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Found: 4 894
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Single-cell transcriptomics reveals hair growth retardation mediated by aberrant connective tissue sheath contraction in male androgenetic alopecia.
Androgenetic alopecia (AGA) manifests as progressive hair follicle (HF) miniaturization; however, its drivers remain poorly elucidated. Combining spatial and single-cell transcriptomics, we generate a concise single-cell atlas of anagen HFs in male AGA, revealing early changes in cell subpopulations, altered HF stem cell fate determination, and disrupted cell-cell communications. Through ex vivo HF organ culture and humanized mouse models, we demonstrate that hypercontractility of connective tissue sheath (CTS) activates the mechanosensitive channel PIEZO1 in anagen HFs. This mechanotransduction induces ectopic apoptosis of HF progenitor cells and suppresses matrix/ORS cell proliferation, depleting progenitor pools and impairing HF growth, thereby driving progressive miniaturization. Critically, pharmacological inhibition of CTS contraction via ML-7, a selective myosin light chain kinase (MLCK) inhibitor, improves HF growth in both male AGA patient-derived ex vivo models and humanized mice. Our study delineates the cellular dynamics underlying male AGA pathogenesis and identifies mechanopathologically activated CTS as a key driver of HF miniaturization, positioning the peri-follicular CTS as a promising therapeutic target for AGA intervention.
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MFSD12 promotes proliferation, metastasis and invasion of hepatocellular carcinoma cells and its potential correlation with HAVCR2/LGALS9 immune checkpoint axis.
BACKGROUND: Major Facilitator Superfamily Domain-containing 12 (MFSD12) has emerged as a critical transmembrane protein with increasingly recognized roles in various cancers. The complex pathogenesis and therapeutic resistance of liver hepatocellular carcinoma (LIHC) present significant clinical challenges. This study investigates MFSD12's potential involvement in LIHC progression. METHODS AND RESULTS: We performed an extensive pan-cancer analysis of MFSD12 utilizing integrated datasets from The Cancer Genome Atlas (TCGA), the Gene Expression Omnibus (GEO), and the ArrayExpress database. Our investigation focused on evaluating its prognostic significance, clinical implications, associated signaling pathways, immune cell infiltration, gene mutations, and sensitivity to chemotherapeutic agents. Through the application of R and various online analytical tools, our study demonstrated that MFSD12 expression levels were significantly higher in LIHC compared to other cancer types within the TCGA pan-cancer dataset. This finding highlights the specificity of MFSD12 expression in LIHC, a conclusion further validated by immunohistochemical analysis. Survival analysis indicated that this upregulation is associated with unfavorable clinical outcomes. Furthermore, single-cell RNA sequencing revealed that MFSD12 was predominantly expressed in tumor cells and innate lymphoid cells (ILCs) within the tumor microenvironment. Functional vitro studies showed MFSD12-siRNA treatment effectively suppressed LIHC cell proliferation, migration, and invasion. Mechanistically, MFSD12-siRNA enhanced E-cadherin while reducing vimentin, MMP-2, and MMP-9 levels. Further analyses revealed significant associations between MFSD12 expression and immune infiltration, immune checkpoint molecules, tumor mutation burden, and microsatellite instability in LIHC. Notably, MFSD12-siRNA decreased HAVCR2(TIM3) and its ligand galectin-9 (LGALS9) expression in LIHC cells. CONCLUSIONS: Our findings demonstrated that MFSD12 upregulation in LIHC strongly correlates with poor prognosis. This association was potentially attributed to MFSD12's dual roles: promoting tumor cell proliferation, migration, and metastasis while critically modulating the tumor immune microenvironment, particularly through interaction with the HAVCR2/LGALS9 immune checkpoint axis.
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Single-cell RNA sequencing illuminates the ontogeny, conservation and diversification of cartilaginous and bony fish lymphocytes.
Elucidating cellular architecture and cell-type evolution across species is central to understanding immune system function and susceptibility to disease. Adaptive immunity is a shared trait of the common ancestor of cartilaginous and bony fishes. However, evolutionary features of lymphocytes in these two jawed vertebrates remain unclear. Here, we present a single-cell RNA sequencing atlas of immune cells from cartilaginous (white-spotted bamboo shark) and bony (zebrafish and Chinese tongue sole) fishes. Cross-species comparisons show that the same cell types across different species exhibit similar transcriptional profiles. In the bamboo shark, we identify a phagocytic B cell population expressing several pattern recognition receptors, as well as a T cell sub-cluster co-expressing both T and B cell markers. In contrast to a division by function in the bony fishes, we show close linkage and poor functional specialization among lymphocytes in the cartilaginous fish. Our cross-species single-cell comparison presents a resource for uncovering the origin and evolution of the gnathostome immune system.
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Metabolic reprogramming in lacrimal gland GVHD: Stage-specific shifts in acinar cells as drivers of disease progression.
PURPOSE: Ocular graft-versus-host disease (oGVHD) progresses through inflammatory and fibrotic phases, yet the temporal dynamics of the lacrimal gland (LG) cellular ecosystem remain unclear. This study aims to delineate the phase-specific alterations driving oGVHD pathogenesis. METHODS: We performed integrated single-cell RNA sequencing on murine LGs at acute (7-day) and chronic (28-day) GVHD stages. Transcriptional profiling was combined with pseudotime trajectory analysis, computationally inferred cell-cell communication networks, and immunofluorescence validation. RESULTS: Temporal analysis revealed extensive phase-specific cellular reprogramming. Acute GVHD was characterized by expansion of globulin-specific acinar cells with altered glycan metabolism, alongside inflammatory fibroblasts predicted to license cytotoxic T-cell responses via H2-k1-Cd8 interactions. Chronic GVHD featured metabolic diversification of acinar subtypes, including upregulated N-glycan biosynthesis in lipid-associated cells and activated α-linolenic acid metabolism in water/electrolyte-secreting cells, along with emergent myeloid-epithelial crosstalk. Computational analyses identified novel ligand-receptor pairs, suggesting plasmacytoid dendritic cells engage water/electrolyte-secreting acinar cells via Gm-Sort1, and mast cells target lipid-associated subtypes via Ptprc-Cd22. Infiltration of pDCs and mast cells was validated by immunofluorescence. Trajectory analysis indicated acinar plasticity reflects environment-instructed adaptation rather than hierarchical differentiation. CONCLUSIONS: These results define a phase-shift mechanism in oGVHD: acute damage involves a fibroblast-T cell-epithelium triad, while chronic dysfunction is driven by acinar metabolic reprogramming and myeloid-mediated epithelial dysregulation. Our temporal single-cell atlas integrates computational predictions with morphological validation to reveal stage-specific therapeutic targets for intervening in disease progression.
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Comparative Single-Nucleus Transcriptomic Analysis of the Intact Left Ventricle in Acomys cahirinus and Mus musculus.
BACKGROUND/OBJECTIVES: Acomys cahirinus exhibits more favorable cardiac remodeling after ischemic injury than Mus musculus, yet the molecular organization of the intact myocardium remains poorly characterized. This study aimed to identify baseline interspecies differences in the adult left ventricle, with particular emphasis on ventricular cardiomyocyte transcriptional states. METHODS: Intact left ventricles from adult male A. cahirinus and M. musculus were analyzed by single-nucleus RNA sequencing using three biological samples per species. Cross-species integration was followed by cell type annotation, pseudobulk differential expression analysis, Augur-based assessment of interspecies separability, coexpression module analysis, and focused reintegration analysis of ventricular cardiomyocytes. Cardiomyocyte profiles were further compared with published embryonic and early postnatal M. musculus heart datasets. RESULTS: Both species contained comparable major myocardial cell populations, whereas marked interspecies transcriptional differences persisted within individual cell types. Ventricular cardiomyocytes exhibited the largest number of differentially expressed genes and were classified into three transcriptional states: contractile, matrix-associated, and alternative. Adult A. cahirinus cardiomyocytes retained a mature cardiomyocyte phenotype but showed greater enrichment of developmental, morphogenetic, and Hippo-associated gene programs than adult M. musculus cardiomyocytes. Their transcriptional profile did not correspond to embryonic or early postnatal mouse states. The integrated atlas further identified interspecies differences in fibroblast-associated and extracellular matrix-related programs. CONCLUSIONS: The intact myocardium of A. cahirinus exhibits cell type-specific transcriptional differences relative to M. musculus. Ventricular cardiomyocytes display a distinct mature transcriptional configuration rather than a direct immature state, which may contribute to the favorable response of A. cahirinus to myocardial injury.
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Divergent CD45+ immune landscapes shape the lung tumor microenvironment.
BACKGROUND: The lung tumor microenvironment (TME) plays a crucial role in the progression and metastasis of lung cancer. It consists of various cell types that interact in complex ways to influence tumor behavior. CD45+ cells, as a component of the TME, have complex and multifaceted roles in lung cancer. The balance between the anti-tumor and pro-tumor functions of CD45+ cells can significantly affect lung cancer outcomes. Understanding these roles is essential for developing targeted therapies that harness the beneficial effects of CD45+ cells while mitigating their harmful effects. METHODS: We performed single-cell RNA sequencing of sorted CD45+ immune cells from healthy lungs, orthotopic LLC1 tumors, and KrasLA2 (Kras) genetically engineered tumors. Analyses included immune composition, transcriptional programs, differentiation trajectories, metabolic states, and ligand-receptor-based intercellular communication networks. RESULTS: Four major immune compartments, B cells, T cells, NK cells, and macrophages, underwent model-specific remodeling. LLC1 tumors showed B cell expansion and T and NK cell reduction, with inflammatory, stress-response, and NF-κB/TNF-dominant programs. KrasLA2 tumors retained a balanced immune composition but exhibited metabolic rewiring, elevated antigen-presentation signatures, and selective intercellular signaling. Subclustering revealed specialized changes across B cell (resting, mature, pre-Bcr, late pro-B, plasma), T cell (Cd4+, Cd8+, memory, activated, Treg, Th17), NK cell (Fcgr3high, Fcgr3low, Xcl1+), and macrophage (Ace+, Bcr+, Ccr2+, Cd3+, metabolic, MHCII+) subsets. Ligand-receptor analyses highlighted dense inflammatory networks in LLC1 tumors versus metabolically tuned signaling in KrasLA2 tumors. CONCLUSION: Distinct CD45+ immune landscapes, characterized by inflammatory suppression in LLC1 and metabolic adaptation in KrasLA2 tumors, shape lung tumor biology. This atlas identifies genotype-specific immune vulnerabilities with potential relevance for precision immunotherapy in non-small cell lung cancer.
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Single-cell transcriptomic atlas uncovers immune/structural lineage remodeling and fibrosis in Klebsiella pneumoniae-infected porcine lungs.
Klebsiella pneumoniae (KP) is a predominant pathogen in respiratory infections, whose widespread antibiotic resistance poses severe public health risks and economic burdens. As the primary target of KP infection, the lung contains diverse immune cells, while pulmonary cellular responses to KP remain poorly understood. This study integrated single-cell RNA sequencing, flow cytometry, RT-qPCR, and immunofluorescence to investigate porcine lung cell response from healthy pigs and those infected with multidrug-resistant, highly virulent KP. Post-infection, myeloid cells (neutrophils, monocytes, and interstitial macrophages) were rapidly activated with upregulated signatures related to neutrophil migration and interferon production. Alveolar macrophages (AM) exhibited marked heterogeneity: KP infection was associated with apoptosis in proliferating, monocyte-derived, and tissue-resident AM subsets, indicating a disruption of homeostasis, while infection-specific subsets (AM_MHCII, AM_CXCL2) displayed enhanced antigen presentation, inflammatory activity, and pro-fibrotic potential. Under homeostasis, γδ T and CD8αα+ T cells were the predominant T cell populations. After infection, CX3CR1-CD8αα+ T cells were activated, and CD8+ γδ T cells increased their interactions with myeloid cells, predominantly through ligand-receptor pairs such as TNF-TNFRSF1B and IFNG-IFNGR1/2. Furthermore, KP induced lung fibroblast proliferation and activation via the ROS-mediated TGF-β/SMAD pathway, WNT pathway, and aerobic glycolysis. Concurrently, infection reduced the proportion of ATII and transitional AT0 cells, which may impair their differentiation into ATI cells and compromise epithelial barrier function. Thus, this study is the first to characterize the dynamics of KP infection in porcine lungs at single-cell resolution. It advances our understanding of KP-host interactions and provides a framework for anti-KP therapeutic development.
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Single-cell and spatial transcriptomics map lung-adaptive metastasis programs through Exoc4, Cd36-vasculogenic mimicry, and Cxcr2 signaling in triple-negative breast cancer.
Triple-negative breast cancer (TNBC) is an aggressive subtype associated with high metastatic potential and poor outcomes, with lung metastasis representing one of the most frequent and life-threatening events. However, the mechanism how cellular plasticity and reprogramming that enable TNBC cells to colonize in the lung remain incompletely understood. Here, we integrated single-cell RNA sequencing and spatial transcriptomics on paired MMTV-PyMT primary mammary tumors and lung metastatic tumors, complemented by functional assays in 4T1 mouse models, to delineate the cellular heterogeneity and molecular mechanisms driving TNBC lung metastasis. We identified three metastasis-associated subtypes-C12-Cd, Cdh5-like, and Wfdc12-each enriched in metastatic lesions and exhibiting distinct biological programs. The C12-Cd subcluster was characterized by the upregulation of Exoc4, a vesicle-trafficking regulator associated with a poor prognosis in patients with TNBC. The Cdh5-like cluster displayed a hypoxia-driven vascular phenotype, in which Hif-2α-mediated Cd36 expression promoted vasculogenic mimicry and metastatic colonization. The Wfdc12 cluster secreted Cxcr2 ligands (Cxcl1/2) and Cxcr2 blockade significantly reduced lung metastasis in vivo, underscoring therapeutic potential. Notably, cross-subtypes of lung metastatic TNBC analysis revealed Sftpc upregulation, reflecting organ-adaptive transcriptional reprogramming that may facilitate tumor cell survival in the pulmonary niche. Collectively, our findings provide a comprehensive cellular and molecular atlas of TNBC lung metastasis. We establish Exoc4, the Hif-2α-Cd36 vasculogenic mimicry axis, Cxcrl1/2-Cxcr2 signaling, and Sftpc as critical mediators of metastatic adaptation. These results not only bridge key knowledge gaps in metastatic heterogeneity and organ-specific adaptation but also highlight novel prognostic markers and therapeutic vulnerabilities with translational potential for treating TNBC lung metastasis.
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Single-cell transcriptomic profiling of cerebrospinal fluid reveals immune-cell heterogeneity and multicompartment MIF/CD74-related communication in tuberculous and purulent meningitis.
BACKGROUND: Tuberculous meningitis (TBM) is a severe central nervous system infection in which dysregulated host inflammation contributes to neurological injury. The cellular organization of the cerebrospinal fluid (CSF) immune microenvironment in TBM, particularly in comparison with other inflammatory meningitis conditions, remains incompletely defined. This study characterized CSF immune-cell heterogeneity in TBM and purulent meningitis (PM) using single-cell transcriptomic profiling. METHODS: Pre-treatment CSF immune cells from five patients with TBM and five patients with PM were profiled using 10x Genomics single-cell RNA sequencing. After quality control, ambient RNA assessment, and doublet filtering, 96,594 cells were retained. Major immune-cell populations and myeloid and granulocyte subclusters were annotated using canonical lineage markers and cluster-specific marker genes, with additional evaluation of doublet-related quality-control metrics and ambient RNA estimates. Immune-cell composition, CD4+ T-cell transcriptional states, macrophage migration inhibitory factor (MIF)/CD74 expression, CellChat-inferred communication, and in silico perturbation profiles were evaluated using donor-level comparisons where appropriate. RESULTS: Seven major CSF immune-cell populations were identified, including CD4+ T cells, CD8+ T cells, myeloid cells, granulocytes, B cells, plasma cells, and natural killer T (NKT)-like cells. Immune-cell composition varied markedly across donors. Several PM donors exhibited myeloid- or granulocyte-rich profiles, whereas several TBM donors showed greater CD4+ T-cell representation; group-level differences were exploratory and did not consistently reach statistical significance. Reannotation of the innate immune-cell compartment identified broad macrophage-like, monocyte-like, neutrophil-like, and CD1C+ dendritic cell-like populations. Two originally defined myeloid subclusters displayed coordinated T-cell-associated transcriptional programs and were interpreted as potentially misclassified or technically mixed cells rather than bona fide myeloid states. CD4+ T cells occupied a continuous transcriptional landscape comprising central memory (CM)-like, cytotoxicity/senescence-associated, and activated effector memory (EM)-like states with overlapping transcriptional programs. MIF was broadly detectable across immune-cell compartments, whereas CD74 was most prominent in antigen-presentation-associated populations. CellChat identified MIF-related communication in both disease groups, supporting a shared multicompartment inflammatory communication program rather than a TBM-specific pathway. Exploratory in silico perturbation prioritized MIF- and CD74-associated transcriptional programs for future validation. CONCLUSIONS: This study provides a donor-aware single-cell transcriptomic atlas of the inflammatory CSF immune microenvironment in TBM and PM. The findings highlight substantial inter-individual heterogeneity, broad innate immune-cell patterns, overlapping CD4+ T-cell transcriptional states, and multicompartment MIF/CD74-related communication. These transcriptome-inferred findings are hypothesis-generating and require validation in larger cohorts using protein-level and functional approaches.
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Multi-omics Integration of Single-cell and Spatial Transcriptomics with Tissue and Urine Proteomics Identifies TRIM28 as a Translationally Relevant Candidate Regulator in Acute Kidney Injury.
Acute kidney injury (AKI) lacks disease-modifying therapies, partly because cell type-specific injury programs remain incompletely resolved and tissue mechanisms are not readily translated into clinically accessible biomarkers. We constructed a cross-scale, multi-omics atlas to prioritize candidate regulator linking renal injury circuitry with urine-detectable signals. Human single-cell, bulk, and spatial transcriptomics were integrated with mouse renal ischemia-reperfusion injury (RIRI) kidney proteomics and clinical urine proteomics. Overlap of differentially expressed genes and differentially abundant proteins nominated candidates, which were ranked by a random forest model. Immune remodeling was assessed by deconvolution and pathway enrichment, with spatial localization supported by reference-based deconvolution. Therapeutic tractability was explored by structure-based virtual screening, molecular docking, molecular dynamics simulation, and cellular thermal shift assay (CETSA). TRIM28 was evaluated in HK-2 hypoxia/reoxygenation (H/R) and mouse RIRI models using genetic perturbation, expression validation, and in vitro pharmacologic evaluation. Integration converged on five genes (TRIM28, HNRNPH1, ARHGEF10L, C1RL, and UCHL3), with TRIM28 showing the highest feature importance and links to inflammatory, immune, metabolic, and proliferative programs. AKI exhibited intensified intercellular communication and an innate-skewed immune landscape. TRIM28 was robustly upregulated in HK-2 H/R and mouse RIRI kidneys and was also directly detected in the human urine proteome. In HK-2 cells, TRIM28 knockdown dampened, whereas overexpression amplified, IL-17-linked inflammatory signaling and apoptotic responses. Docking-prioritized HY-N10592 improved viability, reduced H/R-associated TRIM28 induction, IL-17-linked output, and apoptotic marker activation, and showed CETSA-supported cellular engagement of TRIM28. This integrative framework prioritizes TRIM28 as a candidate regulator linking tubular injury mechanisms with clinically relevant urinary signals and nominates HY-N10592 as a candidate chemical tool with CETSA-supported cellular target engagement for further mechanistic and in vivo evaluation in AKI.