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STAB: a spatio-temporal cell atlas of the human brain.
The human brain is the most complex organ consisting of billions of neuronal and non-neuronal cells that are organized into distinct anatomical and functional regions. Elucidating the cellular and transcriptome architecture underlying the brain is crucial for understanding brain functions and brain disorders. Thanks to the single-cell RNA sequencing technologies, it is becoming possible to dissect the cellular compositions of the brain. Although great effort has been made to explore the transcriptome architecture of the human brain, a comprehensive database with dynamic cellular compositions and molecular characteristics of the human brain during the lifespan is still not available. Here, we present STAB (a Spatio-Temporal cell Atlas of the human Brain), a database consists of single-cell transcriptomes across multiple brain regions and developmental periods. Right now, STAB contains single-cell gene expression profiling of 42 cell subtypes across 20 brain regions and 11 developmental periods. With STAB, the landscape of cell types and their regional heterogeneity and temporal dynamics across the human brain can be clearly seen, which can help to understand both the development of the normal human brain and the etiology of neuropsychiatric disorders. STAB is available at http://stab.comp-sysbio.org.
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Single-nucleus transcriptomic profiling reveals cell type-specific responses of the soybean root tip to aluminum stress.
Aluminum (Al) toxicity resulting from soil acidification poses a major constraint on crop productivity. Although the root apex serves as the primary site for Al perception and adaptive remodeling, cell type-resolved responses to prolonged Al exposure remain poorly characterized. Here, we employed single-nucleus RNA sequencing (snRNA-seq) to generate a cell type-resolved transcriptomic atlas of the soybean (Glycine max) root tip under Al stress. We profiled a total of 79,201 high-quality nuclei and identified nine major root cell types. Our results reveal that Al stress elicits shared transcriptional responses across cell types while reshaping root cell type composition. Notably, the proportion of nuclei increased in the epidermal cell layer (from 34.16% to 70.41%). In contrast, a significant reduction in nuclear number was detected within the cortical cells (from 40.70% to 8.53%). Interestingly, microscopic examination further indicated a pronounced expansion of regions exhibiting patterns inconsistent with the decrease in cortical nuclei. Cell type-specific analyses identified a total of 20,544 differentially expressed genes (DEGs) and showed that epidermal cells primarily responded to Al stress by activating transcriptional programs associated with transport, cell wall reinforcement, and defense, accompanied by enhanced fatty acid biosynthesis and cuticle-related pathways. In contrast, cortical cells exhibited repression of cell cycle-related transcriptional programs, consistent with their reduced cell abundance and indicating that limitations in cell division are closely associated with cortical cell loss. Furthermore, untargeted metabolomic profiling supported an important role of lipid metabolism in the response to Al stress. Collectively, our study reveals cell type-specific response patterns of the soybean root tip to long-term Al stress at single-nucleus resolution and provides new insights into the cellular mechanisms underlying aluminum tolerance in crop roots.
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Integrated multi-omic atlas reveals the hierarchy of spatiotemporal regulatory networks of mouse gastrulation.
Spatiotemporal coordination of cellular and molecular events is crucial for cell fate commitment during mouse gastrulation. However, the high-precision mechanisms governing the timing and spatial dynamics remain poorly understood. Here, we present a time-series single-cell multi-omic dataset of the gastrulating mouse embryos and construct a hierarchical gene regulatory landscape. Integrating this with real three-dimensional transcriptomic coordinate, we created ST-MAGIC and ST-MAGIC (+) atlas, dissecting the spatiotemporal logics of regulatory networks and signaling responsiveness underpinning the lineage commitment at gastrulation. Specifically, we delineated the multi-omic basis for left-right symmetry breaking events in the gastrula and also revealed the spatiotemporal molecular relay for axial mesendoderm lineage, where early and intermediate transcription factors first open the chromatin regions and setup the responsiveness to signaling, followed by terminal factors to consolidate the transcriptomic architecture. In summary, our study presents a spatiotemporal regulatory logic framework of mouse gastrulation for advancing our understanding of mammalian embryogenesis.
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Single-cell RNA sequencing reveals the induction of novel myeloid and myeloid-associated cell populations in visceral fat with long-term obesity.
Macrophages and other immune cells are important contributors to obesity-associated inflammation; however, the cellular identities of these specific populations remain unknown. In this study, we identified individual populations of myeloid cells found in mouse epididymal/visceral adipose tissue by single-cell RNA sequencing, immunofluorescence, and flow cytometry. Multiple canonical correlation analysis identified 11 unique myeloid and myeloid-associate cell populations. In obese mice, we detected an increased percentage of monocyte-derived pro-inflammatory cells expressing Cd9 and Trem2, as well as significantly decreased percentages of multiple cell populations, including tissue-resident cells expressing Lyve1, Mafb, and Mrc1. We have identified and validated a novel myeloid/macrophage population defined by Ly6a expression, exhibiting both myeloid and mesenchymal characteristics, which increased with obesity and showed high pro-fibrotic characteristics in vitro. Our mouse adipose tissue myeloid cell atlas provides an important resource to investigate obesity-associated inflammation and fibrosis.
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The local cellular response to Human Papillomavirus focuses on basal layer restoration as visualized in situ by specific cellular neighborhoods near infected cells.
BACKGROUND: Human papillomavirus type 16 (HPV16) is known to deregulate and cause hyperproliferation of the infected epithelium, but its full effect on the host's tissue has remained elusive as earlier comprehensive studies were restricted to in vitro models. AIM: The aim of the current study was to study HPV16-induced tissue changes in vulvar tissue in its full natural context by using single-cell spatial transcriptomics. METHODS: We applied spatial single-cell spatial transcriptomics to formalin-fixed paraffin-embedded healthy vulvar tissue (n=5) and HPV16+ high grade vulvar lesions (vHSIL, n=31). RESULTS: More than 415,000 individual cells were identified and annotated in situ, to create complete digital atlases of the healthy vulvar and HPV16+ vHSIL tissues for comparison. Two subpopulations of basal cells were identified, one of which lined the basal membrane of healthy tissue, the other is characterized by a transcriptomic signature like HPV16-infected keratinocytes and upregulated inflammatory genes and observed predominantly in vHSIL. Epithelial cells in the parabasal layers of vHSIL upregulated the expression of genes associated with inflammation and proliferation. Importantly, HPV16 profoundly remodeled stromal fibroblasts, endothelial, and immune cells, reorganizing them into distinct cellular neighborhoods of which three dominated vHSIL. A regenerative niche adjacent to the basal layer, a perilesional niche characterized by immune suppression, and a more distal niche enriched for adaptive immune activity. CONCLUSION: In conclusion, spatial analysis reveals that HPV16 infection orchestrates a coordinated tissue response, driving basal layer restoration while locally suppressing immune activation to prevent pathological damage.
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CD74+ macrophages are associated with favorable prognosis and immune contexture in hepatocellular carcinoma.
CD74 was initially thought to participate mainly in antigen presentation as an MHC class II chaperone. Recent studies have shown that CD74 plays an important role within the cell and throughout the immune system in a wide spectrum of neoplasms. However, the role of CD74 in hepatocellular carcinoma (HCC) remains elusive. In this study, HCC tissues from Zhongshan Hospital and data from The Cancer Genome Atlas (TCGA) were obtained and analyzed. Immunohistochemistry, flow cytometry, and single-cell RNA sequencing (scRNA-seq) were performed to detect the characteristics of CD74+ cells and explore their impact on the tumor microenvironment (TME) of HCC. Our data revealed that stromal CD74+ cell enrichment was associated with favorable prognosis in patients with HCC. CD74 was abundant in a large portion of HCC specimens and prominently distributed on stromal macrophages. scRNA-seq data also indicated that the pathways related to immune response were significantly upregulated in CD74+ macrophages. High infiltration of CD74+ macrophages was associated with increased infiltration of CD8+ cytotoxic T lymphocytes (CTLs) with enhanced effector functions in HCC. Besides, blocking CD74 weakened the antitumor activity and proliferation ability of CD8+ CTLs in HCC. Our findings highlight the critical role of CD74 in HCC. New drugs and antibodies targeting CD74 may be effective strategies for HCC therapy.
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The architecture of silk-secreting organs during the final larval stage of silkworms revealed by single-nucleus and spatial transcriptomics.
Natural silks are renewable proteins with impressive mechanical properties and biocompatibility that are useful in various fields. However, the cellular and spatial organization of silk-secreting organs remains unclear. Here, we combined single-nucleus and spatially resolved transcriptomics to systematically map the cellular and spatial composition of the silk glands (SGs) of mulberry silkworms late in larval development. This approach allowed us to profile SG cell types and cell state dynamics and identify regulatory networks and cell-cell communication related to efficient silk protein synthesis; key markers were validated via transgenic approaches. Notably, we demonstrated the indispensable role of the ecdysone receptor (ultraspiracle) in regulating endoreplication in SG cells. Our atlas presents the results of spatiotemporal analysis of silk-secreting organ architecture late in larval development; this atlas provides a valuable reference for elucidating the mechanism of efficient silk protein synthesis and developing sustainable products made from natural silk.
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Construction of a multi-tissue immune atlas for Chinese tongue sole (Cynoglossus semilaevis) reveals granulocyte functional adaptation and underlying regulatory mechanisms.
Innate immunity in teleost fish relies heavily on granulocytes for host defense. However, how these cells functionally adapt to distinct tissue microenvironments remains poorly understood. To address this, we constructed a multi-tissue immune atlas for Cynoglossus semilaevis by integrating single-cell RNA sequencing (scRNA-seq) data from blood, liver, spleen, and head kidney. We identified five transcriptionally distinct granulocyte subsets (Gr1-Gr5), each with divergent roles in inflammation, immunoregulation, and complement activity; moreover, these subsets exhibited tissue-specific distributions. Pseudotime analysis revealed a bifurcated developmental trajectory from a shared progenitor pool residing in the head kidney and spleen, characterized by the dynamic expression of the cxcr2/cxcr4 axis and branch-specific transcription factors. While sharing core metabolic pathways, granulocyte subsets displayed tissue-specific adaptations and an inferred communication strategy involving a conserved cd44b-mediated module. Our findings systematically characterize the patterns of granulocyte adaptation in a teleost model, providing insights into fish immunology and aquaculture disease control.
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Analysis of single-cell transcriptomes links enrichment of olfactory receptors with cancer cell differentiation status and prognosis.
Ectopically expressed olfactory receptors (ORs) have been linked with multiple clinically-relevant physiological processes. Previously used tissue-level expression estimation largely shadowed the potential role of ORs due to their overall low expression levels. Even after the introduction of the single-cell transcriptomics, a comprehensive delineation of expression dynamics of ORs in tumors remained unexplored. Our targeted investigation into single malignant cells revealed a complex landscape of combinatorial OR expression events. We observed differentiation-dependent decline in expressed OR counts per cell as well as their expression intensities in malignant cells. Further, we constructed expression signatures based on a large spectrum of ORs and tracked their enrichment in bulk expression profiles of tumor samples from The Cancer Genome Atlas (TCGA). TCGA tumor samples stratified based on OR-centric signatures exhibited divergent survival probabilities. In summary, our comprehensive analysis positions ORs at the cross-road of tumor cell differentiation status and cancer prognosis.
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Comprehensive Analysis of the Prognostic Value and Molecular Function of CRNDE in Glioma at Bulk and Single-Cell Levels.
Colorectal neoplasia differentially expressed (CRNDE) is an oncogenic long noncoding RNA (lncRNA) overexpressed in diverse malignancies. Here, we comprehensively analyze the prognostic value and molecular function of CRNDE in glioma. Bulk RNA-sequencing data from The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA), and single-cell RNA-sequencing data from the Tumor Immune Single-Cell Hub (TISCH) were analyzed. Kaplan-Meier survival analysis was applied to verify the prognostic value of CRNDE. Then, a nomogram based on multivariate Cox regression was established for individualized survival prediction. Subsequently, the expression characteristic and biological function of CRNDE were analyzed at the single-cell level. Lastly, the effects of CRNDE on the proliferation and invasion of glioma cell were explored in vitro. We discovered that CRNDE was a powerful marker for risk stratification of glioma patients. Regardless of the status of IDH and 1p/19q, CRNDE could effectively stratify patients' prognosis. The nomogram that incorporated the CRNDE expression was proved to be a reliable tool for survival prediction. In addition, epithelial-mesenchymal transition may be the most important biological process regulated by CRNDE, which was identified at both the bulk and single-cell levels. Moreover, CRNDE knockdown significantly inhibited the proliferation and invasion of glioma cell. Overall, CRNDE is a vital oncogene and may be a valuable supplement to improve the clinical stratification of glioma.