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Found: 4 934
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Exploring Cellular Heterogeneity: Single-Cell and Spatial Transcriptomics of Alzheimer Disease Brains and iPSC-Derived Microglia.
BACKGROUND: Substantial evidence has established the critical role of microglia, the brain's resident immune cells, in the pathogenesis of Alzheimer's disease (AD). Microglia exhibit diverse transcriptional states in response to neuroinflammatory stimuli, and understanding these states is crucial for elucidating the underlying mechanisms of AD. METHODS: In this work, we integrated single-cell and spatially resolved transcriptomics data from multiple cohorts and brain regions, including microglia from experimental and human brains. RESULTS: This comprehensive atlas revealed a great heterogeneity of microglial states, with a significant enrichment of specific states, including activated microglia, in AD brains compared to controls. Further integration of spatial transcriptomics and immunohistochemistry showed that activated microglia are predominantly located in the external cortical layers near amyloid plaques, while homeostatic microglia are more prevalent in the internal cortical layers and further away from the plaques. These spatial patterns were further validated using P2RY12 immunostaining, which confirmed the reliability of the transcriptomic data. CONCLUSION: By integrating single-cell and spatial transcriptomics, we have provided a detailed atlas of microglial diversity, revealing the regional and pathological specificity of microglial states.
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L2,1-Extreme Learning Machine: An Efficient Robust Classifier for Tumor Classification.
With the development of cancer research, various gene expression datasets containing cancer information show an explosive growth trend. In addition, due to the continuous maturity of single-cell RNA sequencing (scRNA-seq) technology, the protein information and pedigree information of a single cell are also continuously mined. It is a technical problem of how to classify these high-dimensional data correctly. In recent years, Extreme Learning Machine (ELM) has been widely used in the field of supervised learning and unsupervised learning. However, the traditional ELM does not consider the robustness of the method. To improve the robustness of ELM, in this paper, a novel ELM method based on L2,1-norm named L2,1-Extreme Learning Machine (L2,1 -ELM) has been proposed. The method introduces L2,1-norm on loss function to improve the robustness, and minimizes the influence of noise and outliers. Firstly, we evaluate the new method on five UCI datasets. The experiment results prove that our method can achieve competitive results. Next, the novel method is applied to the problem of classification of cancer samples and single-cell RNA sequencing datasets. The experimental results on The Cancer Genome Atlas (TCGA) datasets and scRNA-seq datasets prove that ELM and its variants has great potential in the classification of cancer samples.
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Single-cell and spatial transcriptomics reveal a potential role of ATF3 in brain metastasis of lung adenocarcinoma.
BACKGROUND: Brain metastasis (BrM) has been a challenge for lung cancer treatment, but the mechanisms underlying lung cancer BrM remain elusive. This study aims to dissect cellular components and their spatial distribution in human BrM tumors of lung adenocarcinoma (LUAD) and identify potential therapeutic targets. METHODS: We performed single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics (ST) on three LUAD BrMs, and validated our findings using public scRNA-seq data of 10 LUAD BrMs. Western blotting, quantitative real-time polymerase chain reaction (qRT-PCR) and functional experiments were employed for experimental studies. RESULTS: By combining scRNA-seq and ST, our analysis revealed the inter- and intra-tumoral heterogeneity of cellular components and their spatial localization within LUAD BrMs. Through RNA velocity and transcription factor (TF) regulatory activity analyses, we identified ATF3 as a potential regulator of the mesenchymal-epithelial transition (MET) program, which plays crucial roles in the colonization of tumor cells at metastatic sites. Furthermore, we demonstrated that knockdown of ATF3 significantly inhibited cancer cell proliferation while promoting cancer cell migration. Mechanistically, ATF3 knockdown could reverse the MET program. Additionally, we revealed that LGALS3/ANXA2-mediated cell-cell interaction between macrophage and tumor cells may also promote the MET program. CONCLUSIONS: Our study provides a single-cell atlas of the cellular composition in BrM of LUAD and identifies ATF3 as a potential therapeutic target for BrM treatment.
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PYCR1 promotes glutamine metabolism and the progression of lung adenocarcinoma by regulating the expression of OPLAH.
Lung adenocarcinoma (LUAD) is the most common subtype of lung cancer. Glutamine plays a critical role in the progression of LUAD. However, the function of pyrroline-5-carboxylate reductase 1 (PYCR1) and its regulatory role in glutamine metabolism remain unclear. Transcriptomic and clinical data for LUAD were obtained from The Cancer Genome Atlas (TCGA) and validated using Gene Expression Omnibus (GEO) datasets (GSE19188, GSE13213). Glutamine metabolism-related genes were analyzed for differential expression and prognostic significance. Functional enrichment was performed via gene ontology (GO) and kyoto encyclopedia of genes and genomes (KEGG) analyses. Single-cell RNA-seq data (GSE117570) were processed using Seurat, and cell-cell communication was inferred with CellChat. In vitro, lentiviral overexpression, Western blotting, EdU, CCK-8, and glutamine uptake assays were conducted. An orthotopic xenograft model was established in nude mice to assess tumor growth in vivo. Six glutamine-metabolism-related genes were found significantly overexpressed in LUAD tissues and associated with poor overall survival. Single-cell sequencing revealed predominant PYCR1 expression in malignant cells. Functional assays demonstrated that PYCR1 overexpression enhanced glutamine uptake, proliferation, and inhibited apoptosis in LUAD cells, effects mediated via suppression of the P53 pathway. PYCR1 promoted tumor growth in a xenograft model and was found to transcriptionally upregulate 5-oxoprolinase (OPLAH), which augmented its oncogenic effects. Our findings identify the PYCR1/OPLAH axis as a key driver of LUAD progression via p53 signaling, revealing a promising therapeutic target.
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Cochlear Cell Atlas of Two Laryngeal Echolocating Bats-New Evidence for the Adaptive Nervous Physiology in Constant Frequency Bat.
Bats have evolved highly adapted auditory mechanisms associated with ecological specialisation. However, there is scattered knowledge about the neurophysiological and cellular basis underlying high-frequency hearing in echolocating bats. Herein, the total cochlear cell atlas of Rhinolophus ferrumequinum (constant frequency (CF) bat) and Myotis pilosus (frequency modulated (FM) bat) was conducted using the 10x Genomics single-nucleus RNA sequencing method. Differences in the proportion of cochlear cell types, especially for the neural cells, were detected between these two bat species. Previously, genes upregulated in the cochlea of CF compared with FM bats, were found to be mostly related to nervous activities. After mapping to the cochlear cell atlas, we found that the upregulated genes were from neural cells, lateral wall cells and neurosensory epithelium cells. A class of specific neurons and associated functions was detected in the cochlea of R. ferrumequinum, revealed by cross-species single-cell transcriptomic analyses. Furthermore, molecular evidence for the differentiation from glial cells to neuronal cells was also uncovered in the cochlea of R. ferrumequinum. Overall, this study identified specific cellular molecular properties that constitute the neuroanatomical evolutionary dynamics underlying distinct echolocating types of bats and provided new molecular evidence for high-frequency hearing of echolocating bats, promoting related studies about ecological adaptation and evolution.
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Decoding epithelial-T cell interactions in colorectal cancer through single-cell and spatial transcriptomics.
BACKGROUND: Colorectal cancer (CRC) is a heterogeneous malignancy shaped by genetic alterations and immune microenvironmental interactions. While single-cell RNA sequencing (scRNA-seq) has uncovered diverse epithelial and T cell subsets, the spatial architecture of their crosstalk remains poorly understood. METHODS: We integrated scRNA-seq and spatial transcriptomics data from 36 CRC patients to comprehensively characterize epithelial and T cell heterogeneity, differentiation dynamics, and intercellular communication networks. Data preprocessing and integration were conducted using Seurat and Harmony. Cell trajectory inference was performed via CytoTRACE and Slingshot. Ligand-receptor signaling was assessed using CellChat, while spatial mapping was achieved using CellTrek. RESULTS: Nine epithelial and eight T cell subpopulations were identified, each exhibiting distinct transcriptional states, CNV burdens, and pseudotime trajectories. CD8⁺ T_GZMK cells displayed tumor-specific activation signatures and engaged in enriched communication with epithelial subsets through CEACAM, APP, and MIF signaling pathways. Spatial transcriptomics confirmed the in situ colocalization of CD8⁺ T_GZMK cells with PTP4A3⁺ epithelial cells in tumor regions, revealing spatially organized epithelial-immune niches. These interactions suggest potential mechanisms of immune modulation and tumor progression. CONCLUSION: This study provides an integrative single-cell and spatial atlas of CRC, revealing structured epithelial-T cell communication and spatial architecture within the tumor microenvironment. Our findings offer novel insights into immune-epithelial crosstalk and identify signaling pathways that may serve as therapeutic targets or biomarkers for CRC precision treatment.
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A chromosome-scale epigenetic map of the Hydra genome reveals conserved regulators of cell state.
The epithelial and interstitial stem cells of the freshwater polyp Hydra are the best-characterized stem cell systems in any cnidarian, providing valuable insight into cell type evolution and the origin of stemness in animals. However, little is known about the transcriptional regulatory mechanisms that determine how these stem cells are maintained and how they give rise to their diverse differentiated progeny. To address such questions, a thorough understanding of transcriptional regulation in Hydra is needed. To this end, we generated extensive new resources for characterizing transcriptional regulation in Hydra, including new genome assemblies for Hydra oligactis and the AEP strain of Hydra vulgaris, an updated whole-animal single-cell RNA-seq atlas, and genome-wide maps of chromatin interactions, chromatin accessibility, sequence conservation, and histone modifications. These data revealed the existence of large kilobase-scale chromatin interaction domains in the Hydra genome that contain transcriptionally coregulated genes. We also uncovered the transcriptomic profiles of two previously molecularly uncharacterized cell types: isorhiza-type nematocytes and somatic gonad ectoderm. Finally, we identified novel candidate regulators of cell type-specific transcription, several of which have likely been conserved at least since the divergence of Hydra and the jellyfish Clytia hemisphaerica more than 400 million years ago.
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Single-cell transcriptomics of the Drosophila wing disc reveals instructive epithelium-to-myoblast interactions.
In both vertebrates and invertebrates, generating a functional appendage requires interactions between ectoderm-derived epithelia and mesoderm-derived cells. To investigate such interactions, we used single-cell transcriptomics to generate a temporal cell atlas of the Drosophila wing disc from two developmental time points. Using these data, we visualized gene expression using a multilayered model of the wing disc and cataloged ligand-receptor pairs that could mediate signaling between epithelial cells and adult muscle precursors (AMPs). We found that localized expression of the fibroblast growth factor ligands, Thisbe and Pyramus, in the disc epithelium regulates the number and location of the AMPs. In addition, Hedgehog ligand from the epithelium activates a specific transcriptional program within adjacent AMP cells, defined by AMP-specific targets Neurotactin and midline, that is critical for proper formation of direct flight muscles. More generally, our annotated temporal cell atlas provides an organ-wide view of potential cell-cell interactions between epithelial and myogenic cells.
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Prediction of cell position using single-cell transcriptomic data: an iterative procedure.
Single-cell sequencing reveals cellular heterogeneity but not cell localization. However, by combining single-cell transcriptomic data with a reference atlas of a small set of genes, it would be possible to predict the position of individual cells and reconstruct the spatial expression profile of thousands of genes reported in the single-cell study. With the purpose of developing new algorithms, the Dialogue for Reverse Engineering Assessments and Methods (DREAM) consortium organized a crowd-sourced competition known as DREAM Single Cell Transcriptomics Challenge (SCTC). Within this context, we describe here our proposed procedures for adequate reference genes selection, and an iterative procedure to predict spatial expression profile of other genes.
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Single-cell RNA sequencing reveals Shen-Bai-Jie-Du decoction retards colorectal tumorigenesis by regulating the TMEM131-TNF signaling pathway-mediated differentiation of immunosuppressive dendritic cells.
Colorectal tumorigenesis generally progresses from adenoma to adenocarcinoma, accompanied by dynamic changes in the tumor microenvironment (TME). A randomized controlled trial has confirmed the efficacy and safety of Shen-Bai-Jie-Du decoction (SBJDD) in preventing colorectal tumorigenesis. However, the mechanism remains unclear. In this study, we employed single-cell RNA sequencing (scRNA-seq) to investigate the dynamic evolution of the TME and validated cell infiltration with multiplex immunohistochemistry and flow cytometry. Bulk RNA sequencing was utilized to assess the underlying mechanisms. Our results constructed the mutually verifiable single-cell transcriptomic atlases in Apc Min/+ mice and clinical patients. There was a marked accumulation of CCL22+ dendritic cells (DCs) and an enhanced immunosuppressive action, which SBJDD and berberine reversed. Combined treatment with cholesterol and lipopolysaccharide induced characteristic gene expression of CCL22+ DCs, which may represent "exhausted DCs". Intraperitoneal injection of these DCs after SBJDD treatment eliminated its therapeutic effects. TMEM131 derived CCL22+ DCs generation by TNF signaling pathway and may be a potential target of berberine in retarding colorectal tumorigenesis. These findings emphasize the role of exhausted DCs and the regulatory mechanisms of SBJDD and berberine in colorectal cancer (CRC), suggesting that the multi-component properties of SBJDD may help restore TME homeostasis and offer novel cancer therapy.