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Single-Cell RNA-Seq Reveals a Population of Smooth Muscle Cells Responsible for Atherogenesis.
Understanding the regional propensity differences of atherosclerosis (AS) development is hindered by the lack of animal models suitable for the study of the disease process. In this paper, we used 3S-ASCVD dogs, an ideal large animal human-like models for AS, to interrogate the heterogeneity of AS-prone and AS-resistant arteries; and at the single-cell level, identify the dominant cells involved in AS development. Here we present data from 3S-ASCVD dogs which reliably mimic human AS pathophysiology, predilection for lesion sites, and endpoint events. Our analysis combined bulk RNA-seq with single-cell RNA-seq to depict the transcriptomic profiles and cellular atlas of AS-prone and AS-resistant arteries in 3S-ASCVD dogs. Our results revealed the integral role of smooth muscle cells (SMCs) in regional propensity for AS. Notably, TNC+ SMCs were major contributors to AS development in 3S-ASCVD dogs, indicating enhanced extracellular matrix remodeling and transition to myofibroblasts during the AS process. Moreover, TNC+ SMCs were also present in human AS-prone carotid plaques, suggesting a potential origin of myofibroblasts and supporting the relevance of our findings. Our study provides a promising large animal model for pre-clinical studies of ASCVD and add novel insights surrounding the regional propensity of AS development in humans, which may lead to interventions that delay or prevent lesion progression and adverse clinical events.
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Comprehensive Transcriptomic Analysis Reveals Cell-Type-Specific Roles of Human Odorant Receptors in Glioblastoma and the Tumor Microenvironment.
Odorant receptors (ORs), which constitute approximately 50% of all human G protein-coupled receptors, are increasingly recognized for their diverse roles beyond odor perception, including functions in various pathological conditions like brain diseases and cancers. However, the roles of ORs in glioblastoma (GBM), the most aggressive primary brain tumor with a median survival of only 15 months, remain largely unexplored. Here, we performed an integrated transcriptomic analysis combining The Cancer Genome Atlas RNA-seq and single-cell RNA sequencing data from GBM patients to uncover cell-type-specific roles of ORs within the tumor and its microenvironment. Our findings reveal that ORs display distinct expression patterns, with OR51E1 enriched in pericytes linked to vascular remodeling and angiogenesis, OR2B11 associated with tumor-associated macrophages supporting immunosuppressive phenotypes, and OR2L13 correlated with synaptic activity in recurrent tumors, potentially mediating treatment-induced neuronal adaptations. These results highlight ORs as potential therapeutic targets, offering new insights into their regulatory roles in GBM progression, immune modulation, and treatment resistance.
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Single-Nucleus RNA-Seq Reveals Spermatogonial Stem Cell Developmental Pattern in Shaziling Pigs.
Normal testicular development ensures the process of spermatogenesis, which is a complex biological process. The sustained high productivity of spermatogenesis throughout life is predominantly attributable to the constant proliferation and differentiation of spermatogonial stem cells (SSCs). The self-renewal and differentiation processes of SSCs are strictly regulated by the SSC niche. Therefore, understanding the developmental pattern of SSCs is crucial for spermatogenesis. The Shaziling pig is a medium-sized indigenous pig breed originating from central China. It is renowned for its superior meat quality and early male sexual maturity. The spermatogenic ability of the boars is of great economic importance to the pig industry. To investigate testicular development, particularly the pattern of SSC development in Shaziling pigs, we used single-cell transcriptomics to identify gene expression patterns in 82,027 individual cells from nine Shaziling pig testes at three key postnatal developmental stages. We generated an unbiased cell developmental atlas of Shaziling pig testicular tissues. We elucidated the complex processes involved in the development of SSCs within their niche in the Shaziling pig. Specifically, we identified potential marker genes and cellular signaling pathways that regulate SSC self-renewal and maintenance. Additionally, we proposed potential novel marker genes for SSCs that could be used for SSC isolation and sorting in Shaziling pigs. Furthermore, by immunofluorescence staining of testicular tissues of different developmental ages using marker proteins (UCHL1 and KIT), the developmental pattern of the spermatogonia of Shaziling pigs was intensively studied. Our research enhances the comprehension of the development of SSCs and provides a valuable reference for breeding Shaziling pigs.
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CCDC86 modulates immune cell infiltration and disease progression in head and neck squamous cell carcinoma.
BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is a prevalent and aggressive cancer with poor prognosis despite advancements in treatment. The immune system plays a crucial role in HNSCC progression, yet the specific mechanisms linking immune cells to tumor development remain poorly understood. Coiled-coil domain-containing protein 86 (CCDC86) has been implicated in immune dysregulation, but its role in HNSCC has not been explored. This study investigates the expression of CCDC86 in HNSCC, its association with immune infiltration, and its potential as a prognostic biomarker. METHODS: This study integrates single-cell RNA sequencing (scRNA-seq), The Cancer Genome Atlas (TCGA) data, and Mendelian randomization (MR) analysis. scRNA-seq datasets from normal oral mucosa and HNSCC tissues were used to analyze CCDC86 expression in different cell populations. TCGA data were employed to assess the correlation between CCDC86 expression and clinicopathological features of HNSCC. MR analysis was conducted to explore the causal relationship between CCDC86 and immune cell phenotypes in HNSCC. RESULTS: CCDC86 was significantly overexpressed in HNSCC tissues compared to normal tissues. High expression of CCDC86 was associated with poor prognosis, correlating with histological grade, clinical stage, and survival outcomes. Gene ontology (GO) and KEGG pathway analyses revealed that CCDC86 is involved in immune cell activation and receptor complex assembly. A negative correlation between CCDC86 expression and immune infiltration, especially in dendritic cells (DCs) and T cells, was observed. MR analysis confirmed a causal relationship between CCDC86 expression and HNSCC risk, with a notable effect on immune cell populations, particularly myeloid DCs. CONCLUSION: CCDC86 expression is upregulated in HNSCC and is associated with adverse clinicopathological features and poor prognosis. CCDC86 modulates immune cell infiltration, particularly inhibiting the function of conventional dendritic cells. These findings suggest that CCDC86 could serve as a prognostic biomarker and a potential therapeutic target for HNSCC treatment.
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Defining the urine proteome in boys with posterior urethral valves: a pilot study.
INTRODUCTION: Posterior urethral valves (PUV) is the most common cause of congenital bladder outlet obstruction and a major etiology of end-stage kidney disease in boys. There are significant knowledge gaps about the pathogenesis and prognostic indicators of kidney and bladder dysfunction in boys with PUV. METHODS: We utilized liquid chromatography-tandem mass spectrometry to analyze the urine proteome in a pilot cohort of 20 boys with PUV compared to 20 unaffected controls, with a focus on estimated glomerular filtration rate (eGFR) variation within the PUV group and its impact on urine protein signatures. Eight complementary workflows for differential expression analysis were developed to ensure robust detection of differential protein expression. A single-cell RNA-seq atlas of 162,083 healthy kidney, ureter, and bladder cells was assembled to infer tissue and cellular origins of PUV-associated proteins. RESULTS: In cases of PUV with preserved eGFR, upregulation of keratins and uroplakins was detected, suggestive of urothelial injury and remodeling that may reflect bladder dysfunction that occurs early in the disease process, even before a decline in renal function. In contrast, cases with low eGFR were associated with declining levels of the proteins related to viability and synthetic function of specific nephron and collecting duct segments, along with increased levels of proteins related to complement activation and inflammation, suggestive of progressive renal injury. The single-cell atlas provided biological context, identifying putative renal and urothelial cell sources for these proteins. CONCLUSION: This integrative analysis highlights biological pathways and proteins that may reflect kidney and urinary tract injury and dysfunction in a pilot cohort of boys with PUV. These initial findings warrant further testing in longitudinal studies with larger cohorts to link the urine proteome to clinically relevant kidney and bladder outcomes.
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Integration of Single-Cell Transcriptomics and Network-Based Machine Learning Identifies Bone Marrow Mesenchymal Stem Cell-Associated Candidate Biomarkers and Exploratory Immune Correlates in Osteoarthritis.
INTRODUCTION: Osteoarthritis (OA) is a whole-joint disease involving coordinated changes in subchondral bone, Bone Marrow Mesenchymal Stem cells (BM-MSCs), and synovium. This study aimed to identify BM-MSC-associated and OA-related candidate biomarkers and evaluate their potential diagnostic and immune-related relevance. METHODS: The scRNA-seq dataset GSE147287 was used to construct an OA subchondral bonemarrow atlas, identify BM-MSC populations, perform BM-MSC sub-clustering, and derive BMMSC co-expression modules and hub genes using hdWGCNA. Three synovial transcriptomic datasets (GSE55457, GSE55235, and GSE55584) were integrated as the training cohort after datasetspecific log2 (expression + 1) transformation and ComBat correction, whereas GSE12021 was processed independently as an external validation cohort. BM-MSC hub genes were intersected with OA-related synovial DEGs and further prioritized using LASSO, SVM-RFE, and XGBoost. A combined four-gene model was constructed using Firth's penalized logistic regression. Diagnostic performance was evaluated by ROC analysis, cellular expression was validated in IL-1β-stimulated hBMSCs by qRT-PCR, and immune-cell and Hallmark pathway correlations were assessed using ssGSEA and Spearman analysis with Benjamini-Hochberg correction. RESULTS: The single-cell atlas contained nine major cell types, and BM-MSC sub-clustering identified four transcriptionally distinct subclusters. Cross-tissue integration yielded 35 BM-MSCassociated and OA-related candidate genes, from which EFEMP2, CTSO, SPRY1, and NFIC were selected. In the training cohort, the AUCs were 0.890 (95% CI, 0.792-0.989) for EFEMP2, 0.896 (95% CI, 0.802-0.990) for CTSO, 0.892 (95% CI, 0.797-0.987) for SPRY1, and 0.769 (95% CI, 0.630-0.908) for NFIC. In GSE12021, the corresponding AUCs were 0.867 (95% CI, 0.698-1.000), 0.922 (95% CI, 0.801-1.000), 0.922 (95% CI, 0.797-1.000), and 0.856 (95% CI, 0.674-1.000), respectively. The combined four-gene model achieved AUCs of 0.998 (0.993-1.000) in the training cohort and 1.000 (1.000-1.000) in GSE12021. qRT-PCR confirmed the upregulation of EFEMP2 and CTSO and the downregulation of SPRY1 and NFIC in IL-1β-stimulated hBMSCs. After Benjamini- Hochberg correction, no immune-cell or Hallmark pathway correlations remained statistically significant, although several moderate exploratory trends were observed. DISCUSSION: EFEMP2, CTSO, SPRY1, and NFIC represent BM-MSC-associated and OA-related candidate biomarkers. These findings provide a hypothesis-generating framework for characterizing OA-related stromal states and developing future tissue-fitness or patient-stratification tools, but further clinical and tissue-specific validation is required. CONCLUSION: EFEMP2, CTSO, SPRY1, and NFIC were identified as BM-MSC-associated and OArelated candidate biomarkers. These findings provide a hypothesis-generating framework for characterizing OA-related stromal states and developing future tissue-state assessment or patientstratification tools, although further tissue-specific and clinical validation is required.
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Revealing the Key MSCs Niches and Pathogenic Genes in Influencing CEP Homeostasis: A Conjoint Analysis of Single-Cell and WGCNA.
Degenerative disc disease (DDD), a major contributor to discogenic pain, which is mainly resulted from the dysfunction of nucleus pulposus (NP), annulus fibrosis (AF) and cartilage endplate (CEP) cells. Genetic and cellular components alterations in CEP may influence disc homeostasis, while few single-cell RNA sequencing (scRNA-seq) report in CEP makes it a challenge to evaluate cellular heterogeneity in CEP. Here, this study conducted a first conjoint analysis of weighted gene co-expression network analysis (WGCNA) and scRNA-seq in CEP, systematically analyzed the interested module, immune infiltration situation, and cell niches in CEP. WGCNA and protein-protein interaction (PPI) network determined a group of gene signatures responsible for degenerative CEP, including BRD4, RAF1, ANGPT1, CHD7 and NOP56; differentially immune analysis elucidated that CD4+ T cells, NK cells and dendritic cells were highly activated in degenerative CEP; then single-cell resolution transcriptomic landscape further identified several mesenchymal stem cells and other cellular components focused on human CEP, which illuminated niche atlas of different cell subpopulations: 8 populations were identified by distinct molecular signatures. Among which, NP progenitor/mesenchymal stem cells (NPMSC), also served as multipotent stem cells in CEP, exhibited regenerative and therapeutic potentials in promoting bone repair and maintaining bone homeostasis through SPP1, NRP1-related cascade reactions; regulatory and effector mesenchymal chondrocytes could be further classified into 2 different subtypes, and each subtype behaved potential opposite effects in maintaining cartilage homeostasis; next, the potential functional differences of each mesenchymal stem cell populations and the possible interactions with different cell types analysis revealed that JAG1, SPP1, MIF and PDGF etc. generated by different cells could regulate the CEP homeostasis by bone formation or angiogenesis, which could be served as novel therapeutic targets for degenerative CEP. In brief, this study mainly revealed the mesenchymal stem cells populations complexity and phenotypic characteristics in CEP. In brief, this study filled the gap in the knowledge of CEP components, further enhanced researchers' understanding of CEP and their cell niches constitution.
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Comprehensive analysis of gene signatures associated with aging in human aortic dissection.
BACKGROUND: Aortic dissection (AD) is a lethal aortic disease with limited effective therapeutic strategies. Aging increases the risk of AD, yet the underlying mechanisms remain unclear. This study aims to analyze the association of aging-related genes (Args) and AD using bioinformatic analysis. This helps provide novel insights into AD pathogenesis and contributes to developing novel therapeutic strategies. METHODS: mRNA (GSE52093, GSE153434), miRNA (GSE98770) and single-cell RNA-sequencing (scRNA-seq, GSE213740) datasets of AD were downloaded from GEO database. Args were downloaded from Aging Atlas database. Differentially-expressed Args were determined by intersecting Args and differentially-expressed mRNAs of two mRNA datasets. Cytoscape was used to identify hub genes and construct hub gene regulatory networks related to miRNAs. Seurat and clusterProfiler R package were used for investigating expression patterns of hub genes at single-cell level, and functional analysis, respectively. To validate the cellular expression pattern of hub genes, the same analysis was applied to our own scRNA-seq data. Drugs targeting hub Args were determined using the DGIdb database. RESULTS: HGF, CXCL8, SERPINE1, HIF1A, TIMP1, ESR1 and PLAUR were identified as aging-related hub genes in AD. miR-221-3p was predicted to interact with ESR1. A decreased ESR1 expression in smooth muscle cell subpopulation 4 (SMC4) was observed in AD versus normal aortic tissues, which was validated by sequencing 197,605 aortic cells from 13 AD patients. Additionally, upregulated genes of SMC4 in AD tissues were enriched in the "cellular senescence" pathway. These data indicated that decreased ESR1 might promote SMC4 aging during AD formation. Eleven existing drugs targeting hub genes were identified, including ruxolitinib and filgrastim, which are associated with AD. CONCLUSIONS: By sequencing transcriptomic data, this study revealed aging-related hub genes and regulatory network involved in AD formation. Additionally, this study proposed a noteworthy hypothesis that downregulated ESR1 may exacerbate AD by promoting SMC aging, which requires further investigation.
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GSK3β as a potential regulator in AML: A pan-cancer multi-omics analysis.
The distinct roles of GSK3 isoforms (GSK3α/β) in tumorigenesis and immune modulation remain poorly characterized across malignancies. We integrated multi-omics data from TCGA, GTEx, and single-cell RNA-seq to analyze GSK3α/β expression patterns in 31 cancers. Functional clustering, survival analysis (Cox regression), immune infiltration, and in vitro validation (AML cell lines treated with CHIR-99021) were performed. Integrated multi-omics analysis of 31 malignancies revealed divergent dysregulation of GSK3 isoforms: GSK3α was upregulated in 19 solid tumors but suppressed in AML, while GSK3β was elevated in 23 cancers and high-risk AML subtypes (FAB-M0/M1, P = 0.0013). GSK3β outperformed GSK3α as a pan-cancer diagnostic biomarker, achieving superior AUC in 9 tumors. Prognostically, high GSK3α predicted poor OS in ACC (HR = 8.80, P = 0.0047) and MESO (HR = 2.75, P < 0.0067), whereas GSK3β independently stratified cytogenetic-risk AML (HR = 4.22, P = 0.007). Immune profiling uncovered isoform-specific TME modulation: GSK3α correlated with protumorigenic immune infiltration (Treg/Th17, r = 0.38), contrasting GSK3β's broad negative associations with cytotoxic effectors (r = -0.27). Functional validation in AML THP-1 cells demonstrated that the GSK3 inhibitor CHIR-99021 (10 μM) significantly suppressed proliferation, induced apoptosis, and caused S-phase cell cycle arrest, concomitant with downregulation of c-Myc. These findings establish GSK3β as a key regulator of oncogenic programs in AML. This study provides a comprehensive pan-cancer atlas of GSK3 isoform-specific functionality, nominating GSK3β as a high-priority therapeutic target.
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The Predictive Value of Neutrophil Extracellular Trap-Related Risk Score in Prognosis and Immune Microenvironment of Colorectal Cancer Patients.
Colorectal cancer (CRC) has brought great healthy burden for patients. Neutrophil extracellular traps (NETs) have been explored in several tumors, while it remains largely unclear in CRC. CRC-related data were downloaded from Cancer Genome Atlas and Gene Expression Omnibus databases. Then, a NET risk score was built after univariate Cox and LASSO Cox regression analysis. Prognostic value was evaluated via survival analysis, stratification analysis, and ROC analysis. The functional enrichment analysis was conducted basing on bulk and scRNA-seq data. The immune landscape difference was analyzed using CIBERSORT, XCell, and MCPcounter portals. NET risk score was built for CRC patients, basing on G0S2, HIST1H2BC, CRISPLD2, and IL17A. In TCGA-CRC and validation datasets, regardless of age or gender, high-risk CRC patients had significantly worse prognosis, besides higher NET risk score was mainly found in samples with MSI-H and advanced T, N, and M stages. Employing multiple databases, we noticed that M0 and M2 Macrophages infiltrated the most in high-risk CRC patients, besides M2 Macrophages and neutrophils showed positive correlation with NET risk score. A novel reliable prognostic NET risk score was developed for CRC patients, and high-risk patients had unfavorable prognosis with advanced disease status.