 2.5 million circulating immune cells from 428 patients across time points (840 PBMC samples), encompassing three contemporaneous SARS-CoV-2 cohorts: acutely infected patients across five WHO disease severity levels and three time points, patients from the first randomized control trial to study the efficacy of tocilizumab in the management of COVID-19, and convalescent patients three months after infection. We used linear modeling to integrate multiple data types - including single-cell RNA-seq, CITE-seq, TCR and BCR sequencing, viral load measurements, viral neutralization assays, detection of 75 autoantibodies, HLA genotype data, and serum proteomics covering 1,463 targets - to derive the most comprehensive view to-date of the biological features of COVID-19 disease severity. Our findings show that myeloid-derived suppressor cells (MDSCs) act as a key immunologic pivot point in severe COVID-19. Myeloid dysfunction, which is marked by impaired antigen presentation, drives a non-productive adaptive immune response, as reflected by reduced expression of B and T cell gene programs involved in antigen recognition, immune synapse formation, and cytotoxicity. Severe disease is also linked to autoantibodies targeting type I interferons, influenced by specific HLA-DQB1 allelic variants, and strongly correlated with serum IL-6 levels. Tocilizumab treatment eliminates CLU -expressing MDSCs and ISG-positive myeloid subsets, restores antigen presentation, and reactivates productive adaptive immunity. These changes align with improved clinical outcomes and better clinical laboratory measures, including reduced CRP. While many immunologic abnormalities in acute severe COVID-19 resolve during convalescence 3-months post-infection, we observed persistently high ICOS expression in regulatory T cells, potentially linking acute infection to chronic post-COVID syndromes. Overall, we define distinct innate and adaptive host immune responses associated with acute, IL-6-responsive, and convalescent SARS-CoV-2 infection. Our multimodal and high-dimensional dataset with curated clinical metadata provides a foundational and clinically relevant resource for modeling host immune response biology in health and disease.
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Assessing the effects of aging on the renal endothelial cell landscape using single-cell RNA sequencing.
Endothelial cells (ECs) with senescence-associated secretory phenotypes (SASP) have been identified as a key mechanism of aging that contributes to various age-related kidney diseases. In this study, we used single-cell RNA sequencing (scRNA-seq) to create a transcriptome atlas of murine renal ECs and identify transcriptomic changes that occur during aging. We identified seven different subtypes of renal ECs, with glomerular ECs and angiogenic ECs being the most affected by senescence. We confirmed our scRNA-seq findings by using double immunostaining for an EC marker (CD31) and markers of specialized EC phenotypes. Our analysis of the dynamics of capillary lineage development revealed a chronic state of inflammation and compromised glomerular function as prominent aging features. Additionally, we observed an elevated pro-inflammatory and pro-coagulant microenvironment in aged glomerular ECs, which may contribute to age-related glomerulosclerosis and renal fibrosis. Through intercellular communication analysis, we also identified changes in signaling involved in immune regulation that may contribute to a hostile microenvironment for renal homeostasis and function. Overall, our findings provide new insights into the mechanisms of aging in the renal endothelium and may pave the way for the discovery of diagnostic biomarkers and therapeutic interventions against age-related kidney diseases.