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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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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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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.
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A single-cell and spatial wheat root atlas with cross-species annotations delineates conserved tissue-specific marker genes and regulators.
Despite the broad use of single-cell/nucleus RNA sequencing in plant research, accurate cluster annotation in less-studied plant species remains a major challenge due to the lack of validated marker genes. Here, we generated a single-cell RNA sequencing atlas of soil-grown wheat roots and annotated cluster identities by transferring annotations from publicly available datasets in wheat, rice, maize, and Arabidopsis. The predictions from our orthology-based annotation approach were next validated using untargeted spatial transcriptomics. These results allowed us to predict evolutionarily conserved tissue-specific markers and generate cell type-specific gene regulatory networks for root tissues of wheat and the other species used in our analysis. In summary, we generated a single-cell and spatial transcriptomics resource for wheat root apical meristems, including numerous known and uncharacterized cell type-specific marker genes and developmental regulators. These data and analyses will facilitate future cell type annotation in non-model plant species.
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Integrating single-cell and spatial transcriptomics to decipher the neuro-immune microenvironment of breast cancer brain metastasis: a key regulatory axis, prognostic model, and drug discovery.
BACKGROUND: Breast cancer brain metastasis (BCBM) is a lethal complication of advanced disease, facilitated by a specialized neuro-immune microenvironment, whereas its molecular regulators and spatial dynamics remain poorly understood. This study aimed to resolve cellular heterogeneity and intercellular signaling networks crosstalk in BCBM microenvironment by using integrated single-cell RNA sequencing (scRNA-seq) single-cell and spatial transcriptomics to identify key regulators, build a prognostic model, and computationally screen for potential therapies. METHODS: We analyzed public scRNA-seq and 10× Visium spatial transcriptomics datasets. Cell landscapes were resolved with Seurat, communication networks were inferred with CellChat, and spatial mapping was performed with Tangram. A prognostic risk model was developed from bulk RNA sequencing (RNA-seq) data from The Cancer Genome Atlas-Breast Cancer (TCGA-BRCA), the Gene Expression Omnibus (GEO) datasets using Least Absolute Shrinkage and Selection Operator-Cox (LASSO-Cox) regression and validated in an independent cohort. Potential small-molecule inhibitors were screened by molecular docking (AutoDock Vina) against AlphaFold-predicted target structures. RESULTS: The BCBM microenvironment exhibited high heterogeneity, with macrophages serving as the central signaling hub. A novel regulatory axis, interleukin-18 and myosin light chain kinase (IL-18/MYLK), was found to be specifically upregulated and co-localized at the tumor-brain interface. A risk-score model based on the IL-18/MYLK axis demonstrated robust prognostic value in both training and validation cohorts. The model further revealed that the upregulation of IL-18 and MYLK was associated with better overall survival. Virtual screening identified the MEK inhibitor, PD98059, as a high-affinity dual inhibitor of IL-18 and MYLK. CONCLUSIONS: This study delineates the neuro-immune landscape of BCBM progression and proposes the IL-18/MYLK axis as a critical driver of neuroinflammation and cytoskeletal remodeling. The prognostic model and the candidate compound PD98059 provide avenues for novel targeted therapeutic strategies.
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A single-cell atlas of chromatin accessibility in mouse organogenesis.
Organogenesis is a highly complex and precisely regulated process. Here we profiled the chromatin accessibility in >350,000 cells derived from 13 mouse embryos at four developmental stages from embryonic day (E) 10.5 to E13.5 by SPATAC-seq in a single experiment. The resulting atlas revealed the status of 830,873 candidate cis-regulatory elements in 43 major cell types. By integrating the chromatin accessibility atlas with the previous transcriptomic dataset, we characterized cis-regulatory sequences and transcription factors associated with cell fate commitment, such as Nr5a2 in the development of gastrointestinal tract, which was preliminarily supported by the in vivo experiment in zebrafish. Finally, we integrated this atlas with the previous single-cell chromatin accessibility dataset from 13 adult mouse tissues to delineate the developmental stage-specific gene regulatory programmes within and across different cell types and identify potential molecular switches throughout lineage development. This comprehensive dataset provides a foundation for exploring transcriptional regulation in organogenesis.
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Single-cell transcriptomics in MI identify Slc25a4 as a new modulator of mitochondrial malfunction and apoptosis-associated cardiomyocyte subcluster.
Myocardial infarction (MI) is the leading cause of premature death. The death of cardiomyocytes (CMs) and the dysfunction of the remaining viable CMs are the main pathological factors contributing to heart failure (HF) following MI. This study aims to determine the transcriptional profile of CMs and investigate the heterogeneity among CMs under hypoxic conditions. Single-cell atlases of the heart in both the sham and MI groups were developed using single-cell data (GSE214611) downloaded from Gene Expression Omnibus (GEO) database ( https://www.ncbi.nlm.nih.gov/geo/ ). The heterogeneity among CMs was explored through various analyses including enrichment, pseudo time, and intercellular communication analysis. The marker gene of C5 was identified using differential expression analysis (DEA). Real-time polymerase chain reaction (RT-PCR), bulk RNA-sequencing dataset analysis, western blotting, immunohistochemical and immunofluorescence staining, Mito-Tracker staining, TUNEL staining, and flow cytometry analysis were conducted to validate the impact of the marker gene on mitochondrial function and cell apoptosis of CMs under hypoxic conditions. We identified a cell subcluster named C5 that exhibited a close association with mitochondrial malfunction and cellular apoptosis characteristics, and identified Slc25a4 as a significant biomarker of C5. Furthermore, our findings indicated that the expression of Slc25a4 was increased in failing hearts, and the downregulation of Slc25a4 improved mitochondrial function and reduced cell apoptosis. Our study significantly identified a distinct subcluster of CMs that exhibited strong associations with ventricular remodeling following MI. Slc25a4 served as the hub gene for C5, highlighting its significant potential as a novel therapeutic target for MI.