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Found: 4 939
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Inference of cell-type composition and single-cell spatial maps from spatial transcriptomics data with SWOT.
Spatially resolved single-cell transcriptomics is crucial for mapping the cellular atlas of organisms, but many spatial transcriptomics data lack single-cell resolution. Most cell-type deconvolution methods are limited to estimating cell-type proportions, and they cannot further identify the exact cells needed to reconstruct a single-cell spatial map. To overcome this limitation, we introduce a spatially weighted optimal transport method, named SWOT, for learning a mapping from cells to spots to infer both cell-type composition and single-cell spatial maps from spot-based spatial transcriptomics data. Experimental results demonstrate that the learned cell-to-spot mapping offers advantages in estimating cell-type proportions, cell numbers per spot, and spatial coordinates per cell. SWOT also depicts cell-type spatial distributions and maps single cells to their spatial locations in different morphological tissues. We further showcase the utility of SWOT in assistance of accurately identifying and functionally annotating cellular neighborhoods for deciphering tissue architecture. In summary, SWOT represents a useful tool for transforming abundant spot-resolution spatial transcriptomics data into single-cell resolution, thereby facilitating cell-level discoveries within tissues.
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Delineating Tissue-Specific Cell Identity of Oral Mucosa in Humans and Mice From a Single-Cell Perspective.
The oral mucosa exhibits superior healing and minimal scarring. Although mouse models are widely used to study wound healing and various diseases, their translational relevance remains unclear. Here, we performed a comparative single-cell transcriptomic analysis of human and mouse oral mucosa to identify both shared and species-specific mechanisms. A total of 34,969 cells from human and mouse datasets were integrated using Harmony for batch effect correction, allowing us to establish a unified oral mucosa transcriptome atlas. Fibroblasts emerged as the prominent cell population in both species, displaying conserved gene expression profiles and cell communication networks, underscoring their central role in tissue homeostasis. Key pathways involved in extracellular matrix remodelling and wound healing were highly conserved, supporting the utility of mouse models for studying fibroblast-mediated tissue regeneration. These findings suggest that mouse models can effectively replicate human fibroblast biology, offering valuable insights for developing translational therapies that target fibroblast activity and regulatory gene networks to enhance wound healing and tissue regeneration. Additionally, we identified species-specific cell populations, including human-specific capillary endothelial cells and melanocytes, as well as mouse-specific salivary gland epithelial cells. Their distinct cellular composition and functional differences suggest that these subpopulations may not be directly translatable from mouse models to human contexts. Overall, our study highlights the evolutionary conservation of fibroblasts while identifying species-specific differences that warrant consideration in translational research. These findings provide a valuable resource for researchers using mouse models to study oral mucosa-related diseases, facilitating the translation of preclinical discoveries into clinical applications.
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Spatiotemporal analysis of human intestinal development at single-cell resolution.
Development of the human intestine is not well understood. Here, we link single-cell RNA sequencing and spatial transcriptomics to characterize intestinal morphogenesis through time. We identify 101 cell states including epithelial and mesenchymal progenitor populations and programs linked to key morphogenetic milestones. We describe principles of crypt-villus axis formation; neural, vascular, mesenchymal morphogenesis, and immune population of the developing gut. We identify the differentiation hierarchies of developing fibroblast and myofibroblast subtypes and describe diverse functions for these including as vascular niche cells. We pinpoint the origins of Peyer's patches and gut-associated lymphoid tissue (GALT) and describe location-specific immune programs. We use our resource to present an unbiased analysis of morphogen gradients that direct sequential waves of cellular differentiation and define cells and locations linked to rare developmental intestinal disorders. We compile a publicly available online resource, spatio-temporal analysis resource of fetal intestinal development (STAR-FINDer), to facilitate further work.
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DNA methylation abnormalities induced by advanced maternal age in villi prime a high-risk state for spontaneous abortion.
BACKGROUND: Advanced maternal age (AMA) has increased in many high-income countries in recent decades. AMA is generally associated with a higher risk of various pregnancy complications, and the underlying molecular mechanisms are largely unknown. In the current study, we profiled the DNA methylome of 24 human chorionic villi samples (CVSs) from early pregnancies in AMA and young maternal age (YMA), 11 CVSs from early spontaneous abortion (SA) cases using reduced representation bisulfite sequencing (RRBS), and the transcriptome of 10 CVSs from AMA and YMA pregnancies with mRNA sequencing(mRNA-seq). Single-cell villous transcriptional atlas presented expression patterns of targeted AMA-/SA-related genes. Trophoblast cellular impairment was investigated through the knockdown of GNE expression in HTR8-S/Vneo cells. RESULTS: AMA-induced local DNA methylation changes, defined as AMA-related differentially methylated regions (DMRs), may be derived from the abnormal expression of genes involved in DNA demethylation, such as GADD45B. These DNA methylation changes were significantly enriched in the processes involved in NOTCH signaling and extracellular matrix organization and were reflected in the transcriptional alterations in the corresponding biological processes and specific genes. Furthermore, the DNA methylation level of special AMA-related DMRs not only significantly changed in AMA but also showed more excessive defects in CVS from spontaneous abortion (SA), including four AMA-related DMRs whose nearby genes overlapped with AMA-related differentially expressed genes (DEGs) (CDK11A, C19orf71, COL5A1, and GNE). The decreased DNA methylation level of DMR near GNE was positively correlated with the downregulated expression of GNE in AMA. Single-cell atlas further revealed comparatively high expression of GNE in the trophoblast lineage, and knockdown of GNE in HTR8-S/Vneo cells significantly impaired cellular proliferation and migration. CONCLUSION: Our study provides valuable resources for investigating AMA-induced epigenetic abnormalities and provides new insights for explaining the increased risks of pregnancy complications in AMA pregnancies.
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Single cell atlas reveals multilayered metabolic heterogeneity across tumour types.
BACKGROUND: Metabolic reprogramming plays a pivotal role in cancer progression, contributing to substantial intratumour heterogeneity and influencing tumour behaviour. However, a systematic characterization of metabolic heterogeneity across multiple cancer types at the single-cell level remains limited. METHODS: We integrated 296 tumour and normal samples spanning six common cancer types to construct a single-cell compendium of metabolic gene expression profiles and identify cell type-specific metabolic properties and reprogramming patterns. A computational approach based on non-negative matrix factorization (NMF) was utilised to identify metabolic meta-programs (MMPs) showing intratumour heterogeneity. In-vitro cell experiments were conducted to confirm the associations between MMPs and chemotherapy resistance, as well as the function of key metabolic regulators. Survival analyses were performed to assess clinical relevance of cellular metabolic properties. FINDINGS: Our analysis revealed shared glycolysis upregulation and divergent regulation of citric acid cycle across different cell types. In malignant cells, we identified a colorectal cancer-specific MMP associated with resistance to the cuproptosis inducer elesclomol, validated through in-vitro cell experiments. Furthermore, our findings enabled the stratification of patients into distinct prognostic subtypes based on metabolic properties of specific cell types, such as myeloid cells. INTERPRETATION: This study presents a nuanced understanding of multilayered metabolic heterogeneity, offering valuable insights into potential personalized therapies targeting tumour metabolism. FUNDING: National Key Research and Development Program of China (2021YFA1300601). National Natural Science Foundation of China (key grants 82030081 and 81874235). The Shenzhen High-level Hospital Construction Fund and Shenzhen Basic Research Key Project (JCYJ20220818102811024). The Lam Chung Nin Foundation for Systems Biomedicine.
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Single-cell multiomics analysis reveals CTCF as a key regulator of lung morphogenesis and progenitor maintenance.
Lung development generates a complex tree-like architecture through proximal-distal patterning and branching morphogenesis. However, the gene regulatory programs governing embryonic lung development remain poorly understood. Here, we present a comprehensive single-cell multi-omics atlas of mouse embryonic lungs, integrating gene expression and chromatin accessibility profiles. Through systematic analysis, we identify 13 distinct cell types and map cis-regulatory elements, peak-to-gene linkages, and transcription factors underlying lung development. Leveraging this multi-modal dataset, we uncover lineage-determining transcription factors driving cell differentiation, including the Activated Protein-1 complex. We further delineate gene regulatory networks involving diverse transcription regulators, including CCCTC-binding factor (CTCF). Using the Ctcf conditional knockout mouse, coupled with histological and multi-omics analyses, we demonstrate that CTCF orchestrates lung progenitor maintenance and branching morphogenesis by modulating both gene expression and chromatin accessibility. Thus, our study provides a multi-omics resource and mechanistic insights for transcriptional regulation of lung morphogenesis.
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Single-nucleus multiomics reveals the gene regulatory networks underlying sex determination of murine primordial germ cells.
Accurate specification of female and male germ cells during embryonic development is critical for sexual reproduction. Primordial germ cells (PGCs) are the bipotential precursors of mature gametes that commit to an oogenic or spermatogenic fate in response to sex-determining cues from the fetal gonad. The critical processes required for PGCs to integrate and respond to signals from the somatic environment in gonads are not well understood. In this study, we developed the first single-nucleus multiomics map of chromatin accessibility and gene expression during murine PGC development in both XX and XY embryos. Profiling of cell-type-specific transcriptomes and regions of open chromatin from the same cell captured the molecular signatures and gene networks underlying PGC sex determination. Joint RNA and ATAC data for single PGCs resolved previously unreported PGC subpopulations and cataloged a multimodal reference atlas of differentiating PGC clusters. We discovered that regulatory element accessibility precedes gene expression during PGC development, suggesting that changes in chromatin accessibility may prime PGC lineage commitment prior to differentiation. Similarly, we found that sexual dimorphism in chromatin accessibility and gene expression increased temporally in PGCs. Combining single-nucleus sequencing data, we computationally mapped the cohort of transcription factors that regulate the expression of sexually dimorphic genes in PGCs. For example, the gene regulatory networks of XX PGCs are enriched for the transcription factors, TFAP2c, TCFL5, GATA2, MGA, NR6A1, TBX4, and ZFX. Sex-specific enrichment of the forkhead-box and POU6 families of transcription factors was also observed in XY PGCs. Finally, we determined the temporal expression patterns of WNT, BMP, and RA signaling during PGC sex determination, and our discovery analyses identified potentially new cell communication pathways between supporting cells and PGCs. Our results illustrate the diversity of factors involved in programming PGCs toward a sex-specific fate.
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Single-nucleus RNA sequencing reveals RUNX1 regulation of muscle hypertrophy through PI3K/AKT/mTOR pathway.
We used snRNA-seq to construct a high-resolution atlas of pectoral muscle development in broiler chickens from neonatal to adult stages. This analysis revealed pronounced molecular heterogeneity among satellite cells across developmental phases and uncovered a previously uncharacterized Runx1 + satellite cell subpopulation. By integrating pseudotime trajectory reconstruction, gene set enrichment analysis, dynamic expression profiling and loss-of-function assays, we established a critical regulatory role for RUNX1 in muscle hypertrophy. Mechanistically, RUNX1 promotes myotube hypertrophy by transcriptionally repressing Pik3r1, thereby reducing PI3K p85α levels, destabilizing PTEN, and activating the PI3K/AKT/mTOR signaling cascade, which enhances protein synthesis and drives myotube growth.
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Comprehensive SHAP Values and Single-Cell Sequencing Technology Reveal Key Cell Clusters in Bovine Skeletal Muscle.
The skeletal muscle of cattle is the main component of their muscular system, responsible for supporting and movement functions. However, there are still many unknown areas regarding the ranking of the importance of different types of cell populations within it. This study conducted in-depth research and made a series of significant findings. First, we trained 15 bovine skeletal muscle models and selected the best-performing model as the initial model. Based on the SHAP (Shapley Additive exPlanations) analysis of this initial model, we obtained the SHAP values of 476 important genes. Using the contributions of these 476 genes, we reconstructed a 476-gene SHAP value matrix, and relying solely on the interactions among these 476 genes, successfully mapped the single-cell atlas of bovine skeletal muscle. After retraining the model and further interpretation, we found that Myofiber cells are the most representative cell type in bovine skeletal muscle, followed by neutrophils. By determining the key genes of each cell type through SHAP values, we conducted analyses on the correlations among key genes and between cells for Myofiber cells, revealing the critical role these genes play in muscle growth and development. Further, by using protein language models, we performed cross-species comparisons between cattle and pigs, deepening our understanding of Myofiber cells as key cells in skeletal muscle, and exploring the common regulatory mechanisms of muscle development across species.
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Interferon-responsive neutrophils and macrophages extricate SARS-CoV-2 Omicron critical patients from the nasty fate of sepsis.
The SARS-CoV-2 Omicron variant is characterized by its high transmissibility, which has caused a worldwide epidemiological event. Yet, it turns ominous once the disease progression degenerates into severe pneumonia and sepsis, presenting a horrendous lethality. To elucidate the alveolar immune or inflammatory landscapes of Omicron critical-ill patients, we performed single-cell RNA-sequencing (scRNA-seq) of bronchoalveolar lavage fluid (BALF) from the patients with critical pneumonia caused by Omicron infection, and analyzed the correlation between the clinical severity scores and different immune cell subpopulations. In the BALF of Omicron critical patients, the alveolar violent myeloid inflammatory environment was determined. ISG15+ neutrophils and CXCL10+ macrophages, both expressed the interferon-stimulated genes (ISGs), were negatively correlated with clinical pulmonary infection score, while septic CST7+ neutrophils and inflammatory VCAN+ macrophages were positively correlated with sequential organ failure assessment. The percentages of ISG15+ neutrophils were associated with more protective alveolar epithelial cells, and may reshape CD4+ T cells to the exhaustive phenotype, thus preventing immune injuries. The CXCL10+ macrophages may promote plasmablast/plasma cell survival and activation as well as the production of specific antibodies. As compared to the previous BALF scRNA-seq data from SARS-CoV-2 wild-type/Alpha critical patients, the subsets of neutrophils and macrophages with pro-inflammatory and immunoregulatory features presented obvious distinctions, suggesting an immune disparity in Omicron variants. Overall, this study provides a BALF single-cell atlas of Omicron critical patients, and suggests that alveolar interferon-responsive neutrophils and macrophages may extricate SARS-CoV-2 Omicron critical patients from the nasty fate of sepsis.