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Single-cell transcriptome profiling reveals the heterogeneity of ossification of the posterior longitudinal ligament (OPLL) and its immune microenvironment.
BACKGROUND: Ossification of the posterior longitudinal ligament (OPLL) is a heterotopic ossification process of the posterior longitudinal ligament (PLL) that can compress the spinal cord and nerve roots, yet its cellular heterogeneity and pathogenesis remain unclear. METHODS: We performed single-cell RNA sequencing (scRNA-seq) with integrative computational analyses and histological validation on 4,683 cells from surgically resected cervical OPLL lesions obtained from human patients. RESULTS: We identified 15 major cell subsets, including chondrocyte-lineage populations-progenitor/proliferative fibrocartilage chondrocytes (ProFCs), pre-hypertrophic chondrocytes (preHTCs), and hypertrophic chondrocytes (HTCs)-as well as osteoblasts, endothelial cells, and diverse immune cells. Pseudotime analysis suggested an inferred trajectory from cartilage progenitor-like cells through inflammatory/reactive and hypertrophic states toward osteogenic programs, with progressive activation of ossification, extracellular-matrix, and inflammation-related pathways. Cell-cell communication analyses showed coordinated immune-stromal crosstalk, with FGF signaling enriched in earlier pseudotime states and SPP1-CD44 signaling enriched in later states. SPP1 signals originated predominantly from HTCs, whereas macrophages were prominently involved in the broader inflammatory niche and immune-stromal communication within OPLL lesions. Consistently, SPP1/CD44-positive cells were enriched in OPLL tissues and further increased by IL-1β stimulation in vitro and in an Enpp1-driven OPLL mouse model. CONCLUSIONS: This exploratory single-cell atlas suggests that an inflammatory niche may couple chondrocyte hypertrophy with osteogenic activation and highlights candidate immune-stromal pathways for future biomarker and therapeutic exploration in OPLL.
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Decoding benign prostatic hyperplasia at single-cell resolution: heterogeneity, inflammation, and beyond androgen-driven pathogenesis.
Benign prostatic hyperplasia (BPH) represents a highly prevalent age-related disorder, traditionally managed through androgen-driven pathways. However, the limited efficacy of conventional hormonal therapies in a substantial subset of patients necessitates the investigation of alternative pathogenic mechanisms. The emergence of single-cell RNA sequencing (scRNA-seq) has provided the necessary resolution to map cellular heterogeneity and microenvironmental dynamics within the prostate. This review synthesizes recent advancements in applying scRNA-seq to BPH research, highlighting a transition from a homogeneous, hormone-centric view toward recognizing BPH as a complex, heterogeneous process driven by multifaceted cell-immune interactions. We detail how scRNA-seq has identified distinct cellular subsets within the hyperplastic transition zone, including novel basal epithelial subtypes and activated fibroblast populations that contribute directly to nodule formation and disease progression. Furthermore, we examine the central role of chronic inflammation, mediated by immune cell infiltration and senescence-associated secretory phenotypes (SASP), in perpetuating a proliferative microenvironment. The technology also clarifies mechanisms underlying treatment resistance and identifies potential biomarkers and novel therapeutic targets beyond the androgen axis, such as the CXCL13/CD4+T cell axis and granzyme K pathways. Looking forward, integrating scRNA-seq with spatial multi-omics aims to construct a comprehensive spatiotemporal atlas of BPH, facilitating molecular subtyping and the development of precision, microenvironment-targeted therapies. In conclusion, scRNA-seq is redefining the pathophysiological landscape of BPH, offering a path toward innovative, non-androgenic therapeutic strategies aimed at achieving true disease modification.
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Construction of T-Cell-Related Prognostic Risk Models and Prediction of Tumor Immune Microenvironment Regulation in Pancreatic Adenocarcinoma via Integrated Analysis of Single-Cell RNA-Seq and Bulk RNA-Seq.
Pancreatic adenocarcinoma (PAAD) is a fatal malignant tumor of the digestive system, and immunotherapy has currently emerged as a key therapeutic approach for treating PAAD, with its efficacy closely linked to T-cell subsets and the tumor immune microenvironment. However, reliable predictive markers to guide clinical immunotherapy for PAAD are not available. We analyzed the single-cell RNA sequencing (scRNA-seq) data focused on PAAD from the GeneExpressionOmnibus (GEO) database. Then, the information from the Cancer Genome Atlas (TCGA) database was integrated to develop and validate a prognostic risk model derived from T-cell marker genes. Subsequently, the correlation between these risk models and the effectiveness of immunotherapy was explored. Analysis of scRNA-seq data uncovered six T-cell subtypes and 1837 T-cell differentially expressed genes (DEGs). Combining these data with the TCGA dataset, we constructed a T-cell prognostic risk model containing 16 DEGs, which can effectively predict patient survival and immunotherapy outcomes. We have found that patients in the low-risk group had better prognostic outcomes, increased immune cell infiltration, and signs of immune activation compared to those in the high-risk group. Additionally, analysis of tumor mutation burden showed higher mutation rates in patients with PAAD in the high-risk group. Risk scores with immune checkpoint gene expression and drug sensitivity analysis provide patients with multiple therapeutic targets and drug options. Our study constructed a prognostic risk model for PAAD patients based on T-cell marker genes, providing valuable insights into predicting patient prognosis and the effectiveness of immunotherapy.
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Single-cell transcriptomic profiling of immune microenvironment remodeling in unresectable hepatocellular carcinoma after TACE combined therapies.
BACKGROUND: The mechanisms underlying immune microenvironment remodeling remain unclear for patients with unresectable hepatocellular carcinoma (uHCC) undergoing transarterial chemoembolization (TACE) combined with tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs). This study aims to identify the key features that change following the combination therapy in patients with uHCC. METHODS: Single-cell transcriptomic profiling was conducted on uHCC samples from the control group, pre-treatment group, and post-treatment group. The Cancer Genome Atlas (TCGA) database was obtained for prognostic analysis. Enriched genes and pathways were identified, and the association and underlying mechanisms of the identified sub-cluster of cells were elucidated in relation to other cellular components. RESULTS: A total of 82,687 cells were obtained from seven patients with uHCC. In the pre-treatment group, the CancerCells_1 was associated with epithelial-mesenchymal transition, indicating a poor prognosis, as evidenced by data from 370 HCC patients in TCGA database. In the post-treatment group, a high proportion of macrophages_FOLR2 was observed corresponding to an elevated interferon response signature score and a diminished pro-angiogenic signature score. The exhaustion of CD8+ effector T cell (CD8Teff) was mitigated by downregulating the notable expression of BHLHE40 and CXCL13. Following treatment, there was an increase in liver sinusoidal endothelial cell (LSEC), while both angiogenesis and TGF-β pathway scores were reduced. Notable changes were observed in the interactions across different cells, particularly concerning the key signatures of LGALS9_HAVCR2, CSF1_CSF1R, and VEGFB_FLT1. CONCLUSION: After combined treatment, uHCC patients were characterized by macrophages_FOLR2, CD8Teff, and LSEC, indicating a remodeling of the immune microenvironment.
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Identification of tumor initiating cells and early marker genes in histologically normal colonic mucosa that lead to neoplastic transformation.
BACKGROUND & AIMS: Colorectal cancer (CRC) remains a leading cause of cancer‑related morbidity and mortality worldwide. Although the adenoma-carcinoma sequence and its genetic drivers are well described, the earliest cellular and molecular events initiating tumorigenesis within histologically normal colonic epithelium remain poorly defined. This study aims to identify tumor‑initiating cells (TICs), distinguish them from normal stem‑like cells (nSTMs), and delineate early transcriptional and signaling programs using single‑cell RNA sequencing (scRNA‑seq) from paired normal‑appearing and transformed human colonic tissues. METHODS: Fresh biopsies from histologically normal mucosa and matched polyps, including tubular adenomas, sessile serrated adenomas, and adenocarcinomas, were collected from seven subjects. Single‑cell transcriptomes were generated using the 10x Genomics platform and analyzed with Seurat, Monocle2, CytoTRACE, GSEA/GSVA, RNA velocity, InferCNV, CellChat, and NicheNet. Spatial validation was performed using RNA‑FISH. RESULTS: We resolved 51,054 high‑quality single‑cell transcriptomes into 33 clusters. Tumor-specific stem-like (tSTM) and deep crypt secretory (tDCS) populations were enriched in adenomas. Subclustering of tSTM identified TIC-like subsets predominantly derived from histologically normal mucosa that localized to the root of lineage trajectories leading to polyp-enriched tSTM states. Compared to nSTMs, TICs exhibited enhanced stemness potential, early epithelial-mesenchymal transition (EMT) and interferon signaling, suppression of oxidative phosphorylation, and distinct genomic and signaling features, indicating early neoplastic reprogramming. ETS2, SLC12A2, and LEFTY1 were identified as TIC‑specific markers; SOD3 and GPRC5A increased along the TIC‑to‑tSTM trajectory. RNA‑FISH confirmed candidate marker localization. Independent validation using the COLONMAP dataset (30 polyps, 35 normal samples) demonstrated that TIC-like cells were predominantly enriched in tubular adenomas but were scarce in serrated lesions. Across this independent cohort, TIC marker genes showed reproducible upregulation in TIC-like populations, supporting the robustness of these observations across cohorts. CONCLUSIONS: Our results identify TICs as the origin of neoplastic stem‑like states in the conventional tubular adenoma pathway and define early transcriptional, metabolic, and microenvironmental reprogramming events that distinguish TICs from nSTMs. In contrast to serrated pathways described in other atlases, our data support a stem‑like expansion model for tubular adenomas and nominate biomarkers with translational potential for early CRC detection and intervention.
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Deciphering the pulmonary fibrosis niche: A single-cell transcriptomic perspective on cellular crosstalk and microenvironment remodeling.
Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal interstitial lung disease driven by aberrant repair after repetitive alveolar micro-injury. The classical paradigm - that fibrosis is a passive consequence of epithelial injury followed by fibroblast activation - has been substantially reshaped by single-cell RNA sequencing (scRNA-seq) and, more recently, spatial transcriptomics. These technologies have resolved the lung into a constellation of molecularly distinct cell states and exposed a highly structured fibrotic niche in which epithelial, mesenchymal, immune, and endothelial compartments are engaged in active, ligand-receptor-mediated crosstalk. This review synthesizes the emerging single-cell and spatial atlas of human PF/ILD, with a focus on four themes: (i) the ectopic KRT5⁻/KRT17⁺ aberrant basaloid epithelium and the persistence of a KRT8⁺ alveolar differentiation intermediate; (ii) the lipofibroblast-to-myofibroblast trajectory and the collagen-producing fibroblast atlas that explains heterogeneous drug response; (iii) immune remodeling, particularly the metabolic reprogramming of SPP1⁺/MERTK⁺ macrophages and the exhaustion of CD8⁺ T cells; and (iv) the spatial organization of disease-associated niches at the fibroblast-focus edge. We then translate these findings into a framework for molecular subtyping and precision medicine, arguing that the future of IPF therapy lies in disrupting specific niche communication axes rather than broadly antagonizing collagen synthesis. Beyond cataloguing cell types, we emphasize the systems-level principle that emerges from the single-cell literature: IPF is not a disease of one cell type gone wrong, but a disease of the communication network that binds multiple compartments into a self-sustaining, maladaptive ecosystem.
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Distinct gene expression profiles in blood-brain barrier capillary endothelial cells between mice and humans.
OBJECTIVE: Endothelial cells (ECs) are key structural and functional components of the blood-brain barrier (BBB). Mouse models are frequently used to study EC biology within the BBB, yet the extent to which human and mouse BBB ECs share conserved transcriptomic features remains unclear. Here, we systematically compare transcriptomic profiles of BBB capillary ECs from adult mice and humans. METHODS: We analyzed single-cell and single-nucleus RNA-sequencing datasets from adult mouse and human BBB capillary ECs. Candidate species-specific genes were further validated using two whole brain vasculature datasets, along with data from Allen Brain Atlas and Human Protein Atlas. RESULTS: Despite substantial overall conservation between species, 169 genes were consistently enriched in human BBB capillary ECs compared to mouse, whereas 386 genes were enriched in mouse BBB capillary ECs compared to human. Several genes, including A2M, RUNDC3B, BTNL9 and SPOCK3 exhibited predominant expression in human BBB capillary ECs, with minimal or undetected expression in mouse. Conversely, Tspan13, Pglyrp1, Ucp2 and Slco1c1 were specifically expressed in mouse BBB capillary ECs compared with human. Notably, a considerable proportion of differentially expressed genes belonged to the solute carrier (SLC) transporter family. CONCLUSIONS: Our cross-species in-depth analysis reveals both broad conservation and distinct transcriptomic differences between human and mouse BBB capillary ECs. Together, our findings provide a valuable framework for interpreting mouse BBB data in a translational context and for guiding future studies of endothelial biology in the human brain.
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Integrative Single-Cell and Spatial Transcriptomics Reveal Organelle Stress-Associated Heterogeneity and Immune Microenvironment Remodeling in Lung Adenocarcinoma.
BACKGROUND: Lung adenocarcinoma (LUAD) exhibits marked heterogeneity. Organelle stress-adaptive programs that tumor cells develop under hypoxia, nutrient limitation, and proteostasis pressure may drive functional reprogramming of tumor biology, remodel the immune microenvironment, and ultimately influence the benefits of immunotherapy. Therefore, it is necessary to systematically characterize the coordinated changes across organelle stress-related pathways in LUAD, establish a subtyping and prognostic stratification framework, and identify key molecules as well as potential cell-cell communication axes. METHODS: Transcriptomic profiles and clinical follow-up data from The Cancer Genome Atlas LUAD (TCGA-LUAD) cohort and public cohorts were collected. Pathway activities were quantified using organelle stress-related gene sets, and core stress programs associated with overall survival (OS) and progression-free survival (PFS) were screened by Cox regression and Kaplan-Meier analyses. Nonnegative matrix factorization (NMF) was used for unsupervised subtyping and stability evaluation. Functional enrichment, genomic features, and immune landscapes were compared between subtypes, and potential benefit from immune checkpoint blockade (ICB) was inferred using tumor immune dysfunction and exclusion (TIDE) and immunophenoscore (IPS). Single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics (ST) were integrated to characterize malignant cell states, spatial niches, and cell-cell communication networks. In LUAD cell lines, the candidate gene was silenced by small interfering RNA (siRNA), and phenotypic assays were performed to validate its effects. RESULTS: The organelle stress activity-based system robustly classified LUAD into two biologically distinct subtypes (the mitochondrial-ribosome biogenesis, MRB, subtype and the lysosomal catabolism, LC, subtype), which showed systematic differences in prognosis and functional programs. The MRB subtype exhibited enhanced stress and metabolic adaptation accompanied by immune exclusion features, whereas the LC subtype showed a relatively immune-active tumor microenvironment. Immunotherapy-related analyses suggested divergent trends in potential ICB benefit between the two subtypes. Multiscale evidence highlighted SLC16A14 (MCT14) as a key node linking stress heterogeneity to malignant progression. At the single-cell level, SLC16A14 was mainly expressed in malignant cells, and communication analyses suggested that CALCR-related signaling may mediate tumor-endothelial interactions and contribute to an immune-excluded microenvironment. In vitro, SLC16A14 silencing suppressed tumor cell proliferation, invasion, and migration, supporting its role as a key molecule connecting stress adaptation and tumor progression. CONCLUSION: We established an organelle stress program-based subtyping and prognostic framework for LUAD, revealed the coupling between stress adaptation and TME remodeling, and proposed SLC16A14 and its associated communication network as potential intervention targets, providing multiomics evidence for interpreting LUAD heterogeneity and for stratifying immunotherapy and combination strategies.
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Multi-omics analysis reveals key genes associated with clear cell renal cell carcinoma.
BACKGROUND: The most common type of kidney cancer is ccRCC (Clear Cell Renal Cell Carcinoma). Existing research has shown that when kidney cancer progresses from T2 to T3 or T4 stage, the treatment options and prognosis significantly differ. The aim of this study is to identify prognosis-related genes in ccRCC using single-cell data and Mendelian randomization analysis. METHODS: Single-cell RNA sequencing (scRNA-seq) data from six ccRCC patients (GSE156632) were analyzed in R. After quality control and normalization, cells were embedded, clustered, and annotated to define major cell types. Cell-cell signaling networks were inferred using CellChat. Stage-related co-expression programs were identified using high-dimensional weighted gene co-expression network analysis (hdWGCNA), and modules enriched in advanced disease were prioritized. To connect expression patterns with germline variation, we obtained expression quantitative trait loci (eQTL) summary statistics from the UK Biobank and performed two-sample Mendelian randomization using the ukb-b-1316 exposure dataset. For clinical validation, bulk RNA-seq and survival data from The Cancer Genome Atlas (TCGA) were incorporated, and candidate genes were evaluated using univariable Cox proportional hazards models. RESULTS: hdWGCNA identified three modules, from which we selected 150 genes. eQTL combined with Mendelian randomization analysis revealed a potential causal relationship between RBP5, PRDX2, GTSF1, BSG, and COX14 and tumorigenesis. Further TCGA data analysis indicated that PRDX2 might serve as a protective factor in ccRCC, consistent with the Mendelian randomization results. Furthermore, its expression exhibited a gradual decline with tumor stage progression. Kaplan-Meier(KM) curves demonstrated better prognosis for patients with high PRDX2 expression. Cell communication analysis revealed more frequent communication between cells with reduced PRDX2 expression and vascular endothelial cells. Moreover, the experiments demonstrate that the migration and proliferation abilities of ccRCC cells are enhanced after knocking down PRDX2. CONCLUSION: These results suggest that PRDX2 may play a role in the progression of ccRCC and could potentially serve as a prognostic factor and therapeutic target for ccRCC.
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Integrated single-cell and spatial transcriptomics reveal divergent immunological and stromal programs in peritoneal versus ovarian endometriosis.
BACKGROUND: Endometriosis encompasses heterogeneous lesions, primarily peritoneal and ovarian subtypes, with distinct immunological and fibrotic features. The subtype-specific roles of the immune microenvironment in pathogenesis remain unclear. Integrated analysis combining high-resolution cellular atlases with spatial context is needed to decipher these mechanisms. METHODS: We performed an integrative analysis of published single-cell RNA sequencing (n = 81,676 cells) from control endometrium (Ctrl), eutopic endometrium (EuE), peritoneal endometriosis (EcP), and ovarian endometriosis (EcO), and spatial transcriptomic (n = 60 segments) data from Ecp and match EuE. Analytical pipelines include cellular atlas construction, differential expression, spatial co-expression, and cell-cell communication inference. RESULTS: Our single-cell atlas revealed fundamentally distinct cellular ecosystems. EcP was enriched for CCL19 + perivascular cells (6.4-fold vs. control) and immune-active niches, whereas EcO exhibited pronounced smooth muscle differentiation and NNMT upregulation. Spatial analysis compartmentalized these programs, with the CCL19-CCR7 chemokine axis localized to stromal niches in EcP strongly correlated (ρ = 0.872). In contrast, EcO showed enhanced smooth muscle gene expression (MYH11, log₂FC = 3.87). Cell-cell communication networks diverged, with EcP dominated by chemokine and TGF-β signaling, and EcO dominated by smooth muscle and PDGF pathways. Therapeutic target analysis revealed subtype-specific patterns: immune checkpoints (CTLA4 and PDCD1) were upregulated in EcP, whereas MMP9 was dramatically downregulated in EcO. CONCLUSION: EcP and EcO exhibit fundamentally divergent programs. We propose to conceptualize these as an ‘immune-hot’, chemokine-driven inflammatory niche (EcP) versus an ‘immune-cold’, fibromuscular survival niche (EcO). These findings underscore that lesion-specific immune-stromal crosstalk may dictates pathogenesis and suggest a potential paradigm shift toward immunologically-informed, subtype-specific precision therapeutics, which warrant further experimental validation.