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Single-cell RNA sequencing reveals transcriptional profiles of endometrial epithelial remodeling and identifies candidate genes regulating glandular cell development in Chinese Meishan pigs.
The porcine endometrium undergoes dynamic cellular remodeling across the estrous cycle, yet epithelial heterogeneity and differentiation trajectories remain incompletely characterized. In this study, a single-cell transcriptomic atlas of the endometrial epithelium during the follicular and luteal phases in Meishan pigs was generated using high-resolution single-cell RNA sequencing. Canonical epithelial cell types were identified, including glandular epithelium (GE), secretory glandular epithelium (secretory GE), luminal epithelium (LE), ciliated epithelium, as well as an epithelial stem cell subpopulation marked by ALDH1A3 and LGR5 and a progenitor subpopulation marked by ALDH1A1. During the follicular phase, the epithelium was primarily composed of ALDH1A3+LGR5+ stem cells and ALDH1A1+ progenitor cells, whereas GE, secretory GE, and LE predominated during the luteal phase. Integrated trajectory inference and RNA velocity analyses suggested a continuous differentiation trajectory from ALDH1A3+LGR5+ stem cells through ALDH1A1+ progenitors toward GE. Gene expression patterns indicated that glandular epithelial formation was associated with activation of transcriptional regulatory programs and increased mitochondrial respiratory activity. In contrast, differentiation toward the secretory glandular epithelial lineage was characterized by early activation of stress-response pathways, secretion-related genes, and specific metabolic programs. Several transcription factors, including ZFP36L1, TRPS1, and KLF6, were associated with glandular differentiation, whereas MBD4, CREB3L4, ZNF524, SPDEF, USF1, XBP1, and MLX were predicted to contribute to glandular secretory function. These genes showed significant associations with sow reproductive traits in a phenome-wide association study. Overall, this study provides a single-cell framework for understanding epithelial dynamics in the porcine endometrium across the estrous cycle.
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A single-cell atlas identifies oncogenic transcriptional programs and immune escape mechanisms in CTCL.
Primary cutaneous T-cell lymphomas (CTCL) are a heterogeneous group of extranodal non-Hodgkin lymphomas. Outcomes for patients with advanced-stage disease are suboptimal, because few complete and durable responses are achieved with currently available therapeutic agents. However, improved understanding of oncogenic transcriptional programs in malignant T cells and their engagement with the tumor microenvironment (TME) may unveil therapeutic vulnerabilities. Therefore, we have compiled the largest available single-cell RNA-sequencing CTCL atlas that includes >2 million skin and blood cells from 116 individual patients. We identified recurrent transcriptional programs in malignant T cells, a subset of which are associated with GATA binding protein 3-dependent transcriptional programs, especially in the setting of large cell transformation and advanced-stage disease. Many of the transcriptional programs identified are therapeutically targetable with clinically available agents, including HDAC, XPO1, CDK9, JAK/CSF1R, and IKZF1/IKZF3 antagonists. The CTCL TME is dominated by infiltrating and exhausted effector and cytotoxic T cells that are restrained by a robust infiltrate of regulatory T cells, transcriptionally polarized monocytes/macrophages, and cancer-associated fibroblasts. Collectively, these findings have significant implications for the rational design of combinatorial strategies targeting immune checkpoints, including programmed cell death protein 1. We have identified transcriptional programs, driven by oncogenic transcription factors, and constituents of the TME as therapeutic vulnerabilities in CTCL, and hope that the CTCL atlas constructed will provide a valuable resource for future studies exploiting these therapeutic vulnerabilities.
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Deciphering the Transcription Factor-Dominated Ecosystem During Esophageal Squamous Cell Carcinoma Progression at the Single-Cell Level.
Esophageal squamous cell carcinoma (ESCC) progression involves dynamic cellular state transitions and tumor microenvironment remodeling, accompanied by extensive transcriptional regulation reprogramming. Here, we systematically mapped the TF-mediated regulatory landscape underlying ESCC progression at single-cell resolution by integrating stage-specific ESCC single-cell transcriptomic datasets comprising over 200,000 cells with TF-target interaction networks. Using a random walk algorithm combined with hypergeometric testing, we identified malignant progression-associated TFs (mpTFs) across multiple cell types and disease stages. Our analysis revealed extensive stage-dependent regulatory remodeling during ESCC progression. TCF4 was identified as an early-stage regulator associated with epithelial-mesenchymal transition activation and malignant invasive phenotypes. In immune lineages, BATF and IRF4 exhibited trajectory-associated activation during CD4+ T-cell differentiation and CD8+ T-cell exhaustion, suggesting critical roles in immunosuppressive T-cell state transitions. Additionally, mpTF-mediated remodeling of M2 macrophage subpopulations contributed to immunosuppressive tumor microenvironment formation during advanced ESCC progression. We further identified prognosis-associated cell-type-specific and shared mpTFs, including TFAP2C, which was associated with stabilized fibroblast and monocyte functional states and a less aggressive tumor microenvironment phenotype. Collectively, this study provides a comprehensive single-cell atlas of TF-mediated regulatory programs during ESCC progression and offers potential therapeutic targets for precision oncology.
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Single-Cell Transcriptome Profiles of Foxl1-Lineage Cells Along the Intestinal Crypt-Villus Axis.
BACKGROUND & AIMS: Intestinal epithelial cells rely on a complex array of stromal signals to determine their fate and function along the crypt-villus axis, but the precise cellular sources and combinations of signals at each position remain poorly defined. METHODS: We generated an atlas of Foxl1-lineage cells along the crypt-villus axis using single-cell RNA sequencing integrated with in situ hybridization, immunofluorescence, and reporter mouse models. RESULTS: We identify 4 spatially distinct Foxl1-lineage subepithelial populations: crypt, villus-base, villus-mid and villus-tip, that segregate into 2 related pairs. Crypt and villus-mid Foxl1-lineage cells share a low platelet-derived growth factor receptor α transcriptional program enriched for canonical Wnts and R-spondins, consistent with regenerative signaling functions. In contrast, villus-base and villus-tip Foxl1-lineage cells are platelet-derived growth factor receptor α-high and express noncanonical Wnt5a and bone morphogenetic protein ligands. Crypt Foxl1-lineage cells are additionally enriched for extracellular matrix proteins and complement components, whereas villus-base Foxl1-lineage cells express contractility-associated genes, suggesting a role in villus architecture. Villus-mid Foxl1-lineage cells display signatures of immune regulation and inflammation, whereas villus-tip Foxl1-lineage cells are specialized for regulation of ribonucleoprotein complexes and nutrient sensing. CONCLUSIONS: This atlas provides a foundational resource for understanding how diverse stromal populations coordinate signaling niches and influence intestinal epithelial homeostasis.
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Identification of succinylation-related genes in bladder cancer: integration of single-cell and transcriptomic data.
BACKGROUND: Bladder cancer (BLCA) exhibits a poor prognosis, highlighting the urgent need for reliable prognostic genes. Although succinylation is linked to tumor progression, its role in BLCA remains understudied. This study aimed to identify and validate prognostic succinylation-related genes (SRGs) in BLCA and elucidate their impact on the tumor microenvironment (TME). METHODS: SRGs were initially identified through transcriptomic sequencing of 15 paired BLCA and adjacent normal tissues (Soochow-BLCA cohort) and further refined by integrating single-cell and bulk transcriptomic data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets. A prognostic risk model was developed using LASSO and multivariable Cox regression, incorporating clinical factors for nomogram construction. Mechanistic insights were obtained through functional enrichment, immune profiling, somatic mutation, and drug sensitivity analyses. The Scissor algorithm mapped bulk transcriptome risk signatures to single-cell resolution, enabling identification of high-risk cell subpopulations. Pseudotime and cell-cell communication analyses characterized dynamic expression patterns of the core genes. Finally, the expression profiles and functional roles of the core genes were validated using RT-qPCR and CCK-8 proliferation assays in vitro. RESULTS: KCTD16, CD3D and GSDMB were identified as prognostic genes. The risk score derived from these genes, in combination with age and N stage, was incorporated into a risk model that exhibited robust predictive accuracy (AUC > 0.7). Expression of these genes differed significantly between non-muscle-invasive and muscle-invasive subtypes. The high-risk group displayed enhanced immune evasion (higher TIDE score, p < 0.001), while the TME appeared to be in an "inflamed yet dysfunctional" state. Single-cell analysis indicated epithelial cells as key subpopulations, with additional involvement of T cells and fibroblasts. Scissor+ cells were correlated with the high-risk phenotype and exhibited pseudotime-dependent expression patterns. RT-qPCR revealed significant upregulation of GSDMB and downregulation of KCTD16 and CD3D in BLCA (p < 0.05). Functionally, knockdown of GSDMB and KCTD16 significantly promoted T24 cell proliferation, supporting their tumor-suppressive roles. CONCLUSIONS: The succinylation-related prognostic model accurately predicts outcomes in BLCA, reveals links to immune escape and TME, and highlights the pivotal role of epithelial cells, offering potential targets for individualized therapy.
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Generation of a prop1 knock-in zebrafish enables single-cell transcriptomics of early pituitary development.
The adenohypophyseal placode is a developmental structure that is conserved among vertebrates and gives rise to the anterior pituitary. The earliest steps of its formation remain poorly understood. Here, we present a powerful new genetic tool: a zebrafish GAL4 knock-in reporter line for prop1. The targeted integration disrupts prop1 function, generating the first prop1-/- zebrafish, which exhibits dwarfism, impaired sexual maturation, and pigmentation defects. The generation of this new reporter line enabled the study of early pituitary development at single-cell resolution, using both scRNA-seq and live imaging. We identified epcam/Epcam as a conserved epithelial marker of the adenohypophysis in both zebrafish and mouse. We further studied transcriptional programs underlying endocrine lineage specification, discovering several previously unrecognized markers for hormone-producing lineages, including tfcp2l1, as a likely regulator of lactotrope differentiation. Cell-cell interaction analyses indicated Notch, Fgf, and Slit/Robo signaling as key regulators of progenitor maintenance and differentiation. Overall, this work provides the first single-cell atlas of early zebrafish pituitary development, a robust new genetic tool to study fundamental mechanistic insights into pituitary lineage specification and differentiation.
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Immune landscape in NOD.H-2h4 mouse model thyroid revealed by single-cell RNA sequencing.
BACKGROUND: Hashimoto's thyroiditis is a common autoimmune disorder characterized by lymphocytic infiltration and thyroid follicular cell destruction, leading to permanent hypothyroidism and an increased, clinically risk of thyroid malignancy. However, the specific roles of each thyroidal cell types participating the immune dysregulation of HT remain incompletely elucidated. METHODS: We performed single-cell RNA sequencing on thyroid tissues from NOD.H-2h4 mice at three disease stages (4, 8, and 16 weeks). A total of 38,461 cells were analyzed to characterize the transcriptomic profiles of twelve distinct populations, comprising immune infiltrates and resident tissue cells. RESULTS: Our single-cell atlas revealed a downregulation of Nkx2-1, suggesting a potential loss of thyrocyte identity and function. Inferred intercellular communication predicted that thyrocytes and stromal cells might interact with immune cells via the putative App-Cd74 axis. Tregs displayed transcriptional signatures of dysfunction and instability. Furthermore, the transcriptomic landscape indicated that chronic stress potentially induces thyrocytes into inflammatory and antigen-presenting phenotypes. Collectively, our single-cell transcriptomic insights highlight thyrocyte plasticity and Treg dysfunction as potential drivers of disease progression. CONCLUSION: We constructed a single-cell transcriptomic atlas of the NOD.H-2h4 mouse model. This work provides a dataset for further research into the cellular mechanisms of Hashimoto's thyroiditis.
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A Single-Cell Transcriptomic Atlas of Epithelial Cell Heterogeneity During the Crown-to-Root Transition in the Mouse Molar.
The mechanisms driving the crown-to-root transition in tooth development remain incompletely understood, particularly the functional heterogeneity of dental epithelium. To address this gap and deconstruct this complexity, we aimed to analyze dental epithelial heterogeneity during this critical transition and to identify subpopulation-specific programs relevant to root development. We therefore established a single-cell transcriptomic atlas of the mouse molar at postnatal days 3.5 and 7.5, integrating 30,951 cells to profile the pan-tissue landscape and performing an in-depth analysis of 4323 dental epithelial cells. Our results reveal that the dental epithelium is composed of seven distinct subpopulations with a clear lineage hierarchy, originating from multipotent progenitors and bifurcating into self-renewing and differentiating trajectories. The identified particular functions of each subcluster include the following: structural maintaining progenitor that inhibits mineralization (Cluster 4), proliferation driver (Cluster 0), key signaling center (Cluster 1), terminally differentiated executing enamel formation (Cluster 3 and Cluster 6), and extracellular matrix-organizing hub (Cluster 5), communicating extensively via the Bmp, Tgf-β, and Wnt pathways. Our work defines dental epithelium as a dynamic and heterogeneous orchestrator of root morphogenesis, providing a foundational framework for understanding developmental biology and pioneering future regenerative strategies based on precise epithelial cell functions.
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Integrated Single-Cell Atlas Reveals Cross-Subtype Heterogeneity in Human Pulmonary Hypertension.
BACKGROUND: Pulmonary hypertension (PH) is a severe vascular disorder characterized by pathological pulmonary vascular remodeling. Although single-cell RNA sequencing has provided insights into PH, patient studies remain fragmented across clinical subtypes and are processed with heterogeneous pipelines, limiting cross-study comparability and integrative interpretation of disease-relevant cellular states in human PH. METHODS: We integrated single-cell RNA sequencing data sets to construct a core PH-specific cellular atlas using a standardized quantification and batch-correction pipeline, followed by hierarchical cell type annotation to define major lineages and finer cell states. We then performed comparative analyses to reassess reported cellular alterations within a unified reference. Building on this atlas, we developed PH-Map, a multitask learning tool pretrained on this atlas for rapid hierarchical cell annotation and validated it in independent external cohorts. RESULTS: The core PH-specific atlas comprises 235 621 high-quality cells from 64 human samples spanning idiopathic pulmonary arterial hypertension, systemic sclerosis-associated pulmonary arterial hypertension, chronic thromboembolic PH, and healthy controls, organized into 6 major lineages and 58 distinct cell states. Cross-subtype comparison revealed shared and subtype-specific remodeling across vascular and immune compartments, including redefined smooth muscle cell states, fibroblast-associated complement activation in idiopathic pulmonary arterial hypertension, and heterogeneous immune transcriptional programs. We additionally observed system-dependent differences, including variable major histocompatibility complex class II activation in capillary endothelial cells across animal models versus human PH and convergent phenotypic shifts in primary cultured endothelial cells relative to native lung endothelial cells. PH-Map showed stable hierarchical annotation performance in external cohorts across multiple levels of annotation granularity with improved computational efficiency. CONCLUSIONS: This core human single-cell PH atlas enables systematic cross-subtype comparison and delineates shared and subtype-specific cellular programs across vascular and immune compartments. Together with PH-Map, it supports reproducible hierarchical annotation and prioritization of candidate cell states and pathways for downstream studies.
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Single-cell analysis of the human retina reveals stage-linked microglial states and neural-immune circuit rewiring in diabetic retinopathy.
Diabetic retinopathy (DR) is a major cause of vision loss worldwide. Here, we conduct single-cell RNA sequencing of twenty human retina samples (from living and post-mortem donors) across non-diabetic, diabetic, and DR states to create a comprehensive transcriptomic atlas. We identify two stable microglial populations-homeostatic and inflammatory-that exist along a functional continuum, plus a neutrophil cluster within C1QA+ myeloid cells with dynamic transitions occurring throughout disease progression. Module-level analysis reveals divergent transcriptional trajectories: homeostatic microglia maintain energetic programs while selectively upregulating stress elements, whereas inflammatory microglia layer additional pro-inflammatory programs onto preserved biosynthetic foundations. Eleven co-expression modules organize into two major axes: an inflammatory-stress axis, and a regulatory/metabolic-motility axis, with a stable translation module persisting across disease stages. Cell communication analysis further highlights sophisticated neural-immune interactions, particularly between photoreceptors and microglia. Our findings provide insights into the complex cellular dynamics of DR progression and suggest potential therapeutic targets for early intervention.