Браузер не даёт сохранять данные (например, приватный режим): закладки пропадут после закрытия вкладки.
Поиск статей PubMed
Ключевые слова, автор, журнал, годы — результаты из PubMed, аннотации с переводом на русский, закладки в браузере.
Найдено: 4 920
Страница 199 из 492-
Single-cell spatial transcriptomic profiling defines a pathogenic inflammatory niche in chronic active multiple sclerosis lesions.
Compartmentalized inflammation is a key driver of multiple sclerosis (MS) progression, but the mechanisms sustaining its persistence remain unclear. A hallmark of this persistent and slowly evolving inflammatory process is chronic active MS lesions. We generated a high-resolution, single-cell molecular and spatial atlas of such lesions by combining single-nucleus RNA sequencing (snRNA-seq) with multiplexed error-robust fluorescence in situ hybridization (MERFISH). Within lesion rims, we identified CD8+ T cell niches associated with inflamed microglia displaying an interferon response and upregulated lipid metabolism. To investigate their function, we deleted ATP-binding cassette transporters A1 and G1 (ABCA1/G1) in the microglia of mice with experimental autoimmune encephalomyelitis (EAE), which increased the formation of lipid-storing phagocytes that amplified inflammation. Moreover, pharmacologically targeting sterol metabolism mitigated foam cell formation and inflammatory demyelination in EAE. Thus, our high-resolution map of immune niches in chronic active MS lesions identifies a role for lipid-storing, dysfunctional microglia in persistent neuroinflammation.
-
A new perspective: deciphering the aberrance and clinical implication of disulfidptosis signatures in clear cell renal cell carcinoma.
Recent research has discovered disulfidptosis as a form of programmed cell death characterized by disulfide stress. However, its significance in clear cell renal cell carcinoma (ccRCC) remains unclear. To investigate this, data from The Cancer Genome Atlas were collected and used to identify ccRCC subgroups. Unsupervised clustering was employed to determine ccRCC heterogeneity. The mutation landscape and immune microenvironment of the subgroups were analyzed. The Disulfidptosis-Related Score was calculated using the LASSO-penalized Cox regression algorithm. The E-MATB-1980 cohort was used to validate the signature. The role of SLC7A11 in ccRCC metastasis was explored using western blotting and Transwell assays. Disulfidptosis-related genes are commonly downregulated in cancers and are linked to hypermethylation and copy number variation. The study revealed that ccRCC is divided into two sub-clusters: the disulfidptosis-desert sub-cluster, which is associated with a poor prognosis, a higher mutation frequency, and an immunosuppressive microenvironment. A 14-gene prognostic model was developed using differentially expressed genes and was validated in the E-MATB-1980 cohort. The low-risk group demonstrated longer overall and disease-free survival and responded better to targeted immunotherapy. Results from in vitro experiments identified SLC7A11 as a key participant in ccRCC metastasis.
-
Leveraging single-cell RNA-seq for uncovering naïve B cells associated with better prognosis of hepatocellular carcinoma.
Hepatocellular carcinoma (HCC) is a typical highly heterogeneous solid tumor with high morbidity and mortality worldwide, especially in China; however, the immune microenvironment of HCC has not been clarified so far. Here, we employed single-cell RNA sequencing (scRNA-seq) on diethylnitrosamine (DEN)-induced mouse HCC model to dissect the immune cell dynamics during tumorigenesis. Our findings reveal distinct immune profiles in both precancerous and cancerous lesions, indicating early tumor-associated immunological alterations. Notably, specific T and B cell subpopulations are preferentially enriched in the HCC tumor microenvironment (TME). Furthermore, we identified a subpopulation of naïve B cells with high CD83 expression, correlating with improved prognosis in human HCC. These signature genes were validated in The Cancer Genome Atlas HCC RNA-seq dataset. Moreover, cell interaction analysis revealed that subpopulations of B cells in both mouse and human samples are activated and may potentially contribute to oncogenic processes. In summary, our study provides insights into the dynamic immune microenvironment and cellular networks in HCC pathogenesis, with a specific emphasis on naïve B cells. These findings emphasize the significance of targeting TME in HCC patients to prevent HCC pathological progression, which may give a new perspective on the therapeutics for HCC.
-
A spatially resolved single-cell atlas identifies blood-brain barrier integrity as a central regulator of macrophages and microglia localization and functional states in gliomas.
Given that glioma-associated macrophages and microglia (GAMs) critically shape tumor evolution, we aimed to define their spatial distribution and functional reprogramming in relation to MRI-defined BBB integrity. Twelve patients underwent MRI-guided sampling, yielding 65 biopsies from 40 enhancing and 25 non-enhancing areas. Single-cell RNA-seq generated a high-resolution cellular atlas, and we analyzed cellular composition, transcriptional programs, macrophage polarization, and transcriptional subtype distribution relative to anatomical region and enhancement status. We profiled 5445 cells and identified 9 major cell populations. Macrophages were enriched in tumoral and enhancing regions, whereas microglia predominated in peritumoral and non-enhancing niches. Tumor cells in enhancing regions exhibited a growth-dominant anabolic state, while non-enhancing and peritumoral tumor cells retained neuronal development and synapse organization programs. GAMs displayed region-specific functional polarization: peritumoral and non-enhancing macrophages were enriched for neural development and tissue remodeling programs, whereas tumoral and enhancing macrophages activated chemotactic, inflammatory, and immunoregulatory pathways. Integration with transcriptional subtypes demonstrated spatial coupling of Mesenchymal/Classical programs with enhancing regions and Proneural features with non-enhancing regions, underscoring substantial intra-tumor spatial mosaicism. MRI-defined BBB permeability spatially organizes a glioma ecosystem where tumor metabolism and macrophage states are tightly coupled, refining understanding of the immune microenvironment and rationale for spatially informed immunotherapy.
-
Single-cell transcriptomics reveals lineage trajectory of human scalp hair follicle and informs mechanisms of hair graying.
Hair conditions, such as hair loss and graying, are prevalent human conditions. But they are often poorly controlled due to our insufficient understanding of human scalp hair follicle (hsHF) in health and disease. Here we describe a comprehensive single-cell RNA-seq (scRNA-seq) analysis on highly purified black and early-stage graying hsHFs. Based on these, a concise single-cell atlas for hsHF and its early graying changes is generated and verified using samples from multiple independent individuals. These data reveal the lineage trajectory of hsHF in unprecedented detail and uncover its multiple unexpected features not found in mouse HFs, including the presence of an innerbulge like compartment in the growing phase, lack of a discrete companion layer, and enrichment of EMT features in HF stem cells (HFSCs). Moreover, we demonstrate that besides melanocyte depletion, early-stage human hair graying is also associated with specific depletion of matrix hair progenitors but not HFSCs. The hair progenitors' depletion is accompanied by their P53 pathway activation whose pharmaceutical blockade can ameliorate hair graying in mice, enlightening a promising therapeutic avenue for this prevalent hair condition.
-
Mechanosensitive ion channel-related genes in hepatocellular carcinoma: Unraveling prognostic genes and their roles in drug resistance and immune modulation.
BACKGROUND AND AIMS: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide, and its etiology involves a complex interplay of genetic and environmental factors. Despite advancements in our understanding of HCC biology and the development of novel therapeutic strategies, the molecular mechanisms underlying its onset, progression, and resistance to therapy remain largely vague. This study aimed to investigate the role of mechanosensitive ion channel-related genes (MICRGs) in HCC, focusing on their potential as prognostic biomarkers and their involvement in immune modulation and drug resistance. METHODS: A comprehensive analysis was conducted using The Cancer Genome Atlas database to identify MICRGs that are upregulated in HCC. Gene expression profiling, bioinformatics tools, and functional experiments were employed to elucidate the role of these channels. In addition, protein-protein interaction (PPI) network analyses and enrichment analyses were performed to explore the biological significance of these genes. An immune cell infiltration analysis was also conducted to understand MICRG-related immune landscape. Single-cell RNA sequencing (scRNA-seq) data were utilized to identify MICRGs in different cell types within the HCC tissue. Deep-learning neural network analysis across patient cohorts was conducted to identify genes associated with sorafenib resistance. Knockdown experiments, cell viability assays, and apoptosis assays on HCC cell lines were performed to examine the role of Piezo-type mechanosensitive ion channel component 1 (PIEZO1) in sorafenib resistance. RESULTS: The analysis identified a subset of MICRGs, including PIEZO1, that were significantly upregulated in HCC and associated with poor prognosis. The PPI network analysis revealed complex interactions among these genes. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses proposed the involvement of these genes in calcium signaling pathways. Immune cell infiltration analysis demonstrated distinct associations between MICRGs and various immune subpopulations, highlighting their potential roles in immune modulation. scRNA-seq data indicated the upregulation of MICRGs in various cell types in HCC tissues, particularly in endothelial cells and tumor-associated macrophages. Deep-learning neural network analysis across different patient cohorts identified PIEZO1 as a crucial regulator of sorafenib resistance in HCC, which was further validated by functional assays on HCC cell lines. CONCLUSIONS: This study provides evidence that MICRGs, particularly PIEZO1, take on crucial roles in HCC progression and drug resistance. The upregulation of PIEZO1 in HCC cells is associated with poor prognosis and resistance to sorafenib. These findings indicate that PIEZO1 could serve as a potential therapeutic target for overcoming drug resistance and a prognostic biomarker in HCC. Future studies should focus on validating these findings in larger patient cohorts and exploring the functional implications of targeting PIEZO1 in preclinical models.
-
Single-cell transcriptomic landscape of sciatic nerve after transection injury.
Peripheral nerve injuries, particularly those affecting the sciatic nerve, often result in incomplete functional recovery due to the limited regenerative capacity of adult peripheral nerves. To elucidate the cellular and molecular mechanisms underlying nerve regeneration, we performed single-cell RNA sequencing (scRNA-seq) on rat sciatic nerve tissues at seven time points (Days 0, 1, 3, 5, 7, 10, and 14) following transection injury. Through unsupervised clustering, we identified four major cellular compartments-neurofibroblasts (NFs), glial cells (Glis), immune cells, and vascular cells-and delineated their dynamic trajectories during regeneration. Early responses were dominated by macrophage (Mac) and granulocyte infiltration (Day 1), followed by proliferative expansion of proliferating mesenchymal fibroblasts (NF5) and repair Schwann cells (Gli0) by Days 3-5. Vascular remodeling commenced from Day 7, while Glis progressively transitioned to mature myelinating states (Gli2/Gli5) by Day 14. Pseudotime analysis revealed subtype-specific reprogramming in both Macs and Glis, and cell-cell communication analysis uncovered key ligand-receptor interactions-particularly collagen and PTN signaling between Macs, NFs, and Glis. Bulk transcriptomic validation confirmed sustained and spatially distinct activation of the TGF-[Formula: see text] signaling pathway across cell types and anatomical locations. Comparative analysis with a sciatic nerve crush injury model revealed a stronger early immune response and delayed Gli recovery in transection injury, indicating a narrowed therapeutic window. Together, this work provides a time-resolved single-cell atlas of peripheral nerve regeneration, defines key regulatory circuits within the immune-NF-Gli axis, and identifies phase-specific therapeutic targets-such as early Mac heterogeneity, NF4-mediated matrix remodeling, and Schwann cell remyelination-for enhancing functional recovery following severe nerve injury.
-
A molecular cell atlas of the human lung from single-cell RNA sequencing.
Although single-cell RNA sequencing studies have begun to provide compendia of cell expression profiles1-9, it has been difficult to systematically identify and localize all molecular cell types in individual organs to create a full molecular cell atlas. Here, using droplet- and plate-based single-cell RNA sequencing of approximately 75,000 human cells across all lung tissue compartments and circulating blood, combined with a multi-pronged cell annotation approach, we create an extensive cell atlas of the human lung. We define the gene expression profiles and anatomical locations of 58 cell populations in the human lung, including 41 out of 45 previously known cell types and 14 previously unknown ones. This comprehensive molecular atlas identifies the biochemical functions of lung cells and the transcription factors and markers for making and monitoring them; defines the cell targets of circulating hormones and predicts local signalling interactions and immune cell homing; and identifies cell types that are directly affected by lung disease genes and respiratory viruses. By comparing human and mouse data, we identified 17 molecular cell types that have been gained or lost during lung evolution and others with substantially altered expression profiles, revealing extensive plasticity of cell types and cell-type-specific gene expression during organ evolution including expression switches between cell types. This atlas provides the molecular foundation for investigating how lung cell identities, functions and interactions are achieved in development and tissue engineering and altered in disease and evolution.
-
Distinct roles of HMOX1 on tumor epithelium and macrophage for regulation of immune microenvironment in ovarian cancer.
BACKGROUND: Ferroptosis has been implicated in the regulation of the tumor immune environment; however, its precise effect on immune checkpoint inhibitors remains contradictory. OBJECTIVE: To elucidate the "double-edged sword effect" of a key ferroptosis-related factor in regulating the immune microenvironment. METHODS: This study utilized single-cell RNA sequencing (scRNA-seq) analysis to characterize the tumor microenvironment in ovarian cancer samples from immunotherapy cohorts. Following quality control and variable gene screening, data from The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), GENE EXPRESSION OMNIBUS (GEO), bulk, and spatial transcriptome databases were analyzed. The AddModuleScore_UCell function was employed for gene set scoring by evaluating the expression patterns of specific gene features in single-cell datasets, which were found to correlate with interactions between tumor cells and stromal cells, recognized as key contributors in the immunosuppressive milieu. Immunohistochemistry, western blot, and multiplex immunohistochemistry (mIHC) analyses were employed to explore the HMOX1/TGF-β1/PI3K/AKT/NF-κB(p65) signaling pathways. In vitro findings were further validated in a mouse model. The correlation between risk factors and progression-free survival (PFS) was analyzed using Cox regression and Kaplan-Meier methods. RESULTS: We demonstrated decreased expression of the ferroptosis-activating gene HMOX1 in ovarian cancer epithelial cells, while being upregulated in macrophages. Ovarian cancer (OV) epithelial cells with HMOX1 inhibition could secrete TGF-β1 to activate three macrophage subtypes: SPP1 + , FOLR2 + , and C1QC + via the PI3K/AKT/NF-κB (p65) pathway. The up-regulation of HMOX1 in macrophages also activated these three macrophage subtypes via the NF-κB pathway. Both pathways simultaneously inhibited Cytotoxic T Lymphocyte (CTL) activation and contributed to the immunosuppressive microenvironment of ovarian cancer, as demonstrated in both in vitro and in vivo models. Targeting HMOX1 alone, whether through activation or inhibition, was only effective in modulating a single pathway while simultaneously inducing negative feedback on the opposing pathway, demonstrating the "double-edged sword effect" of HMOX1 in regulating the immune microenvironment. CONCLUSION: Overall, we proposed and validated two strategies targeting HMOX1 to improve the efficacy of PD-1 inhibitors, and confirmed that HMOX1, TGF-β1, SPP1, FOLR2, and C1QC could be used to construct models predicting the efficacy of immune checkpoint inhibitors.
-
SPINK1-driven cellular heterogeneity and interaction networks in intrahepatic cholangiocarcinoma revealed by integrated multi-omics analysis.
INTRODUCTION: Intrahepatic cholangiocarcinoma (ICC) is a highly heterogeneous and aggressive malignancy with poor prognosis and limited treatment options. The lack of precise molecular classification and incomplete understanding of the tumor microenvironment (TME) impede therapeutic development. OBJECTIVES: This study aims to dissect the cellular heterogeneity and intercellular interactions in ICC, with a particular focus on SPINK1-overexpressing epithelial subsets. We sought to determine the role of SPINK1 in modulating immune cell recruitment and tumor metabolism, and to evaluate its clinical relevance. METHODS: We performed single-cell RNA sequencing (scRNA-seq) on human ICC tumors and adjacent normal tissues to construct a transcriptomic atlas. Integrative proteomic analysis, transwell assays, co-culture systems, and functional perturbation experiments (SPINK1 knockdown and ASCT2 inhibition) were conducted to explore epithelial-macrophage interactions and metabolic dynamics. RESULTS: ScRNA-seq identified a SPINK1-overexpressing epithelial subcluster enriched in ICC tumors. High SPINK1 expression correlated with significantly shorter patient survival. SPINK1-overexpressing epithelial subcluster secretes CCL20, which recruits lipid-associated macrophages (LAMs). This effect was reversed by CCL20 neutralizing antibodies. In co-culture, LAMs increased intracellular glutamine levels in SPINK1-overexpressing epithelial subcluster, promoting proliferation. Disruption of SPINK1 expression or glutamine transport abolished this metabolic support. CONCLUSION: Our findings uncover a novel SPINK1-CCL20-LAMs axis that orchestrates immune recruitment and metabolic reprogramming in ICC. SPINK1 facilitates tumor growth by establishing a glutamine-rich microenvironment via LAMs. These insights highlight SPINK1 as a potential therapeutic target and prognostic biomarker in ICC.