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Cross-tissue organization of the fibroblast lineage.
Fibroblasts are non-haematopoietic structural cells that define the architecture of organs, support the homeostasis of tissue-resident cells and have key roles in fibrosis, cancer, autoimmunity and wound healing1. Recent studies have described fibroblast heterogeneity within individual tissues1. However, the field lacks a characterization of fibroblasts at single-cell resolution across tissues in healthy and diseased organs. Here we constructed fibroblast atlases by integrating single-cell transcriptomic data from about 230,000 fibroblasts across 17 tissues, 50 datasets, 11 disease states and 2 species. Mouse fibroblast atlases and a DptIRESCreERT2 knock-in mouse identified two universal fibroblast transcriptional subtypes across tissues. Our analysis suggests that these cells can serve as a reservoir that can yield specialized fibroblasts across a broad range of steady-state tissues and activated fibroblasts in disease. Comparison to an atlas of human fibroblasts from perturbed states showed that fibroblast transcriptional states are conserved between mice and humans, including universal fibroblasts and activated phenotypes associated with pathogenicity in human cancer, fibrosis, arthritis and inflammation. In summary, a cross-species and pan-tissue approach to transcriptomics at single-cell resolution has identified key organizing principles of the fibroblast lineage in health and disease.
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Single cell atlas of developing mouse dental germs reveals populations of CD24+ and Plac8+ odontogenic cells.
The spatiotemporal relationships in high-resolution during odontogenesis remain poorly understood. We report a cell lineage and atlas of developing mouse teeth. We performed a large-scale (92,688 cells) single cell RNA sequencing, tracing the cell trajectories during odontogenesis from embryonic days 10.5 to 16.5. Combined with an assay for transposase-accessible chromatin with high-throughput sequencing, our results suggest that mesenchymal cells show the specific transcriptome profiles to distinguish the tooth types. Subsequently, we identified key gene regulatory networks in teeth and bone formation and uncovered spatiotemporal patterns of odontogenic mesenchymal cells. CD24+ and Plac8+ cells from the mesenchyme at the bell stage were distributed in the upper half and preodontoblast layer of the dental papilla, respectively, which could individually induce nonodontogenic epithelia to form tooth-like structures. Specifically, the Plac8+ tissue we discovered is the smallest piece with the most homogenous cells that could induce tooth regeneration to date. Our work reveals previously unknown heterogeneity and spatiotemporal patterns of tooth germs that may lead to tooth regeneration for regenerative dentistry.
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TAGAP expression influences CD4+ T cell differentiation, immune infiltration, and cytotoxicity in LUAD through the STAT pathway: implications for immunotherapy.
BACKGROUND: T-cell Activation GTPase Activating Protein (TAGAP) plays a role in immune cell regulation. This study aimed to investigate TAGAP's expression and its potential impact on CD4+ T cell function and prognosis in lung adenocarcinoma (LUAD). METHODS: We analyzed TAGAP expression and its correlation with immune infiltration and clinical data in LUAD patients using multiple datasets, including The Cancer Genome Atlas (TCGA-LUAD), Gene Expression Omnibus (GEO), and scRNA-seq datasets. In vitro and in vivo experiments were conducted to explore the role of TAGAP in CD4+ T cell function, chemotaxis, and cytotoxicity. RESULTS: TAGAP expression was significantly lower in LUAD tissues compared to normal tissues, and high TAGAP expression correlated with better prognosis in LUAD patients. TAGAP was positively correlated with immune/stromal/ESTIMATE scores and immune cell infiltration in LUAD. Single-cell RNA sequencing revealed that TAGAP was primarily distributed in CD4+/CD8+ T cells. In vitro experiments showed that TAGAP overexpression enhanced CD4+ T cell cytotoxicity, proliferation, and chemotaxis. Gene Set Enrichment Analysis (GSEA) indicated that TAGAP was enriched in the JAK-STAT signaling pathway. In vivo experiments in a xenograft tumor model demonstrated that TAGAP overexpression suppressed tumor growth and promoted CD4+ T cell cytotoxicity. CONCLUSIONS: TAGAP influences CD4+ T cell differentiation and function in LUAD through the STAT pathway, promoting immune infiltration and cytotoxicity. This study provides a scientific basis for developing novel LUAD immunotherapy strategies and exploring new therapeutic targets.
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Ferroptosis and low-grade Glioma: The breakthrough potential of NUAK2.
BACKGROUND: Low-grade glioma (LGG) is a primary brain tumor with high cellular heterogeneity and recurrence, leading to poor prognosis. Standard treatments (surgery, radiotherapy, and chemotherapy) have limited efficacy. Ferroptosis, an iron-dependent form of regulated cell death, is a potential therapeutic target, while dysregulated ferroptosis-related genes (FRGs) may drive tumor progression and therapy resistance. METHODS: This study integrated multi-omics data from The Cancer Genome Atlas (TCGA), Chinese Glioma Genome Atlas (CGGA), and Gene Expression Omnibus (GEO) to identify FRGs associated with LGG prognosis. Single-cell RNA sequencing (scRNA-seq) and pseudotime trajectory analysis were performed to investigate their functional roles. Key findings were validated through in vitro and in vivo experiments. RESULTS: We identified 345 FRGs associated with LGG prognosis, which are involved in oxidative stress response, cell proliferation, and immune regulation. High-risk patients exhibited an immunosuppressive tumor microenvironment with elevated levels of M2 macrophages and Treg cells but reduced CD8+ T cell infiltration. Pseudotime trajectory analysis highlighted the dynamic roles of macrophages and astrocytes in immune evasion and microenvironment remodeling. Notably, the NUAK2 gene emerged as a key driver of tumor progression and immune suppression. In vitro and in vivo experiments confirmed that targeting NUAK2 significantly reduced tumor cell viability and growth, underscoring its critical regulatory role in LGG. CONCLUSIONS: Our study provides comprehensive insights into the role of FRGs in LGG prognosis and tumor microenvironment regulation, with a particular focus on the NUAK2 gene. As a potential therapeutic target, NUAK2's critical role in tumor progression and immune evasion offers a new direction for LGG treatment. Future research should focus on validating NUAK2's role in larger cohorts and exploring its clinical application as a biomarker and therapeutic target.
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Up-regulated DSG2 promotes tumor growth and reduces immune infiltration in cervical cancer.
BACKGROUND: Desmoglein-2 (DSG2) has been reported to play pivotal roles in various diseases. However, its roles in cervical cancer (CC) remain insufficiently elucidated. Here, we aimed to comprehensively explore the functional mechanisms of DSG2 in CC using bioinformatics and experimental methods. METHODS: Several online databases, including Gene Expression Profiling Interactive Analysis (GEPIA), ONCOMINE, LinkedOmics, MetaScape, Human protein atlas (HPA), OMICS and single-cell RNA sequencing (scRNA-seq) data were used to explore the expression, prognosis, gene mutations, and potential signaling pathway of DSG2 in CC. Quantitative real-time PCR (qRT-PCR) and western blotting were used to measure DSG2 expression in collected samples. Experimental assays were conducted to verify the effects of dysregulated DSG2 on cervical cell lines in vitro. RESULTS: Bioinformatic analyses revealed that DSG2 was significantly up-regulated in CC compared to normal cervical tissues at both mRNA and protein levels. Elevated DSG2 levels were also associated with poor prognosis and clinical parameters (e.g., cancer stages, tumor grade, nodal metastasis status, etc.). DSG2 expression was predominantly observed in epithelial cells, increasing with disease progression on a single-cell resolution. Additionally, up-regulation of DSG2 significantly enhanced tumor purity by reducing the infiltration of immune cells (e.g., B cells, T cells, NK cells, etc.). Over-expression of DSG2 was further validated in collected CC samples at both mRNA and protein levels. Knockdown of DSG2 markedly reduced the proliferation and invasion of CC cell lines in vitro. CONCLUSIONS: In summary, elevated levels of DSG2 were significantly associated with poor prognosis and diminished immune infiltration in CC. Thus, DSG2 may serve as a potential therapeutic and diagnostic biomarker for CC.
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Multi-omics data reveal that SAA1 + fibroblasts exacerbate periodontitis by regulating macrophage inflammation and chemotaxis.
BACKGROUND: Traditional techniques are limited in their ability to analyze the complex interaction mechanisms among multiple cell types within the periodontal microenvironment, thereby restricting the development of targeted therapies for periodontitis (PD). Utilizing multiomics technologies to investigate the interaction networks of key cell clusters can systematically uncover regulatory mechanisms and identify critical therapeutic targets. METHODS: Through integrative analysis of single-cell RNA sequencing (scRNA-seq), spatial transcriptomics, and bulk transcriptome datasets from periodontal tissues, we systematically characterized the spatial architecture and intercellular communication networks within the inflammatory periodontal microenvironment, identifying a functionally serum amyloid A1 + fibroblasts (SAA1 + Fib) that critically drives disease progression. Combined bioinformatics and functional validations (in vitro and in vivo) revealed the proinflammatory role of SAA1 + Fib, demonstrating their unique transcriptional profile and mechanistic contributions to periodontal inflammation. RESULTS: This study successfully constructed a single-cell transcriptome atlas comprising 65,979 periodontal tissue cells and identified an SAA1 + fibroblast subpopulation with key functions. Cell communication analysis revealed that this subpopulation mediates the infiltration of myeloid cells, such as macrophages, to the lesion site by secreting chemokine-related signaling molecules, including members of the SAA, CXCL, and CSF families. Animal experiments confirmed a significant increase in SAA1 expression levels in both the gingival tissue and peripheral blood of periodontitis model mice. Gene function studies indicated that SAA1 knockout resulted in reduced migration ability and enhanced proliferation activity of L929 cells, while significantly decreasing the secretion of inflammatory factors such as IL-6 and TNF-α. In a co-culture system of L929 cells and RAW264.7 cells, SAA1 knockout not only diminished the chemotactic effect of fibroblasts on macrophages but also suppressed the secretion of inflammatory factors and inhibited M1 polarization of macrophages. Mechanistic studies indicated that these effects were likely mediated by the suppression of NF-κB signaling pathway activity in RAW264.7 cells. CONCLUSION: We elucidated the pro-inflammatory properties of SAA1 + Fib and their role in promoting macrophage infiltration, targeting SAA1 offers a new approach for the treatment of PD.
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Molecular and Chromatin Accessibility Programs Underlying Epithelial Injury and Impaired Regeneration in Neonatal Necrotizing Enterocolitis.
BACKGROUND & AIMS: Neonatal necrotizing enterocolitis (NEC) is a severe gastrointestinal disorder with high mortality, characterized by epithelial cell injury and compromised epithelial repair. The mechanisms underlying defective epithelial regeneration remain poorly understood despite advances in single-cell omics. Addressing these challenges is essential for elucidating the pathogenesis of NEC and identifying therapeutic targets to restore epithelial regeneration and replace the damaged epithelial layer. METHODS: Using a well-established neonatal mouse model of NEC induced by formula feeding, hypoxia, and lipopolysaccharide, we applied an integrated multi-omics framework to map epithelial injury at transcriptomic, chromatin accessibility, and spatial levels. These included bulk RNA sequencing, single-nucleus RNA sequencing (snRNA-seq), single-nucleus assay for transposase-accessible chromatin sequencing (snATAC-seq), and multiplexed error-robust fluorescence in situ hybridization (MERFISH) for spatial transcriptomics. Complementary in vitro experiments and in vivo mouse models were utilized to evaluate NEC phenotypes, intestinal tissue morphology, and organoid formation. RESULTS: Changes in cell type composition, transcriptional network remodeling, and chromatin accessibility were observed in the small intestine of neonatal mice with NEC. Chromatin accessibility significantly changed in epithelial cells, highlighting their pivotal roles in NEC. A marked reduction in intestinal stem cells (ISCs) and transit-amplifying cells, along with an increased proportion of enteroendocrine cells, indicates disrupted epithelial regeneration and functional differentiation. These changes correlated with disrupted WNT signaling and stem cell maintenance genes (eg, Lgr5, Smoc2, Axin2) and activation of inflammatory and hypoxia-related pathways (eg, Il6, Tnfα). The epigenetic regulator Ezh2 was identified as a critical factor in maintaining LGR5+ ISCs and epithelial homeostasis. Knockdown of Ezh2 reduced stemness and proliferation-related gene expression and exacerbated inflammation. Reactivation of WNT signaling restored Ezh2 and Lgr5 expression, improving intestinal regeneration. CONCLUSIONS: This study provides a comprehensive multi-omics atlas of epithelial injury in experimental NEC and reveals Ezh2 as a key regulator of LGR5+ ISC identity and regeneration. By integrating chromatin, transcriptomic, and spatial information, our findings highlight previously unrecognized mechanisms of ISC failure in NEC and support therapeutic strategies targeting Ezh2 and WNT signaling to restore epithelial integrity.
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Palmitoylation-related gene expression and its prognostic value in prostate cancer: insights into immune infiltration and therapeutic potential.
BACKGROUND: Prostate cancer (PRAD/PCa) is a leading malignancy in men, with high incidence and mortality rates globally. Although treatments like androgen deprivation therapy (ADT) and chemotherapy have advanced, the prognosis for advanced or metastatic PCa remains unfavorable. Post-translational modifications (PTMs), particularly protein palmitoylation, have emerged as critical regulators of cancer progression and potential therapeutic targets. This study investigates the features of palmitoylation-related genes (PRGs) in PRAD, their links to immune infiltration, and potential therapeutic applications. METHODS: RNA-seq data and clinical information for PRAD were sourced from The Cancer Genome Atlas (TCGA), Deutsches Krebsforschungszentrum (DKFZ), Memorial Sloan Kettering Cancer Center (MSKCC), Gene Expression Omnibus (GEO), ArrayExpress, PCaProfiler, and PCaDB. Palmitoylation scores were calculated using the single-sample gene set enrichment analysis (ssGSEA) method. A prognostic model was developed based on characteristic genes from single-cell RNA sequencing (scRNA-seq) and validated in multiple external datasets. An integrative machine learning approach combining ten algorithms was used to construct a PRG signature. Potential drug sensitivity was analyzed using the oncoPredict R package, and experimental validation was performed on human prostate samples and PRAD cell lines. RESULTS: Significant variations in palmitoylation scores were observed across different PRAD patient types and cell populations. Higher palmitoylation scores were associated with poorer biochemical recurrence (BCR)-free survival in the TCGA dataset. The developed prognostic signature demonstrated significant differences in BCR among patients stratified by risk score. Patients with elevated risk scores demonstrated advanced clinical features such as increased age, advanced tumor stage, lymph node metastasis, elevated prostate-specific antigen (PSA) levels, higher Gleason scores, and BCR. Transcriptomic analysis identified unique gene expression profiles and pathway activities between high- and low-risk groups, with the high-risk group exhibiting heightened activation of oncogenic and immune-related pathways. PRG risk scores significantly impacted the immune landscape, with the high-risk group showing elevated immune checkpoint expression [e.g., programmed death 1 (PD-1) and programmed death ligand-1 (PD-L1)] and a more immunosuppressive microenvironment. Drug response analysis indicated that patients with different risk scores may respond differently to chemotherapy, with significant differences in the half-maximal inhibitory concentration (IC50) values for common chemotherapeutic agents. Functional importance and validation of hub genes, including cholinergic receptor nicotinic alpha 2 subunit (CHRNA2), supported their potential as therapeutic targets. Experimental validation of CHRNA2 knockdown in PRAD cells demonstrated significant inhibition of cell growth, migration, and invasion. CONCLUSIONS: This study underscores the prognostic importance of PRG expression in PRAD, linking it to tumor biology, immune infiltration, and treatment response. Targeting palmitoylation pathways may offer novel therapeutic opportunities for improving patient outcomes in PRAD. Future research should aim to clarify the molecular mechanisms of palmitoylation in PRAD and investigate its therapeutic potential through preclinical and clinical studies.
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Cross-talk of m6A methylation modification and the tumor microenvironment composition in esophageal cancer.
BACKGROUND: Esophageal cancer (EC) remains a significant clinical challenge, characterized by its aggressive nature and poor prognosis. Current therapeutic strategies, including targeted therapies, have limitations due to the complex interplay between tumor heterogeneity and the tumor microenvironment (TME). However, the specific contributions of N6-methyladenosine (m6A) methylation to the TME in EC are yet to be fully elucidated. METHODS: Through comprehensive bioinformatics analyses, a detailed examination of m6A regulators were conducted in EC using datasets from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). Single-cell RNA sequencing (scRNA-seq) and a consensus clustering algorithm was employed to classify m6A modification patterns and analyze their relationships with immune cell infiltration and clinical outcomes. Additionally, an m6A scoring system was developed based on principal component analysis to assess the prognostic value of identified m6A modification patterns. RESULTS: The findings revealed two distinct m6A modification clusters associated with divergent TME characteristics and immune infiltration profiles. Patients exhibiting the immune-inflamed phenotype (m6A cluster B) demonstrated significantly improved survival compared to those with the immune-excluded phenotype (m6A cluster A). Notably, m6A scores correlated positively with immune cell presence and related with adverse prognostic outcomes, indicating their potential as predictive biomarkers for immunotherapy responses. A low m6A score indicated a better response to immunotherapy. CONCLUSION: This study highlights the critical role of m6A methylation in shaping the TME and influencing immune dynamics in EC. The m6A score developed herein provides a novel quantitative tool for predicting tumor behavior and treatment efficacy, paving the way for more personalized immunotherapeutic strategies in clinical practice. This scoring system illustrates a strong correlation of EC with TME immune cell composition, suggesting potential as a biomarker for targeted therapeutic strategies for EC.
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A single-cell multi-omics atlas of rice.
Cell functions across eukaryotes are driven by specific gene expression programs, which are dependent on chromatin structure1-3. Here we report a single-cell multi-omics atlas of rice, one of the world's major crops. By simultaneously profiling chromatin accessibility and RNA expression in 116,564 cells from eight organs, we identified cell-type-specific gene regulatory networks and described novel cell states, such as a 'transitional state' in floral meristems. On the basis of our network analyses, we uncovered the function of the cell-type-specific regulatory hubs RSR1, F3H and LTPL120 during rice development. Our analysis revealed correlations between cell type and agronomic traits, as well as conserved and divergent cell-type functions during evolution. In summary, this study not only offers a unique single-cell multi-omics resource for a major crop but also advances our understanding of cell-type functions and the underlying molecular programs in rice.