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Peripheral blood transcriptomes and a single-cell atlas suggest a monocyte-associated immune recovery-failure axis in STEMI.
BACKGROUND: Patients with ST-segment elevation myocardial infarction (STEMI) continue to show substantial inflammatory heterogeneity after reperfusion therapy, and recovery trajectories may differ markedly across patients. Compared with traditional diagnostic models, characterizing the dynamic immune trajectory from acute inflammation toward recovery may better identify programs associated with impaired resolution. This study aimed to construct an immune recovery-failure framework that is transferable across cohorts and anchored by single-cell data. METHODS: We integrated six public GEO peripheral-blood bulk transcriptome cohorts and one public single-cell RNA-seq dataset. An acute-to-recovery immune axis was constructed from directionally concordant longitudinal and cross-sectional contrasts, and a recovery-failure phenotype was defined in the discovery longitudinal cohort from paired transcriptomic features. An 18-gene monocyte-associated module was then derived using bulk recovery-failure associations, monocyte specificity, monocyte-state differences, and pseudotime information. External cohorts were used to evaluate temporal transfer and baseline-to-follow-up associations rather than definitive clinical prediction, and the single-cell dataset was used for donor-aware cell-type anchoring and exploratory state-level interpretation. RESULTS: Among 81 STEMI patients who met the longitudinal definition criteria, unsupervised stratification classified 35 as recovery-failure patients and 46 as recovery-sufficient patients. We constructed an 18-gene monocyte-associated recovery-failure module. The module distinguished the two transcriptomically defined groups in the discovery cohort and declined from the acute phase toward recovery in external longitudinal cohorts. Baseline module burden was associated with later composition-adjusted inflammatory burden, but this was interpreted as a baseline-to-follow-up association rather than clinical event prediction. At the single-cell level, donor-aggregated lesion-associated shifts were largest in monocytes, and the module decreased along the acute-high-to-recovery-biased monocyte pseudotime direction. In 1,000 matched random monocyte-gene modules, the observed module showed a higher aggregate recovery statistic than nearly all random signatures. CONCLUSIONS: We propose a STEMI immune recovery-failure framework derived from public peripheral-blood transcriptomes, evaluated across independent longitudinal datasets, and linked to monocyte state variation in a public single-cell context. The framework is does not evidence of a causal mechanism or a validated hard-endpoint prediction model; rather, it provides a reproducible transcriptomic description of impaired inflammatory resolution that should be tested prospectively and experimentally.
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Single-nucleus multiomic profiling of the aging mouse substantia nigra reveals conserved gene alterations linked to Parkinson's disease.
Parkinson's disease (PD) is a prevalent neurodegenerative disorder predominantly affecting individuals over 60. Its motor symptoms stem from the deterioration of dopaminergic neurons within the substantia nigra. Despite aging being a significant risk factor, the specific mechanisms linking aging and PD pathology remain unclear. Leveraging advancements in single-cell genomics, this study utilizes single-nucleus multiome sequencing to capture transcriptomic and epigenetic profiles from 40,125 cells across the lifespan of the mouse substantia nigra. Our analysis pinpoints age-associated changes at a cell type-specific level, revealing a subset of genes that increasingly express with age and are enriched in PD-related pathways, notably in oligodendrocytes at late aging stages. Integration with five public PD single-cell RNA-seq data sets highlights 85 genes consistently differentially expressed with aging and PD. Key genes such as Hsp90aa1 and Hsp90ab1 are upregulated at late aging stages in oligodendrocytes, microglia, and glutamatergic neurons. Additionally, Apoe in microglia and genes related to protein folding in oligodendrocytes are upregulated at late aging stages, whereas genes involved in myelination are downregulated at early aging stages in oligodendrocyte. Our multiomic atlas underscores the substantial regulatory network changes during aging that may predispose to PD, providing valuable insights for furthering understanding of PD pathogenesis and potential therapeutic targets.
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scRNA-Seq: First Atlas and Cellular Landscape of Lacrimal Sac: Implications in Primary Acquired Nasolacrimal Duct Obstruction Pathogenesis.
PURPOSE: The aim of this study was to describe the transcriptional changes of individual cellular components in the lacrimal sac in patients with primary acquired nasolacrimal duct obstruction (PANDO) and attempt to construct the first lacrimal sac cellular atlas to elucidate the potential mechanisms that may drive the disease pathogenesis. METHODS: Lacrimal sac samples were obtained intra-operatively during the endoscopic dacryocystorhinostomy (EnDCR) procedure from five patients. Single-cell RNA sequencing was performed to analyze each individual cell population including epithelial and immune cells during the early inflammatory and late inflammatory phases of the disease. RESULTS: Eleven cell types were identified among 25,791 cells. T cells and B cells were the cell populations with the greatest variation in cell numbers between the two phases and were involved in immune response and epithelium migration-related pathways. The present study showed that epithelial cells highly expressed the genes of senescence-associated secretory phenotype (SASP) and were involved in influencing the inflammation, neutrophil chemotaxis, and migration during the late inflammatory stage. Enhanced activity of CXCLs-CXCRs between the epithelial cells and neutrophils was noted by the cell-cell communication analysis and is suspected to play a role in inflammation by recruiting more neutrophils. CONCLUSIONS: The study presents a comprehensive single-cell landscape of the lacrimal sac cells in different phases of PANDO. The contribution of T cells, B cells, and epithelial cells to the inflammatory response, and construction of the intercellular signaling networks between the cells within the lacrimal sac has further enhanced the present understanding of the PANDO pathogenesis.
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Single cell transcriptomic atlas reveals macrophage polarization dynamics and intercellular communication networks in gingival tissue of periodontitis patients undergoing orthodontic treatment.
BACKGROUND: Periodontitis combined with orthodontic treatment creates a complex inflammatory and biomechanical microenvironment in gingival tissue, where macrophages play pivotal roles in tissue remodeling and immune regulation. However, the heterogeneity of macrophage subtypes and their polarization dynamics in this clinical context remain poorly understood. METHODS: We performed single-cell RNA sequencing (scRNA-seq) on gingival tissue samples from periodontitis patients undergoing orthodontic treatment. Using integrated bioinformatics approaches including dimensionality reduction, pseudotime trajectory analysis, RNA velocity, cell-cell communication inference, and functional enrichment analysis, we comprehensively characterized macrophage subtypes, their polarization states, and intercellular signaling networks. RESULTS: We identified 11 distinct cell populations with significant macrophage heterogeneity, including M1-like pro-inflammatory and M2-like tissue-remodeling subtypes along with intermediate transitional states. Trajectory analysis revealed dynamic polarization pathways with multiple branching points, demonstrating remarkable phenotypic plasticity. Macrophages served as central communication hubs, engaging in extensive crosstalk with fibroblasts, epithelial cells, endothelial cells, and lymphocytes through cytokine, growth factor, chemokine, and extracellular matrix signaling pathways. Transcription factor analysis identified NF-κB, STAT1, and IRF family members driving M1 polarization, while PPARγ, C/EBPβ, and KLF4 promoted M2 phenotypes. Telomere maintenance gene profiling revealed differential cellular aging patterns across subtypes, with pro-inflammatory macrophages showing stress-induced senescence signatures. Functional enrichment demonstrated that macrophages integrate inflammatory responses with mechanotransduction pathways, responding to both periodontal pathogens and orthodontic mechanical forces. CONCLUSIONS: This single-cell transcriptomic atlas provides unprecedented insights into macrophage heterogeneity and functional specialization in periodontitis patients undergoing orthodontic treatment.
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Single-cell atlas of Exopalaemon carinicauda gills provides insights into pillar cell-mediated responses to low-salinity stress in crustaceans.
Low-salinity stress exerts strong constraints on ion homeostasis in crustaceans cultivated in coastal environments. Gills function as central osmoregulatory organs in crustaceans, coordinating transepithelial ion flux and acid-base balance; however, the cellular mechanisms governing gill adaptation to reduced salinity remain poorly understood. Here, integrated ultrastructural characterization and single-cell RNA sequencing (scRNA-seq) were applied to define cellular responses to low-salinity exposure in Exopalaemon carinicauda gills. Low salinity induced pronounced morphological remodeling in pillar cells. Single-cell transcriptomic profiling resolved 11 transcriptionally distinct populations, including two ionocyte lineages represented by pillar cells and septal cells. Comparative analyses demonstrated a marked expansion of pillar cell subcluster 3 under low-salinity stress, accompanied by enrichment of differentially expressed genes (DEGs) in ion transport pathways, notably hydrogen ion transport. Weighted gene co-expression network analysis identified coordinated up-regulation of hub genes associated with pH regulation within pillar cells. Pseudotime reconstruction further indicated that gill adaptation to low-salinity stress proceeds through a defined differentiation trajectory (cell fate 1) originating from pillar cells. Core stress-responsive genes in pillar cells, including V(H +)-ATPases and cytoplasmic carbonic anhydrase, were predominantly associated with acid-base regulation. Collectively, these results delineate gill cellular heterogeneity and identify pillar cell-mediated regulatory mechanisms that underpin crustacean physiological adaptation to low-salinity environments.
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Multiomics Reveals IL-17 Drives Epithelial Keratinization and Proliferation via EHF in Odontogenic Keratocysts.
This study aims to investigate epithelial cell (EpC) heterogeneity in odontogenic keratocysts (OKCs) and the molecular mechanisms driving their characteristic keratinization and rapid proliferation. We integrated single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics to profile OKC EpCs, validating findings via immunostaining and comparative analysis with normal oral mucosa. The regulatory roles of interleukin-17 (IL-17) and the transcription factor EHF were functionally assessed in vitro using human oral keratinocytes. Multi-omics mapping identified a distinct epithelial subpopulation (EpC2) characterized by robust keratinization, elevated keratin 13 (KRT13), and upregulated IL-17 signaling. Clinical OKC tissues exhibited significant upregulation and spatial co-localization of IL-17 and KRT13. In vitro, IL-17 robustly promoted cellular proliferation and KRT13 expression. Regulon analysis pinpointed EHF as the core transcription factor driving EpC2. EHF knockdown suppressed proliferation and downregulated KRT13, while overexpression amplified these processes. Crucially, IL-17 stimulation failed to rescue KRT13 expression in EHF-depleted cells, suggesting EHF as a critical downstream mediator. We present a comprehensive single-cell and spatial transcriptomic atlas of the OKC epithelium. The IL-17/EHF signaling axis appears to be a fundamental driver of OKC pathogenesis, promoting pathological hyperkeratinization and cellular proliferation. Targeting this axis presents a promising therapeutic strategy to manage OKC growth and prevent recurrence.
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[Types of Preeclampsia According to Placental Single Cell RNA Sequencing, Type 1 and Type 2 Levels - Insights and Clinical Implications].
INTRODUCTION: Preeclampsia, one of the Great Obstetrical Syndromes, remains a major contributor to maternal and fetal morbidity worldwide. Its clinical heterogeneity, classically reflected in "early" versus "late" presentations, underscores the need for biologically grounded sub-classifications to guide diagnosis and management. OBJECTIVES: To characterize the cellular and molecular mechanisms underlying preeclampsia subtypes using advanced single-cell and single-nuclei transcriptomic approaches, and to evaluate their alignment with a proposed integrated model distinguishing Type I (placental dysfunction) from Type II (maternal cardiovascular maladaptation) preeclampsia. METHODS: We performed single-cell and single-nuclei RNA sequencing on approximately 90,000 placental cells, encompassing 46 distinct cell populations, including trophoblast, lymphoid, myeloid, stromal, and endothelial lineages. Comparative transcriptomic analyses were conducted between early-onset and late-onset preeclampsia and control pregnancies. RESULTS: Profound cellular dysregulation was identified in early-onset preeclampsia across multiple placental cell types, consistent with widespread placental dysfunction, angiogenic imbalance, inflammatory response and apoptosis. In contrast, late-onset preeclampsia exhibited comparatively subtle transcriptional changes, suggestive of a distinct pathophysiological process driven by maternal cardiovascular maladaptation, placental aging, cellular senescence and oxidative stress. These findings support the classification of preeclampsia into Type I (placental-dominant, early-onset) and Type II (maternal-dominant, late-onset) forms, each characterized by specific risk factors, biomarkers, and therapeutic targets. CONCLUSIONS: This placental molecular atlas integrates single-cell and single-nuclei transcriptomic data with clinical phenotypes, providing mechanistic support for the Type I and Type II preeclampsia framework. These insights inform the development of targeted interventions, including RNA-based therapies to modulate placental angiogenic pathways in early-onset disease, and maternal cardiovascular optimization strategies in late-onset disease.
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A spatiotemporal transcriptomic atlas of porcine (Sus scrofa) female early gonadal development.
The early gonads of mammals contain primordial germ cells (PGCs) and gonadal somatic cells. In females, the gonadal somatic cells promote the specification of PGCs into oogonia and their entry into meiosis, which is crucial for oogenesis. Although single-cell transcriptome sequencing technology holds significant advantages in cell type identification, its inability to resolve spatial positional information substantially hampers research on communication mechanisms between germ cells and adjacent somatic cells. Here, we utilized high-resolution spatial transcriptomic technology to dissect the spatial dynamics of various cell types during the specification of PGCs into oogonia and their entry into meiosis in porcine gonads. We clarified the spatial localization of two waves of granulosa cells in the supporting cell lineage and their roles in regulating germ cell development. Furthermore, we found that interstitial and endothelial cells were predominantly located in the medullary region of the early gonads. Notably, cell-cell communication analysis revealed the critical role of BMP signaling (BMP2, BMP4 and GDF5) in driving the specification of PGCs into oogonia and their subsequent entry into meiosis. Our study provides a spatially resolved understanding of the PGC-to-oogonia specification in vivo and offers critical resources for reconstituting oogenesis in vitro.
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PRECISE: A Prognostic Thyrocyte-Derived Gene Signature for Papillary Thyroid Carcinoma.
PURPOSE: Papillary thyroid carcinoma (PTC) exhibits heterogeneous behavior, underscoring the need for effective biomarkers and improved risk stratification methods. We developed a thyrocyte-derived gene signature, Prognostic RNA Expression Cell-specific Integrated Signature (PRECISE), using single-cell RNA sequencing (scRNA-seq) and single-nucleus RNA sequencing (snRNA-seq) and evaluated its prognostic utility across cohorts. EXPERIMENTAL DESIGN: PRECISE was developed using a discovery cohort of patients with PTC [MD Anderson Cancer Center (MDACC), n = 109, median follow-up = 14 years]. Within the cohort, 11 PTC tumors and 4 normal thyroid samples were successfully sequenced using snRNA-seq. Differentially expressed genes were integrated with previously identified thyrocyte-associated genes from scRNA-seq. Prognostic significance was assessed using bulk RNA-seq in the discovery cohort and validated in two additional cohorts [Vanderbilt University Medical Center (VUMC), n = 65; The Cancer Genome Atlas (TCGA), n = 370]. A rank-based single-sample method was used for score calculation. Associations between PRECISE and progression-free survival (PFS) and disease-specific survival (DSS) were evaluated using multivariate Cox models, and predictive models were compared using Harrell's C-statistic and likelihood ratio tests. RESULTS: PRECISE is comprised of 41 epithelial genes downregulated in PTC tumor cells. Higher PRECISE was significantly associated with shorter PFS across all three cohorts [MDACC: hazard ratio (HR) = 1.64, P = 0.002; VUMC: HR = 2.54, P < 0.001; TCGA: HR = 1.63, P = 0.012] and remained significant after tumor-node-metastasis stage adjustment in two cohorts with ≥5 years of follow-up [MDACC adjusted HR (aHR) = 1.42, P = 0.038; VUMC aHR = 2.12, P = 0.024]. PRECISE was also associated with DSS in these cohorts (MDACC: HR = 4.16, P < 0.001; VUMC: HR = 2.23, P = 0.010). Incorporating PRECISE significantly improved predictive performance for PFS and DSS beyond stage-based models. CONCLUSIONS: PRECISE is a thyroid epithelial gene signature with independent prognostic value in PTC.
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Decoding plant cell heterogeneity and dynamics across responses, development, to evolution with single-cell technologies.
Single-cell technologies are redefining plant cell identity. Traditional classifications based on position, morphology, and a few marker genes yielded static, coarse cell categories. In contrast, single-cell and single-nucleus RNA sequencing reveal hidden cellular heterogeneity and reconstruct developmental trajectories in ostensibly well-characterized plant tissues including vasculature and mesophyll. Environmental cues such as pathogen attack, drought, and wounding generate transient, spatially restricted cell states that bulk profiling masks, and these dynamics are best resolved by integrating single-cell data with spatial transcriptomics and live imaging. Comparative single-cell analyses extend these insights across evolution, revealing conserved core cell-type groups, lineage-specific innovations, and rapid transcriptomic rewiring in particular cell types. Emerging computational strategies mitigate orthology issues caused by genome duplications, enabling robust cross-species atlas alignment. These advances demonstrate that plant cell identity is dynamic, context-dependent, and distributed along continuous spectra. We argue that future frameworks should balance discrete cell-type labels with flexible state-based descriptions and integrate multiomic and spatial information to capture the full plasticity of plant cells, from ephemeral stress responses to millennial evolutionary changes.