Your browser does not allow saving data (e.g. private mode): bookmarks will be lost when the tab closes.
Search PubMed
Keywords, author, journal, years — results from PubMed, abstracts with Russian translation, bookmarks in your browser.
Found: 4 924
Page 206 of 493-
Lymph nodes are innervated by a unique population of sensory neurons with immunomodulatory potential.
Barrier tissue immune responses are regulated in part by nociceptors. Nociceptor ablation alters local immune responses at peripheral sites and within draining lymph nodes (LNs). The mechanisms and significance of nociceptor-dependent modulation of LN function are unknown. Using high-resolution imaging, viral tracing, single-cell transcriptomics, and optogenetics, we identified and functionally tested a sensory neuro-immune circuit that is responsive to lymph-borne inflammatory signals. Transcriptomics profiling revealed that multiple sensory neuron subsets, predominantly peptidergic nociceptors, innervate LNs, distinct from those innervating surrounding skin. To uncover LN-resident cells that may interact with LN-innervating sensory neurons, we generated a LN single-cell transcriptomics atlas and nominated nociceptor target populations and interaction modalities. Optogenetic stimulation of LN-innervating sensory fibers triggered rapid transcriptional changes in the predicted interacting cell types, particularly endothelium, stromal cells, and innate leukocytes. Thus, a unique population of sensory neurons monitors peripheral LNs and may locally regulate gene expression.
-
Characteristics linking ischemia-reperfusion to chronic lung allograft dysfunction in lung transplantation: A single-cell bioinformatics analysis.
BACKGROUND: Lung transplantation offers a life-saving procedure to patients with end-stage lung diseases with 85-89 % one year and 60 % five-year survival rates. Lung transplants are complicated by early ischemia/reperfusion injury (IRI) and late chronic lung allograft dysfunction (CLAD). However, the cellular and molecular links between IRI and CLAD remain unclear. MATERIALS AND METHODS: We integrated single-cell RNA-seq results from GSE220797 and GSE224210 data sets. After quality filtering, we performed Louvain clustering and UMAP visualization. We applied Augur method to prioritize cell populations by transcriptional responsiveness to IRI and CLAD. We also performed dynamic trajectory analyses to map pseudotemporal transitions. Pathway activity was characterized by differential expression analysis and module scoring. Intercellular communication was assessed using CellChat and MEBOCOST analyses. Regulon inference was performed with pySCENIC analysis. RESULTS: Overall, epithelial cells showed progressive metabolic suppression and activation of cuproptosis, a programmed cell death (PCD) triggered by excessive copper accumulation within cells. Club cells, found in the small airways of the lungs, exhibited developmental plasticity and predictive potential across IRI and CLAD conditions. Among myeloid populations, M1 proinflammatory (AM_M1TM) macrophages underwent macrophage-to-myofibroblast transition (MMT) and produced excessive extracellular matrix (ECM) supporting a network of proteins surrounding cells. Metabolite and cell-cell communication analyses revealed declining macrophage/epithelial metabolic crosstalk and differential signaling flux from normal through IRI to CLAD transition. CONCLUSIONS: The integrated single-cell atlas delineates interaction of multiple cells and their signaling pathways linking IRI to CLAD processes. These findings require further verification through studies in animal models and clinical samples.
-
scMMO-atlas: a single cell multimodal omics atlas and portal for exploring fine cell heterogeneity and cell dynamics.
Single-cell multimodal sequencing parallelly captures multiple modalities of the same cell, providing unparalleled insights into cell heterogeneity and cell dynamics. For example, joint profiling of chromatin accessibility and transcriptome from the same single cell (scATAC + RNA) identified new cell subsets within the well-defined clusters. However, lack of single-cell multimodal omics (scMMO) database has led to data fragmentation, seriously hindering access, utilization and mining of scMMO data. Here, we constructed a scMMO atlas by collecting and integrating various scMMO data, then constructed scMMO database and portal called scMMO-atlas (https://www.biosino.org/scMMO-atlas/). scMMO-atlas includes scATAC + RNA (ISSAAS-seq, SNARE-seq, paired-seq, sci-CAR, scCARE-seq, 10X Multiome and so on), scRNA + protein, scATAC + protein and scTri-modal omics data, with 3 168 824 cells from 27 cell tissues/organs. scMMO-atlas offered an interactive portal for visualization and featured analysis for each modality and the integrated data. Integrated analysis of scATAC + RNA data of mouse cerebral cortex in scMMO-atlas identified more cell subsets compared with unimodal omics data. Among these new cell subsets, there is an early astrocyte subset highly expressed Grm3, called Astro-Grm3. Furthermore, we identified Ex-L6-Tle4-Nrf1, a progenitor of Ex-L6-Tle4, indicating the statistical power provided by the big data in scMMO-atlas. In summary, scMMO-atlas offers cell atlas, database and portal to facilitate data utilization and biological insight.
-
Single-cell analyses reveal evolution mimicry during the specification of breast cancer subtype.
Background: The stem or progenitor antecedents confer developmental plasticity and unique cell identities to cancer cells via genetic and epigenetic programs. A comprehensive characterization and mapping of the cell-of-origin of breast cancer using novel technologies to unveil novel subtype-specific therapeutic targets is still absent. Methods: We integrated 195,144 high-quality cells from normal breast tissues and 406,501 high-quality cells from primary breast cancer samples to create a large-scale single-cell atlas of human normal and cancerous breasts. Potential heterogeneous origin of malignant cells was explored by contrasting cancer cells against reference normal epithelial cells. Multi-omics analyses and both in vitro and in vivo experiments were performed to screen and validate potential subtype-specific treatment targets. Novel biomarkers of identified immune and stromal cell subpopulations were validated by immunohistochemistry in our cohort. Results: Tumor stratification based on cancer cell-of-origin patterns correlated with clinical outcomes, genomic aberrations and diverse microenvironment constitutions. We found that the luminal progenitor (LP) subtype was robustly associated with poor prognosis, genomic instability and dysfunctional immune microenvironment. However, the LP subtype patients were sensitive to neoadjuvant chemotherapy (NAC), PARP inhibitors (PARPi) and immunotherapy. The LP subtype-specific target PLK1 was investigated by both in vitro and in vivo experiments. Besides, large-scale single-cell profiling of breast cancer inspired us to identify a range of clinically relevant immune and stromal cell subpopulations, including subsets of innate lymphoid cells (ILCs), macrophages and endothelial cells. Conclusion: The present single-cell study revealed the cellular repertoire and cell-of-origin patterns of breast cancer. Combining single-cell and bulk transcriptome data, we elucidated the evolution mimicry from normal to malignant subtypes and expounded the LP subtype with vital clinical implications. Novel immune and stromal cell subpopulations of breast cancer identified in our study could be potential therapeutic targets. Taken together, Our findings lay the foundation for the precise prognostic and therapeutic stratification of breast cancer.
-
Clock-Related Genes Mark a Developmental Cortical Maturation Program Associated with Stage-Resolved Responses to Prenatal Immune Activation.
Background/Objectives: Sleep and circadian disturbances are common in neurodevelopmental conditions, yet the developmental cortical programs linking clock-related transcriptional regulators to disease vulnerability remain unclear. Methods: Here, we integrated human developmental brain transcriptomes, weighted gene co-expression network analysis (WGCNA), human and mouse cortical single-cell atlases, prenatal immune activation transcriptomes, and ASD postmortem brain datasets to characterize the developmental architecture of BrainSpan-derived cortical programs and examine their behavior in perturbational and disease contexts. Results: In the BrainSpan frontal cortex, canonical clock-related genes followed structured but heterogeneous developmental trajectories rather than behaving as a coordinated oscillator-like unit. WGCNA identified a postnatal-rising BrainSpan-derived primary developmental module that was strongly associated with developmental age and enriched for synaptic signaling, neurotransmitter transport, ion transport, membrane excitability, cellular respiration, metabolic regulation, and proteostatic processes. Network analysis placed multiple canonical clock-related and clock-regulatory genes, including NPAS2, BHLHE40, BHLHE41, PER family members, RORA, NR1D1/2, and CLOCK, within a broader neuronal and homeostatic co-expression architecture, although their module-membership strengths varied substantially. Projection onto a human cortical developmental single-cell atlas revealed a non-uniform distribution of the corrected BrainSpan-derived developmental signature, with relatively higher scores in excitatory and inhibitory neuronal populations and lower scores in neuroblast and radial glial populations. A mouse cortical developmental single-cell atlas provided a comparative view of the stage- and cell-type-dependent expression of clock-related genes and the transferred developmental signature during corticogenesis. In a Poly(I:C)-based maternal immune activation dataset, litter-aware reanalysis identified stage-resolved genome-wide transcriptional responses following E12.5 exposure. However, neither the aggregate core clock-gene expression score nor the independently transferred BrainSpan-derived developmental signature showed a significant overall treatment effect or collection-stage-by-treatment interaction, indicating that this bulk dataset provides a perturbational context rather than evidence for selective disruption of the developmental program. An exploratory region-stratified analysis of GSE28521 yielded near-null effects for the BrainSpan-derived developmental signature, with confidence intervals crossing zero across all examined regions. These ASD postmortem findings were therefore treated as a boundary assessment rather than evidence of ASD-specific convergence. Conclusions: Collectively, these findings position clock-related genes as components of a developmentally regulated cortical maturation program enriched for neuronal signaling, synaptic maturation, metabolic regulation, and stress-response processes.
-
A single-cell atlas deconstructs heterogeneity across multiple models in murine traumatic brain injury and identifies novel cell-specific targets.
Traumatic brain injury (TBI) heterogeneity remains a critical barrier to translating therapies. Identifying final common pathways/molecular signatures that integrate this heterogeneity informs biomarker and therapeutic-target development. We present the first large-scale murine single-cell atlas of the transcriptomic response to TBI (334,376 cells) across clinically relevant models, sex, brain region, and time as a foundational step in molecularly deconstructing TBI heterogeneity. Results were unique to cell populations, injury models, sex, brain regions, and time, highlighting the importance of cell-level resolution. We identify cell-specific targets and previously unrecognized roles for microglial and ependymal subtypes. Ependymal-4 was a hub of neuroinflammatory signaling. A distinct microglial lineage shared features with disease-associated microglia at 24 h, with persistent gene-expression changes in microglia-4 even 6 months after contusional TBI, contrasting all other cell types that mostly returned to naive levels. Regional and sexual dimorphism were noted. CEREBRI, our searchable atlas (https://shiny.crc.pitt.edu/cerebri/), identifies previously unrecognized cell subtypes/molecular targets and is a leverageable platform for future efforts in TBI and other diseases with overlapping pathophysiology.
-
CD109 is associated with an immunosuppressive microenvironment and M2 macrophage polarization: pan-cancer analysis and functional validation.
BACKGROUND: CD109 is a glycosylphosphatidylinositol‑anchored glycoprotein implicated in tumor progression and physiological homeostasis. Although aberrant CD109 expression has been reported in multiple malignancies, its prognostic relevance across cancer types and its potential immunomodulatory roles remain incompletely characterized. METHODS: We performed an integrative pan-cancer analysis of CD109 using RNA sequencing data from the Genotype-Tissue Expression (GTEx) and The Cancer Genome Atlas (TCGA) databases. CD109 expression, genetic alterations, survival associations, and immune infiltration patterns were systematically assessed. Single-cell RNA sequencing (scRNA-seq) data from non-small cell lung cancer (NSCLC) cohorts were analyzed to define cellular CD109 distribution. Functional validation was performed using siRNA-mediated CD109 knockdown in A549 lung adenocarcinoma cells, followed by macrophage co-culture experiments, flow cytometry, qPCR, ELISA, and migration assays. RESULTS: CD109 was markedly upregulated in 15 tumor types and showed heterogeneous prognostic associations across cancers. Elevated CD109 expression was associated predominantly with unfavorable survival in several tumor types, whereas opposite prognostic associations were observed in a subset of cancers. Bioinformatic analysis revealed that high CD109 expression was associated with an immunosuppressive tumor immune microenvironment, characterized by the enrichment of M2-like tumor-associated macrophages (TAMs) and activation of oncogenic signaling axes. Single-cell profiling showed that CD109 was predominantly expressed in malignant cells and a subset of M2 macrophages. Consistent with these clinical and computational insights, functional validation in an in vitro lung cancer model showed that CD109 knockdown in A549 cells significantly suppressed tumor migration and was associated with a shift in macrophage polarization away from a pro-tumorigenic M2 phenotype toward an anti-tumor M1 state. CONCLUSIONS: Our study highlights CD109 as a context-dependent biomarker with tumor type specific prognostic relevance and links its expression to immunosuppressive features of the tumor immune microenvironment. These findings suggest that CD109 warrants further investigation as a potential therapeutic target, particularly in tumor contexts characterized by macrophage-associated immunosuppression, although the macrophage-related functional effects observed here were validated in a lung cancer model and require further investigation in additional tumor types.
-
Single Cell RNA Sequencing in Human Disease: Renal, Pancreatic, and Viral Diseases.
In this chapter, we discussed some of the specific uses of scRNA-seq in exploring viral infections and diseases of the kidney and pancreas. This review, however, is by no means exhaustive, and indeed this technology has advanced the study of pulmonary and cardiac diseases, transplant immunology, cancer, and many others as well. Nevertheless, the above reviewed studies do illustrate the utility and resolution of scRNA-seq in understanding exact cellular compositions, discovering heterogeneity within cellular expression patterns, and uncovering clues that may eventually lead to the development of more targeted and personalized therapies. Additionally, the increasing availability of whole tissue cellular atlases in both health and disease as a result of scRNA-seq studies provides an important resource to better understand complicated molecular signaling patterns and events that are similar and different between human diseases.
-
A human stomach cell type transcriptome atlas.
BACKGROUND: The identification of cell type-specific genes and their modification under different conditions is central to our understanding of human health and disease. The stomach, a hollow organ in the upper gastrointestinal tract, provides an acidic environment that contributes to microbial defence and facilitates the activity of secreted digestive enzymes to process food and nutrients into chyme. In contrast to other sections of the gastrointestinal tract, detailed descriptions of cell type gene enrichment profiles in the stomach are absent from the major single-cell sequencing-based atlases. RESULTS: Here, we use an integrative correlation analysis method to predict human stomach cell type transcriptome signatures using unfractionated stomach RNAseq data from 359 individuals. We profile parietal, chief, gastric mucous, gastric enteroendocrine, mitotic, endothelial, fibroblast, macrophage, neutrophil, T-cell, and plasma cells, identifying over 1600 cell type-enriched genes. CONCLUSIONS: We uncover the cell type expression profile of several non-coding genes strongly associated with the progression of gastric cancer and, using a sex-based subset analysis, uncover a panel of male-only chief cell-enriched genes. This study provides a roadmap to further understand human stomach biology.
-
Single-cell transcriptome atlas of testes from mice with high-fat diets.
Obesity is accompanied by multiple known health risks and increased morbidity, and obese men display reduced reproductive health. However, the impact of obesity on the testes at the molecular levels remain inadequately explored. This is partially attributed to the lack of monitoring tools for tracking alterations within cell clusters in testes associated with obesity. Here, we utilized single-cell RNA sequencing to analyze over 70,000 cells from testes of obese and lean mice, and to study changes related to obesity in non-spermatogenic cells and spermatogenesis. The Testicular Library encompasses all non-spermatogenic cells and spermatogenic cells spanning from spermatogonia to spermatozoa, which will significantly aid in characterizing alterations in cellular niches and the testicular microenvironment during high-fat diet (HFD)-induced obesity. This comprehensive dataset is indispensable for studying how HFD disrupts cell-cell communication networks within the testis and impacts alterations in the testicular microenvironment that regulate spermatogenesis. Being the inaugural dataset of single-cell RNA-seq in the testes of diet-induced obese (DIO) mice, this holds the potential to offer innovative insights and directions in the realm of single-cell transcriptomics concerning male reproductive injury associated with HFD.