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Found: 4 939
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A single-cell atlas of de novo β-cell regeneration reveals the contribution of hybrid β/δ-cells to diabetes recovery in zebrafish.
Regeneration-competent species possess the ability to reverse the progression of severe diseases by restoring the function of the damaged tissue. However, the cellular dynamics underlying this capability remain unexplored. Here, we have used single-cell transcriptomics to map de novo β-cell regeneration during induction and recovery from diabetes in zebrafish. We show that the zebrafish has evolved two distinct types of somatostatin-producing δ-cells, which we term δ1- and δ2-cells. Moreover, we characterize a small population of glucose-responsive islet cells, which share the hormones and fate-determinants of both β- and δ1-cells. The transcriptomic analysis of β-cell regeneration reveals that β/δ hybrid cells provide a prominent source of insulin expression during diabetes recovery. Using in vivo calcium imaging and cell tracking, we further show that the hybrid cells form de novo and acquire glucose-responsiveness in the course of regeneration. The overexpression of dkk3, a gene enriched in hybrid cells, increases their formation in the absence of β-cell injury. Finally, interspecies comparison shows that plastic δ1-cells are partially related to PP cells in the human pancreas. Our work provides an atlas of β-cell regeneration and indicates that the rapid formation of glucose-responsive hybrid cells contributes to the resolution of diabetes in zebrafish.
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Clonal and molecular analysis of the prospective anterior neural boundary in the mouse embryo.
In the mouse embryo the anterior ectoderm undergoes extensive growth and morphogenesis to form the forebrain and cephalic non-neural ectoderm. We traced descendants of single ectoderm cells to study cell fate choice and cell behaviour at late gastrulation. In addition, we provide a comprehensive spatiotemporal atlas of anterior gene expression at stages crucial for anterior ectoderm regionalisation and neural plate formation. Our results show that, at late gastrulation stage, expression patterns of anterior ectoderm genes overlap significantly and correlate with areas of distinct prospective fates but do not define lineages. The fate map delineates a rostral limit to forebrain contribution. However, no early subdivision of the presumptive forebrain territory can be detected. Lineage analysis at single-cell resolution revealed that precursors of the anterior neural ridge (ANR), a signalling centre involved in forebrain development and patterning, are clonally related to neural ectoderm. The prospective ANR and the forebrain neuroectoderm arise from cells scattered within the same broad area of anterior ectoderm. This study establishes that although the segregation between non-neural and neural precursors in the anterior midline ectoderm is not complete at late gastrulation stage, this tissue already harbours elements of regionalisation that prefigure the later organisation of the head.
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A cell and transcriptome atlas of human arterial vasculature.
Arterial segments show differing disease propensities, yet mechanisms remain unknown. We compiled a transcriptomic and spatial atlas of healthy human arterial cells across multiple segments to understand these differences. Arteries demonstrated a stereotyped pattern of cell-specific, segmental heterogeneity not captured by common marker genes. Arterial identities are encoded in fibroblast and smooth muscle cell (SMC) transcriptomes. Differentially expressed genes enrich for disease loci. Fibroblast gene expression enriches for a disproportionate number of disease loci, highlighting an underrecognized role for fibroblasts in disease risk. Cells of different segments cluster more by embryonic origin than anatomy. Global analysis of disease regulons in fibroblasts and SMCs identified developmental transcription factors that persist into adulthood, suggesting a functional role of these factors in disease. Lastly, the heterogeneity of non-coding transcriptomes rivals that of protein-coding transcriptomes. Differentially expressed lncRNAs enrich for genetic signals for vascular diseases, suggesting a role for lncRNAs in vascular disease.
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Single-Nucleus RNA Sequencing and Spatial Transcriptomics Reveal Cellular Heterogeneity and Intercellular Communication Networks in the Hypothalamus-Pituitary-Ovarian Axis of Pregnant Mongolian Cattle.
The hypothalamus-pituitary-ovarian (HPO) axis orchestrates reproductive functions through intricate neuroendocrine crosstalk. Here, we integrated single-nucleus RNA sequencing (snRNA-seq) and spatial transcriptomics (ST) to decode the cellular heterogeneity and intercellular communication networks in the reproductive systems of pregnant Mongolian cattle. We retained a total of 6161 high-quality nuclei from the hypothalamus, 14,715 nuclei from the pituitary, and 26,072 nuclei from the ovary, providing a comprehensive cellular atlas across the HPO axis. In the hypothalamus, neurons exhibited synaptic and neuroendocrine specialization, with glutamatergic subtype Glut4 serving as a TGFβ signaling hub to regulate pituitary feedback, while GABAergic GABA1 dominated PRL signaling, likely adapting maternal behavior. Pituitary stem cells dynamically replenished endocrine populations via TGFβ, and lactotrophs formed a PRL-PRLR paracrine network with stem cells, synergizing mammary development. Ovarian luteal cells exhibited steroidogenic specialization and microenvironmental synergy: endothelial cells coregulated TGFβ-driven angiogenesis and immune tolerance, while luteal-stromal PRL-PRLR interactions amplified progesterone synthesis and nutrient support. Granulosa cells (GCs) displayed spatial-functional stratification, with steroidogenic GCs persisting across pseudotime as luteinization precursors, while atretic GCs underwent apoptosis. Spatial mapping revealed GCs' annular follicular distribution, mediating oocyte-somatic crosstalk, and luteal-endothelial colocalization supporting vascularization. This study unveils pregnancy-specific HPO axis regulation, emphasizing multi-organ crosstalk through TGFβ/PRL pathways and stem cell-driven plasticity, offering insights into reproductive homeostasis and pathologies.
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An immune cell atlas reveals the dynamics of human macrophage specification during prenatal development.
Macrophages are heterogeneous and play critical roles in development and disease, but their diversity, function, and specification remain inadequately understood during human development. We generated a single-cell RNA sequencing map of the dynamics of human macrophage specification from PCW 4-26 across 19 tissues. We identified a microglia-like population and a proangiogenic population in 15 macrophage subtypes. Microglia-like cells, molecularly and morphologically similar to microglia in the CNS, are present in the fetal epidermis, testicle, and heart. They are the major immune population in the early epidermis, exhibit a polarized distribution along the dorsal-lateral-ventral axis, and interact with neural crest cells, modulating their differentiation along the melanocyte lineage. Through spatial and differentiation trajectory analysis, we also showed that proangiogenic macrophages are perivascular across fetal organs and likely yolk-sac-derived as microglia. Our study provides a comprehensive map of the heterogeneity and developmental dynamics of human macrophages and unravels their diverse functions during development.
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Immune characteristics and genetic markers of esophageal cancer by single-cell analysis: implications for immunotherapy.
BACKGROUND: Esophageal cancer (EC) is one of the most common cancers worldwide. The prognoses for patients with the same stage of EC can vary substantially. The progress of single-cell analysis technology has furthered the understanding of tumor heterogeneity. This paper aimed to apply single-cell analysis to explore the characteristics of the tumor environment of EC and provide a basis for personalized treatment. METHODS: The latest gene expression data and clinical follow-up information of single-cell sequencing results of EC samples were downloaded from The Cancer Genome Atlas (TCGA) Genomic Data Commons (GDC) Application Programming Interface (API). A differential gene function analysis of the immune infiltration signature agents in the tumor microenvironment (TME) was performed using bioinformatics analytical methods, and potential molecular targets were sought. RESULTS: We identified specific cell subsets in the EC and paracancerous samples, including panel cells, natural killer (NK) cells, exhausted cluster of differentiation (CD)8+ T cells, CD8+ memory T (Tcm) cells, and effector memory T (Tem) cells, including B cell enrichment in the cancer samples. Differences were detected between B cells and monocytes in stage II and III tumors, which may be related to RNA transcription and degradation. The CXCL8 protein was identified as a valid potential prognostic marker. CONCLUSIONS: Cell groups with homogenous cell surface markers exhibit intercellular variations that exert a considerable effect on cell function. Our study will contribute to the understanding of the TME and cellular heterogeneity in EC patients and serve as a valuable resource for in-depth exploration of the pathogenesis of EC and the identification of potential therapeutic targets in the future.
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Bromodomain containing 4 transcriptionally activated Deltex E3 ubiquitin ligase 2 contributes to glioma progression and predicts an unfavorable prognosis.
BACKGROUND: Glioblastoma multiforme (GBM) is the most common type of glioma, and the most aggressive brain malignancy in adults. This study sought to identify novel survival-status related markers, and examine their function in glioma. METHODS: The gene expression, survival heatmaps, and Kaplan-Meier survival plots of the genes were analyzed by using gene expression profiling interactive analysis (GEPIA) dataset, Linked Omics. The single-cell data analysis and tumor immune infiltration analysis was conducted by Tumor Immune Estimation Resource (TIMER) dataset. DBTRG and U251 cells with silenced Deltex E3 ubiquitin ligase 2 (DTX2) expression were constructed and used for Cell Counting Kit 8 (CCK-8), and wound healing assay in vitro. Chromatin immunoprecipitation sequencing (ChIP-seq) analysis was used to explore the histone activation marks and transcription factors DTX2 promoter. Dual-luciferase assays were carried out to detect the luciferase activities of bromodomain containing 4 (BRD4) binding to DTX2. RESULTS: We first conducted a survival-status analysis to identify survival status-related genes in The Cancer Genome Atlas GBM and low-grade glioma data sets. A subsequent analysis identified 3 novel prognostic biomarkers; that is, DTX2, cytochrome P450 oxidoreductase, and Williams-Beuren syndrome chromosomal region 16 protein. In the validation Chinese Glioma Genome Atlas data sets, DTX2 showed the best performance, and was examined in a further analysis. Next, 3 short-hairpin ribonucleic acids were designed to silence DTX2 expression, and CCK-8 and wound-healing assays were applied to study the function of DTX2. We found that DTX2-silenced glioma cells exhibited a significant decrease in their growth and migration capabilities. Finally, the molecular basis for increased DTX2 in glioma was investigated via ChIP-Seq analysis and luciferase assays. The analysis revealed that DTX2 was transcriptionally activated by BRD4. CONCLUSIONS: In conclusion, BRD4 transcriptionally activates DTX2, contributes to glioma progression, predicts an unfavorable prognosis, and could provide new options for glioma prognosis prediction and treatment.
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The Prognostic Significance of TRs in Hepatocellular Carcinoma: Insights from TCGA and GEO Databases.
BACKGROUND: Reduced expression of thyroid hormone receptors (TRs) has been observed in various human malignancies, though its predictive value in hepatocellular carcinoma (HCC) remains uncertain. OBJECTIVE: To explore the predictive value of TRs in patients with hepatocellular carcinoma. DESIGN: The design was bioinformatic analysis combined with experimental study. METHODS: This study utilized Kaplan-Meier analysis of TR expression profiles from The Cancer Genome Atlas (TCGA). Expression levels of TRs in HCC and immune single cells were assessed using datasets from the Gene Expression Omnibus (GEO) and TCGA, analyzed with R software. Cox and logistic regression analyses were also conducted. Functional assays, including wound healing, CCK-8, and Transwell migration assays, were employed to investigate the role of the THRB gene. RESULTS: Kaplan-Meier analysis revealed that low THRB expression was significantly associated with reduced overall survival (OS), 5-year OS and disease-specific survival (DSS) in HCC patients (P < 0.05), while no significant association was found with THRA expression. Both Cox regression and logistic regression identified low THRB expression as an independent risk factor for HCC. THRB expression was significantly downregulated in tumor tissues compared to non-tumorous tissues in 3 GEO datasets and the TCGA profile. Functional assays confirmed that THRB inhibited HCC cell proliferation and migration. Additionally, single-cell RNA sequencing revealed that THRB was primarily expressed in CD16+ monocytes within tumor tissues and was associated with a poor OS rate. CONCLUSION: Reduced THRB expression, but not THRA, was correlated with decreased OS in HCC patients.
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GAPDH: unveiling its impact as a key hypoxia-related player in head and neck squamous cell carcinoma tumor progression, prognosis, and therapeutic potential.
Head and neck squamous cell carcinoma (HNSCC), characterized by hypoxia patterns, ranks as the sixth most prevalent malignant tumor worldwide. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) plays a role in oncogenesis under hypoxic conditions in various cancers. However, its precise function in HNSCC, especially under varied hypoxic conditions, including at high altitudes, remains unclear. Elevated GAPDH mRNA and protein levels in HNSCC relative to normal tissues have been demonstrated through data from The Cancer Genome Atlas (TCGA), GSE29330, and the Human Protein Atlas (P<0.05). This elevation was further confirmed through in vitro experiments utilizing two HNSCC cell lines and a normal oral mucosal epithelial cell line. Additionally, data from TCGA and GSE41613 reveal a correlation between elevated GAPDH expression and diminished overall and progression-free survival in patients (P<0.05). Subsequent analysis identifies GAPDH as an independent risk factor for HNSCC (P<0.05). Using the ESTIMATE and single-sample gene set enrichment analysis (ssGSEA) algorithms, high GAPDH expression was found to be associated with reduced immune scores and diminished anti-tumor cell infiltration, such as CD8+ T cells, in TCGA and GSE41613 datasets (P<0.05). Analysis of single-cell RNA sequencing data from GSE139324 suggests that elevated GAPDH expression hinders communication between plasmacytoid dendritic cells and mast cells (P<0.05). Furthermore, in the TCGA and GSE41613 datasets, GAPDH's biological function is closely tied to hypoxia through Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Variation Analysis (GSVA) analyses. Moreover, its expression is linked to one cuproptosis-related gene, five N6-methyladenosine-related genes, six immune checkpoint genes, and pivotal pathways such as MYC and E2F (P<0.05). GAPDH showed excellent predictive value in estimating the efficacy of immunotherapy and 11 anti-tumor drugs (e.g., cisplatin) (P<0.05), using TIDE and pRRophetic algorithms on the TCGA and GSE41613 datasets. Under 1% O2 in vitro, HNSCC cells show elevated GAPDH expression, leading to decreased apoptosis and increased migration, clonogenicity, invasiveness, and resistance to cisplatin (P<0.05). At 5% O2, these effects persisted, albeit less pronouncedly. Inhibiting GAPDH reversed these effects under all oxygen concentrations (P<0.05). Overall, our findings reveal GAPDH as a key hypoxia-related player influencing tumor progression, prognosis, and therapeutic potential in HNSCC.
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A unified cell atlas of vascular plants reveals cell-type foundational genes and accelerates gene discovery.
The pace of gene discovery in plants has slowed as forward genetic screens reach saturation. To address this, we built a unified single-cell atlas of shoot apices from six vascular plant species spanning major evolutionary groups. This cross-species resource allowed us to identify a core set of cell-type foundational genes linked to key tissues such as the epidermis, xylem, and phloem, streamlining gene discovery with greater accuracy. Among these, we uncovered a previously unrecognized clade of X8 domain proteins and JULGI-LIKE as regulators of phloem development. We also identified companion-cell-like cells in ferns and gymnosperms that cannot be distinguished by conventional histological methods and developed an automated cell-type annotation tool for vascular plant cell types, expanding the utility of our approach. Our findings establish a high-resolution framework for identifying key regulators of plant cell types and set an innovative paradigm for studying plant cell-type evolution.