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Found: 4 938
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Single-nucleus cross-tissue molecular reference maps toward understanding disease gene function.
Understanding gene function and regulation in homeostasis and disease requires knowledge of the cellular and tissue contexts in which genes are expressed. Here, we applied four single-nucleus RNA sequencing methods to eight diverse, archived, frozen tissue types from 16 donors and 25 samples, generating a cross-tissue atlas of 209,126 nuclei profiles, which we integrated across tissues, donors, and laboratory methods with a conditional variational autoencoder. Using the resulting cross-tissue atlas, we highlight shared and tissue-specific features of tissue-resident cell populations; identify cell types that might contribute to neuromuscular, metabolic, and immune components of monogenic diseases and the biological processes involved in their pathology; and determine cell types and gene modules that might underlie disease mechanisms for complex traits analyzed by genome-wide association studies.
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Single-nucleus RNA sequencing reveals the effects of key regulators on human pancreatic adenocarcinoma and its tumor microenvironment.
BACKGROUND: The aggressive nature and poor prognosis of pancreatic ductal adenocarcinoma (PDAC) are closely linked to its complex tumor microenvironment (TME). However, a detailed mapping of the TME's cellular landscape and its interactions with cancer cells at single-cell resolution is still lacking, limiting our understanding of the disease. This study aims to utilize single-nucleus RNA sequencing technology to construct a panoramic single-cell transcriptomic map of the PDAC TME. Furthermore, the expression characteristics of the key differential genes REG1A and REG1B in the early progression of PDAC and the regulation of the tumor microenvironment are validated through clinical samples. METHODS: To dissect the complex TME of PDAC, we employed single-nucleus RNA sequencing. By performing an integrated analysis of freshly collected and publicly available human PDAC samples, we identified a critical regulatory network involving REG1 and other key factors that modulate tumor progression and metastasis. Our data further delineated the interplay among heterogeneous cancer cell states and distinct populations of cancer-associated fibroblasts and macrophages. RESULTS: Tumor regions showed enrichment of acinar cells and depletion of fibroblasts and endothelial cells, reflecting epithelial and stromal remodeling. Ductal and acinar cells exhibited strong transcriptional reprogramming, with upregulation of REG1A, REG1B and SEMA3C. The expression levels of REG1A and REG1B were quantified by real time quantitative polymerase chain reaction (RT-qPCR) in 48 paired PDAC tissue samples. The results indicated significant overexpression of both genes in tumor tissues. Compared with peritumoral tissues, REG1A and REG1B showed significant upregulation in early-stage (stage I) tumors, but not in advanced stages (stage III/IV), suggesting their potential role in promoting early PDAC tumorigenesis. Furthermore, elevated expression of these genes was confirmed to be significantly associated with unfavorable prognosis in patients. CONCLUSIONS: Our work constructs a detailed single-cell transcriptomic atlas of the PDAC microenvironment. It implicates REG1A and REG1B as promising candidates for both early diagnostic biomarkers and novel therapeutic intervention points.
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A cell and transcriptome atlas of human arterial vasculature.
Contiguous arterial segments show different propensities for different vascular pathologies, yet mechanisms explaining these fundamental differences remain unknown. We sought to build a transcriptomic, cellular, and spatial atlas of human arterial cells across multiple different arterial segments to understand these underlying differences. Analysis of multiple isogenic arterial segments from healthy donors reveals a significant stereotyped pattern of cell type-specific segmental heterogeneity in healthy arteries. Combining single cell analysis with spatial transcriptomic data reveals cellular heterogeneity not captured by commonly used cell-type marker genes. Determinants of arterial transcriptomic identities are predominantly encoded in fibroblasts and smooth muscle cells (SMC), and their differentially expressed genes are particularly enriched for different vascular disease-associated genetic risk- loci and risk-genes. Adventitial fibroblast-specific heterogeneity in gene expression coincides with a disproportionally large number of vascular disease genetic signals, suggesting a previously unrecognized role for this cell type in disease risk. Adult arterial cells from different segments cluster not by anatomical proximity, but by embryonic origin. Global regulon analysis of disease related segment-specific gene expression program in fibroblast and SMC enriches for binding sites of transcription factors that are developmental master regulators whose expression persists into adulthood, suggesting an important functional role of the same developmental master regulators in adult gene expression and disease. Lastly, non-coding transcriptomes across arterial cells contain extensive variation in lncRNAs expressed in cell type- and segment-specific patterns, rivaling heterogeneity in protein coding transcriptomes. Differentially expressed LncRNA demonstrate enrichment for non-coding genetic signals for vascular diseases, suggesting a potential global role of segmental specific LncRNAs in regulating inherited human vascular disease risk.
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A Single-Cell Transcriptomic Atlas of Human Skin Aging.
Skin undergoes constant self-renewal, and its functional decline is a visible consequence of aging. Understanding human skin aging requires in-depth knowledge of the molecular and functional properties of various skin cell types. We performed single-cell RNA sequencing of human eyelid skin from healthy individuals across different ages and identified eleven canonical cell types, as well as six subpopulations of basal cells. Further analysis revealed progressive accumulation of photoaging-related changes and increased chronic inflammation with age. Transcriptional factors involved in the developmental process underwent early-onset decline during aging. Furthermore, inhibition of key transcription factors HES1 in fibroblasts and KLF6 in keratinocytes not only compromised cell proliferation, but also increased inflammation and cellular senescence during aging. Lastly, we found that genetic activation of HES1 or pharmacological treatment with quercetin alleviated cellular senescence of dermal fibroblasts. These findings provide a single-cell molecular framework of human skin aging, providing a rich resource for developing therapeutic strategies against aging-related skin disorders.
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Transcriptomic and metabolic profiling reveals the effects of long-term microwave exposure on testicular tissue.
The effect of electromagnetic exposure on health is becoming increasingly important as it affects many aspects of human life and health. However, the effects in environmental electromagnetic fields on the male reproductive system were still controversial, and the impacts of long-term microwave exposure on testicular tissue remain poorly defined. This study exposed rats to 30 mW/cm2 of microwave radiation (2.856 GHz) for six weeks and revealed that long-term microwave exposure damaged the testis structures, sperm motility, and morphology, affected hormone levels, energy metabolism, and induced oxidative stress. Assays for bulk RNA, metabonomics, single-cell RNA, and transposase-accessible chromatin with high-throughput sequencing were performed to analyze the transcriptional and metabolic atlas of testicular damage after microwave radiation. Differentially expressed genes were enriched in oxidative stress and energy metabolism pathways. Furthermore, ten subgroups were identified with scRNA-seq, including five developmental phases of germ cells, and radiation-associated changes in cell composition, especially stuck in round spermatids, were observed. Radiation significantly upregulated the expression of Atp6v1e2 in round spermatids and enriched the expression of many transcription factors by disturbing the accessibility profile of chromatin. This study provides effective insights into the long-term impacts of microwave radiation on male reproduction.
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The single-cell immune landscape of HIV-associated aggressive B-cell lymphoma.
BACKGROUND: Human immunodeficiency virus (HIV)-associated lymphomas (HAL), mainly aggressive B-cell lymphomas, pose a significant challenge in cancer research due to their multifaceted pathogenesis and aggressive clinical course. Despite the clinical importance, the genomic and immune characteristics of these lymphomas remain poorly elucidated. METHODS: We employed single-cell RNA sequencing (scRNA-seq) on lymph node samples from aggressive B-cell lymphomas, mainly including 6 cases of diffuse large B-cell lymphoma (DLBCL) and 5 cases of Burkitt lymphoma (BL) from people living with HIV (PLWH), along with 3 DLBCL cases from individuals without HIV for comparison. RESULTS: Malignant B cells in HAL consistently exhibited high proliferative and oxidative phosphorylation (OXPHOS)-type metabolic signatures. Moreover, these cells demonstrated loss expression of major histocompatibility complex class I (MHC-I), strategically reducing tumor immunogenicity. HAL harbors special populations of naive and atypical memory B cells that exhibited high metabolic and immune-activated transcriptional profiles. Additionally, HAL exhibited senescence-like dysfunction in T cells, characterized by the reductions in regulatory activity of Treg and cytotoxic activity of CD8+ T cells, as well as decreases expression of IL7R genes and increases expression of FOS and FOSB genes. Our immunofluorescence results showed that the cytotoxic CD8+ T cells in HAL may have a dysfunction of lytic granule polarization. Furthermore, macrophages from HAL exhibited stronger immunosuppressive transcriptional characteristics, and a robust immunosuppressive SPP1-CD44 interaction was predicted between C1QA+ macrophages and T cells. CONCLUSIONS: Our findings clearly indicate that HAL differs significantly from non-HAL, ranging from malignant B cells to the immune microenvironment. This study provides a comprehensive single-cell atlas of HIV-associated aggressive B-cell lymphomas, offering new insights into aggressiveness and immune evasion observed in HAL.
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Dynamic atlas of immune cells reveals multiple functional features of macrophages associated with progression of pulmonary fibrosis.
Idiopathic pulmonary fibrosis (IPF) is a chronic interstitial lung disease with a high mortality rate and unclarified aetiology. Immune response is elaborately regulated during the progression of IPF, but immune cells subsets are complicated which has not been detailed described during IPF progression. Therefore, in the current study, we sought to investigate the role of immune regulation by elaborately characterize the heterogeneous of immune cells during the progression of IPF. To this end, we performed single-cell profiling of lung immune cells isolated from four stages of bleomycin-induced pulmonary fibrosis-a classical mouse model that mimics human IPF. The results revealed distinct components of immune cells in different phases of pulmonary fibrosis and close communication between macrophages and other immune cells along with pulmonary fibrosis progression. Enriched signals of SPP1, CCL5 and CXCL2 were found between macrophages and other immune cells. The more detailed definition of the subpopulations of macrophages defined alveolar macrophages (AMs) and monocyte-derived macrophages (mo-Macs)-the two major types of primary lung macrophages-exhibited the highest heterogeneity and dynamic changes in expression of profibrotic genes during disease progression. Our analysis suggested that Gpnmb and Trem2 were both upregulated in macrophages and may play important roles in pulmonary fibrosis progression. Additionally, the metabolic status of AMs and mo-Macs varied with disease progression. In line with the published data on human IPF, macrophages in the mouse model shared some features regarding gene expression and metabolic status with that of macrophages in IPF patients. Our study provides new insights into the pathological features of profibrotic macrophages in the lung that will facilitate the identification of new targets for disease intervention and treatment of IPF.
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Evaluating the potential causal relationship between carnitine-related metabolites and breast cancer: a Mendelian randomization and transcriptomic analysis.
INTRODUCTION: Breast cancer (BC) is the most common malignancy among women worldwide. Although observational studies have linked carnitine-related metabolites (CRMs) to BC, causal inference has been limited by confounding and reverse causality. This study used Mendelian randomization (MR) analysis to investigate the potential causal link between CRMs and BC. MATERIAL AND METHODS: MR analysis was conducted using the Cancer Genome Atlas-BC and CRM-related datasets to explore the potential causal relationship between CRMs and BC. Variants were screened based on criteria encompassing genome-wide significance (p < 5×10-8), independence (r 2 < 0.001, kb=10000), and sufficient strength (F-statistic > 10). Various MR techniques, including inverse-variance weighted, MR-Egger, simple mode, weighted mode, and weighted median approaches, were applied to assess these potential causal associations. Single-cell RNA sequencing (scRNA-seq) was employed to investigate the expression and biological functions of biomarkers linked to metabolites. RESULTS: The MR analysis suggested that genetically predicted elevated levels of octanoylcarnitine and decanoylcarnitine were associated with increased risk of BC. Functional enrichment analysis identified 12 candidate genes associated with these metabolites, which are involved in fatty acid β-oxidation (FAO) pathways. ScRNA-seq analysis revealed eight distinct cell subpopulations, with macrophages exhibiting the highest intercellular communication. Six biomarkers were identified as potential contributors to BC development: ACADM, FNIP2, RAPGEF2, RABGGTB, PPID, and ST6GALNAC3. CONCLUSIONS: This study provides evidence supporting potential causal associations between octanoylcarnitine and decanoylcarnitine and BC risk. Integrative single-cell transcriptomics revealed six CRM-associated biomarkers and their dynamic expression within tumor microenvironments. Additional experimental and clinical studies are needed to validate these observations and clarify their biological and translational relevance.
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Characterizing hypoxia-orchestrated post-stroke changes in oligodendrocyte precursor cells for optimized cell therapy.
Oligodendrocyte precursor cells (OPCs) are highly adaptable, engaging in diverse functions beyond myelination. However, how OPCs adjust their roles after ischemic stroke and contribute to recovery remains largely unknown. To address this gap, we constructed a "transient middle cerebral artery occlusion (tMCAO) atlas" by integrating mouse single-cell RNA sequencing (scRNA-seq) datasets and combined it with ex vivo OPC cultures and in vivo cell transplantation experiments. This approach revealed the emergence of "angiogenic" OPCs in the subacute phase and "oligogenic" OPCs in the chronic phase, driven by distinct levels of hypoxia-severe hypoxia inducing angiogenic OPCs and mild hypoxia promoting oligogenic OPCs. Ex vivo, severe hypoxic preconditioning faithfully induced angiogenic OPCs, and their intravenous transplantation enhanced angiogenesis and improved recovery in tMCAO mice. These findings highlight "oxygen tone" as a key regulator of OPC dynamic adaptation after ischemic stroke, offering a promising strategy to harness OPCs for stroke cell therapy.
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RNA Sequencing and Spatial Transcriptomics in Traumatic Spinal Cord Injury (Review).
In order to understand the fundamental mechanisms of the spinal cord functioning, it is necessary to reveal a complete set of cell types and their populations, which can be identified by the unique combination of their features. The technologies of single-cell and single-nucleus RNA sequencing serve as effective tools for determining the role of various types of cells in normal and pathological reactions in the spinal cord. Spatial transcriptomics combines these technologies with the methods of obtaining and saving spatial information about cells in the tissue, which allows one to localize more precisely the injured area, characterize in detail the tissue compartments in the specific anatomical region, and analyze the pathological picture at the cellular and molecular level. Atlases of development of RNA-sequencing technologies and spatial transcriptomics created on the basis of the data from single-cell and single-nucleus RNA sequencing open great opportunities for new perspective concepts concerning the mechanisms of rearranging neural connections and restoration of sensorimotor functions in traumatic spine injury. The transcriptomes obtained were a powerful resource for detecting new functions of the nervous tissue cells. To establish therapeutic targets, the detected molecular diversity in neurons of various types enables tracing and comparing their susceptibility and regenerative potential. Determination of causes of selective cell susceptibility in spinal cord injury needs comprehensive information on the specificity of human cell populations in comparison with the known data obtained on the experimental models. In the present review, we have summarized advances in identification and study of cell characteristics in a traumatized spinal cord based on transcription profiling at a single-cell or single-nucleus level.