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Found: 4 935
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Spatial transcriptomics map of the embryonic mouse brain - a tool to explore neurogenesis.
The developing brain has a well-organized anatomical structure comprising different types of neural and non-neural cells. Stem cells, progenitors and newborn neurons tightly interact with their neighbouring cells and tissue microenvironment, and this intricate interplay ultimately shapes the output of neurogenesis. Given the relevance of spatial cues during brain development, we acknowledge the necessity for a spatial transcriptomics map accessible to the neurodevelopmental community. To fulfil this need, we generated spatially resolved RNA sequencing (RNAseq) data from embryonic day 13.5 mouse brain sections immunostained for mitotic active neural and vascular cells. Unsupervised clustering defined specific cell type populations of diverse lineages and differentiation states. Differential expression analysis revealed unique transcriptional signatures across specific brain areas, uncovering novel features inherent to particular anatomical domains. Finally, we integrated existing single-cell RNAseq datasets into our spatial transcriptomics map, adding tissue context to single-cell RNAseq data. In summary, we provide a valuable tool that enables the exploration and discovery of unforeseen molecular players involved in neurogenesis, particularly in the crosstalk between different cell types.
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A single cell atlas of circulating immune cells involved in diabetic retinopathy.
This study focused on examining the exact role of circulating immune cells in the development of diabetic retinopathy (DR). In vitro co-culture experiments showed that peripheral blood mononuclear cells (PBMCs) from patients with type 1 DR crucially modulated the biological functions of human retinal microvascular endothelial cells (HRMECs), consequently disrupting their normal functionality. Single-cell RNA sequencing (scRNA-seq) study revealed unique differentially expressed genes and pathways in circulating immune cells among healthy controls, non-diabetic retinopathy (NDR) patients, and DR patients. Of significance was the observed upregulation of JUND in each subset of PBMCs in patients with type 1 DR. Further studies showed that downregulating JUND in DR patient-derived PBMCs led to the amelioration of HRMEC dysfunction. These findings highlighted the notable alterations in the transcriptomic patterns of circulating immune cells in type 1 DR patients and underscored the significance of JUND as a key factor for PBMCs in participating in the pathogenesis of DR.
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Single-nucleus transcriptome atlas of Brassica developing seeds provides cellular and molecular insights into embryo abortion in interspecific hybrids.
Embryo rescue has been used to recover abortive seeds in distant hybridization; however, its efficiency remains low and rescue frequently fails because the genetic basis of embryo abortion is poorly understood. To address this, time-series single-nucleus RNA sequencing (snRNA-seq) was performed on developing seeds from interspecific crosses between Brassica campestris (syn. Brassica rapa) ssp. chinensis and Brassica oleracea, and compared them to seeds from B. campestris intraspecific crosses. Our analysis of single-nucleus transcriptomic profiles revealed that during normal seed development, embryo and endosperm cells undergo robust proliferation, whereas in interspecific hybrids, both cell types are drastically reduced, suggesting an early and ongoing developmental failure. We identified a previously uncharacterized cell type designated seed coat and suspensor (SC-SUS), characterized by the unique expression of CYP78A6, a cytochrome P450 family gene. Notably, CYP78A6 is deactivated after the globular stage in normal seeds but remains active in hybrid seeds. Analysis of hormone regulatory genes revealed substantial disruption of hormonal balance in hybrids. Additionally, mapping of global cell-cell communication networks mediated by ligand-receptor pairs, revealed extensive dysregulation in interspecific seeds. Cross-species validation in Arabidopsis demonstrated that both maternal CYP78A6 mutation and exogenous hormone application restored hybrid seed viability, with the mutation exhibiting a stronger effect, and their combination provided a modest additional advantage. This study establishes a high-resolution cellular and genetic framework for understanding interspecific embryo abortion, reveals that reproductive isolation can be explained by genetically programmed cell-type-specific programs, and identifies potential genetic targets for improving embryo rescue in crop breeding.
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Polo like kinase 1 expression in cervical cancer tissues generated from multiple detection methods.
BACKGROUND: Existing studies of PLK1 in cervical cancer had several flaws. The methods adopted by those studies of detecting PLK1 expression in cervical cancer were single and there lacks comprehensive evaluation of the clinico-pathological significance of PLK1 in cervical cancer. METHODS: A total of 303 cervical tissue samples were collected for in-house tissue microarrays. Immunohistochemistry was performed for evaluating PLK1 expression between cervical cancer (including cervical squamous cell carcinoma (CESC) and cervical adenocarcinoma) and non-cancer samples. The Expression Atlas database was searched for querying PLK1 expression in different cervical cancer cell lines and different tissues in the context of pan-cancer. Standard mean difference (SMD) was calculated and the summarized receiver's operating characteristics (SROC) curves were plotted for integrated tissue microarrays, exterior high-throughput microarrays and RNA sequencing data as further verification. The effect of PLK1 expression on the overall survival, disease-free survival and event-free survival of cervical cancer patients was analyzed through Kaplan Meier survival curves for cervical cancer patients from RNA-seq and GSE44001 datasets. The gene mutation and alteration status of PLK1 in cervical cancer was inspected in COSMIC and cBioPortal databases. Functional enrichment analysis was performed for genes correlated with PLK1 from aggregated RNA-seq and microarrays. RESULTS: A total of 963 cervical cancer samples and 178 non-cancer samples were collected from in-house tissue microarrays and exterior microarrays and RNA-seq datasets. The combined expression analysis supported overexpression of PLK1 in CESC, cervical adenocarcinoma and all types of cervical cancer (SMD = 1.59, 95%CI [0.56-2.63]; SMD = 2.99, 95%CI [0.75-5.24]; SMD = 1.57, 95% CI [0.85-2.29]) and the significant power of PLK1 expression in distinguishing CESC or all types of cervical cancer samples from non-cancer samples (AUC = 0.94, AUC = 0.92). Kaplan-Meier survival curves showed that the event-free survival rate of cervical cancer patients with higher expression of PLK1 was shorter than that of patients with lower PLK1 (HR = 2.020, P = 0.0197). Genetic alteration of PLK1 including missense mutation and mRNA low occurred in 6% of cervical cancer samples profiled in mRNA expression. Genes positively or negatively correlated with PLK1 were mainly assembled in pathways such as DNA replication, cell cycle, mismatch repair, Ras signaling pathway, melanoma, EGFR tyrosine kinase inhibitor resistance and homologous recombination (P < 0.05). CONCLUSIONS: Here, we provided sufficient evidence of PLK1 overexpression in cervical cancer. The overexpression of PLK1 in cervical cancer and the contributory effect of it on clinical progression indicated the hopeful prospect of PLK1 as a biomarker for cervical cancer.
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Cell type-specific gene regulatory atlas prioritizes drug targets and repurposable medicines in Alzheimer's disease.
Alzheimer's disease (AD) is a complex and poorly understood neurodegenerative disorder that lacks sufficiently effective treatments. Computational and integrative analyses that leverage multiomic data provide a promising strategy to uncover disease mechanisms and identify therapeutic opportunities. Here, we develop a cell type-specific regulatory atlas of the human middle temporal gyrus via leveraging single-nucleus RNA-seq (1,197,032 nuclei) and ATAC-seq (740,875 nuclei) data sets from 84 donors across four stages of AD neuropathological change (ADNC). We observe differential gene expression for six major cell types intensified at severe ADNC. Integrating peak-to-gene linkages and motif enrichment analyses, we reconstruct transcription factor (TF)-target gene networks across six major brain cell types. By integrating genome-wide association study (GWAS) loci with cell type-specific cis-regulatory DNA elements (CREs), we pinpoint 141 ADNC-associated genes. Using gene set enrichment analysis (GSEA) and network proximity analysis, we further identify nine candidate repurposable drugs that were associated with these ADNC-related genes. In summary, this cell type-specific multiomic atlas provides a comprehensive resource for mechanistic understanding, target prioritization, and therapeutic hypothesis generation in AD and AD-related dementia if broadly applied.
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Single-cell transcriptome sequencing atlas of cassava tuberous root.
INTRODUCTION: Single-cell transcriptome sequencing (ScRNA-seq) has emerged as an effective method for examining cell differentiation and development. In non-model plants, it hasn't been employed very much, especially in sink organs that are abundant in secondary metabolites. RESULTS: In this study, we sequenced the single-cell transcriptomes at two developmental phases of cassava tuberous roots using the technology known as 10x Genomics (S1, S2). In total, 14,566 cells were grouped into 15 different cell types, primarily based on the marker genes of model plants known to exist. In the pseudotime study, the cell differentiation trajectory was defined, and the difference in gene expression between the two stages on the pseudotime axis was compared. The differentiation process of the vascular tissue and cerebral tissue was identified by the trajectory. We discovered the rare cell type known as the casparian strip via the use of up-regulated genes and pseudotime analysis, and we explained how it differentiates from endodermis. The successful creation of a protoplast isolation technique for organs rich in starch was also described in our study. DISCUSSION: Together, we created the first high-resolution single-cell transcriptome atlas of cassava tuberous roots, which made significant advancements in our understanding of how these roots differentiate and develop.
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Integrative multi-omics and machine learning approach reveals tumor microenvironment-associated prognostic biomarkers in ovarian cancer.
BACKGROUND: Ovarian cancer (OC) is a globally prevalent malignancy with significant morbidity and mortality, yet its heterogeneity poses challenges in treatment and prognosis. Recognizing the crucial role of the tumor microenvironment (TME) in OC progression, this study leverages integrative multi-omics and machine learning to uncover TME-associated prognostic biomarkers, paving the way for more personalized therapeutic interventions. METHODS: Employing a rigorous multi-omics approach, this study analyzed single-cell RNA sequencing (scRNA-seq) data from OC and normal tissue samples, including high-grade serous OC (HGSOC) from the Gene Expression Omnibus (GEO: GSE184880) and The Cancer Genome Atlas (TCGA) OC cohort, utilizing the Seurat package to annotate 700 TME-related genes. A prognostic model was developed using the least absolute shrinkage and selection operator (LASSO) regression and independently validated against similarly composed HGSOC datasets. Comprehensive gene expression and immune cell infiltration analyses were conducted, employing advanced algorithms like xCell to delineate the immune landscape of HGSOC. RESULTS: Our investigation unveiled distinctive immune cell infiltration patterns and gene expression profiles within the TME of HGSOC. Notably, the prevalence of exhausted CD8+ T cells in high-risk patient samples emerged as a critical finding, underscoring the dualistic nature of the immune response in OC. The developed prognostic model, incorporating immune cell markers, exhibited robust predictive accuracy for patient outcomes, showing significant correlations with immunotherapy responses and drug sensitivities. CONCLUSIONS: This study presents a groundbreaking exploration of the OC TME, offering vital insights into its molecular intricacies. By systematically deciphering the TME-associated gene signatures, the research illuminates the potential of these biomarkers in refining patient prognosis and guiding treatment strategies. Our findings underscore the necessity for personalized medicine in OC treatment, potentially enhancing patient survival rates and quality of life. This study marks a significant stride in understanding and combatting the complexities of OC.
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Transcriptomic response analysis of rubber tree saplings to water-deficit stress at single-cell resolution.
The rubber tree (Hevea brasiliensis) is increasingly affected by climate change, particularly by intensified water-deficit stress, which impacts latex yield and plantation productivity. Understanding how rubber trees adapt to water-deficit stress at the molecular level is crucial for improving their resilience. In this study, we generate a high-resolution single-cell transcriptomic atlas to investigate the cellular and molecular mechanisms underlying the response of rubber tree bark to water-deficit stress. Using droplet-based single-cell RNA sequencing, we profile 17,994 individual cells isolated from control, 4-day, and 7-day drought-stressed bark tissues. We characterize seven major cell types with 12 transcriptionally distinct cell clusters. Differential gene expression analysis reveals significant transcriptional changes, with a notable upregulation of genes involved in abscisic acid (ABA) signaling, metabolic adaptation, and stress response pathways. Additionally, we find that the ABF transcription factors (ABF2, ABF3, and ABF4) are consistently upregulated across all major cell types in response to water-deficit stress. These findings offer valuable insights into the cellular and molecular mechanisms that enable rubber trees to adapt to drought, providing a foundation for future efforts aimed at enhancing drought tolerance in this important economic species.
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Single-cell landscape of alcohol-related hepatitis reveals serum amyloid a hepatocytes as key drivers of disease pathogenesis.
BACKGROUND AIMS: Alcohol-related hepatitis (AH) is a severe form of alcohol-related liver disease (ALD). The cellular subpopulations that contribute to AH and dynamics remain poorly understood. This study aimed to identify key cellular subpopulations and their interactions in AH and explore key mechanisms contributing to disease pathogenesis. APPROACH RESULTS: Single-cell RNA sequencing was performed starting from liver biopsies from patients with AH, early-stage ALD, and healthy individuals. Immunofluorescence was used to validate protein expression of selected markers. Liver biopsy-derived organoids were generated and exposed to a conditioned medium recapitulating AH (AH-medium) to assess serum amyloid A (SAA) secretion by ELISA. Circulating SAA levels were measured in plasma samples obtained from patients at different stages of ALD. Our analysis revealed an atlas of several cell subpopulations of AH, including hepatocytes expressing SAA, scar-associated (SA) endothelial cells, Fibulin-3+ mesenchymal cells, SA-macrophages expressing MMP19, activated CD4+ and stressed/effector CD8+ T cell subsets, and hyperactivated neutrophils expressing FPR2. Cell-communication analysis predicted a strong SAA-FPR2 interaction between hepatocyte and neutrophil subpopulations in AH. We confirmed that AH-hepatocytes secreted SAA in organoid cultures after stimulation with AH-medium. We also found out that circulating SAA levels were elevated in AH and were associated with reduced survival. CONCLUSIONS: The SAA-FPR2 pathway emerges as a potential mediator of inflammation in AH, offering potential therapeutic targets for this severe disease. This study provides new insights into the cellular heterogeneity and dynamics in ALD progression, dissecting AH at a single-cell level.
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Mediators of SARS-CoV-2 entry are preferentially enriched in cardiomyocytes.
BACKGROUND: The coronavirus disease 2019 (COVID-19) has spread rapidly around the world. In addition to common respiratory symptoms such as cough and fever, some patients also have cardiac injury, however, the mechanism of cardiac injury is not clear. In this study, we analyzed the RNA expression atlases of angiotensin-converting enzyme 2(ACE2), cathepsin B (CTSB) and cathepsin L (CTSL) in the human embryonic heart at single-cell resolution. RESULTS: The results showed that ACE2 was preferentially enriched in cardiomyocytes. Interestingly, serine protease transmembrane serine protease 2 (TMPRSS2) had less expression in cardiomyocytes, but CTSB and CTSL, which belonged to cell protease, could be found to be enriched in cardiomyocytes. The results of enrichment analysis showed that differentially expressed genes (DEGs) in ACE2-positive cardiomyocytes were mainly enriched in the processes of cardiac muscle contraction, regulation of cardiac conduction, mitochondrial respiratory chain, ion channel binding, adrenergic signaling in cardiomyocytes and viral transcription. CONCLUSIONS: Our study suggests that both atrial and ventricular cardiomyocytes are potentially susceptible to severe acute respiratory syndrome coronavirus-2(SARS-CoV-2), and SARS-CoV-2 may enter ventricular cardiomyocytes using CTSB/CTSL for S protein priming. This may be the partial cellular mechanism of cardiac injury in patients with COVID-19.