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Found: 4 892
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Single-nucleus RNA sequencing provides insights into the genetic mechanisms underlying reproductive adaptability in Tibetan sheep (Ovis aries).
The Tibetan sheep is an ideal model animal for investigating adaptations to hypoxia and an important livestock species; however, the reproductive mechanisms that characterize its adaptive responses in extreme environments remain poorly understood. In this study, we employ single-nucleus RNA sequencing to characterize the transcriptomic landscape of the Tibetan sheep testis at four key developmental stages: newborn, pre-sexual maturity, and post-sexual maturity to adulthood. We constructed a single-nucleus transcriptomic atlas and identified two distinct subtypes of spermatogonial stem cells (SSCs): quiescent and active. Notably, we observed that pre-sexually mature Sertoli cells exhibit three distinct transcriptional states. Furthermore, we also identified a transitional state Sertoli cell that links immature and mature Sertoli cells. Analysis of testicular intercellular communication networks provides evidence for understanding somatic-germ cell interactions during spermatogenesis. Our study provides a comprehensive atlas of Tibetan sheep testicular development, revealing key insights into the dynamic changes and regulatory mechanisms of spermatogenesis and somatic cell maturation from birth to adulthood. These findings contribute to a detailed understanding of the genetic mechanisms underlying testicular development in Tibetan sheep and offer valuable insights and references for the study and comprehension of reproductive adaptations in other highland male domestic animals.
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Dynamic remodeling of the transcriptional landscape drives Merkel cell specification and mechanosensory differentiation.
Merkel cells (MCs) are specialized mechanosensory receptor cells essential for touch sensation, exhibiting both epithelial and neuroendocrine characteristics. However, the regulatory processes that shape MC fate remain poorly defined. Using single-cell RNA sequencing, we construct a conserved, triphasic atlas of MC ontogeny comprising an epithelial-like stage, a transitional intermediate phase, and a terminal neuroendocrine state. Importantly, we identify JunB as a priming factor essential for initiating MC differentiation, while Pou4f1 acts as a driver of epithelial-neuroendocrine conversion and subsequent functional integration. Moreover, the gene regulatory network analysis further reveals that TUBB3+ primed cells could differentiate into the MC lineage under the regulation of Barhl1 and Atoh1. Genetic lineage tracing and cross-species analyses validate these mechanisms. Together, our work delineates the transcriptional network orchestrating MC fate determination and mechanosensory differentiation, providing not only mechanistic insights but also highlighting actionable targets relevant to MC carcinoma and sensory restoration.
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Single cell spatial transcriptomics track the evolutionary hierarchy and microenvironment remodeling during breast carcinoma invasion.
The progression from ductal carcinoma in situ (DCIS) to invasive breast carcinoma (IBC) critically determines patient outcomes, yet its mechanisms remain incompletely understood. Integrating single-cell RNA sequencing, spatial transcriptomics, and genomics across 28 patients with synchronous DCIS and IBC, we delineate the spatial-molecular hierarchy of this transition. Invasion is primarily driven by clonal expansion of pre-existing DCIS subclones, emphasizing transcriptional reprogramming and tumor microenvironment (TME) remodeling over acquisition of additional driver alterations. IBC cells exhibit pronounced epithelial-mesenchymal transition and metabolic reprogramming. We uncover dynamic TME remodeling at the invasive front, identifying key ligand-receptor interactions (e.g., PPIA-BSG, MDK-LRP1, CXCL12-CXCR4) facilitating basement membrane disruption, angiogenesis and immunosuppression. Deconvolution of basement membrane breach reveals four molecularly defined stages (NMFT1-NMFT4) with progressively worsening patient survival. This study establishes a unified spatial-molecular atlas of DCIS-IBC progression, highlighting clonal expansion, transcriptional plasticity and TME remodeling as key drivers of invasion.
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The brain of the female Anopheles gambiae mosquito at spatial and single-cell resolution.
Blood feeding in Anopheles mosquitoes is at the root of all malaria infections in humans and is supported by a range of physiological and behavioral adaptations. Since behavior is orchestrated at the level of the central nervous system, we surveyed the cellular diversity and spatial organization of the female Anopheles gambiae brain and compared it to other insect species. We then describe transcriptional changes associated with mosquito life history events with single brain and single-cell RNA sequencing. We did not identify expansion of specific cell populations, but a modulation of neurotransmission in the mated mosquitoes, and a metabolic and immune response associated with glia, Kenyon cells and immune cells after bloodmeal, and detected signatures of aging in the mosquito brain. We did not find an effect of Plasmodium falciparum infection. Our atlas will empower the study of non-model insect neurobiology, neural basis of vector behavior, and mechanisms underlying malaria transmission.
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Single-Cell Transcriptomic Characterization of DNCB-Induced Mouse Model Reveals Atopic Dermatitis-Associated Skin Lesions in Skin Microenvironment.
Atopic dermatitis (AD) is a chronic inflammatory skin disorder characterized by complex cellular heterogeneity. While several studies have begun to characterize the single-cell transcriptomic landscape of human AD, comparable high-resolution data from widely used mouse models remain lacking. Here, we employed single-cell RNA sequencing to profile skin from a 2,4-dinitrochlorobenzene (DNCB)-induced AD mouse model, which recapitulates key pathological features of human AD and is frequently used for mechanistic and therapeutic investigations. In this study, we identified 21 transcriptionally distinct clusters encompassing 11 major cell types. DNCB exposure resulted in robust immune infiltration, including Th2/Th17-skewed T cells, monocytes, macrophages, and inflamed endothelial cells. Keratinocytes were depleted and exhibited hyperproliferation, apoptosis, and differentiation defects, while novel fibroblast subsets displayed impaired maturation and pro-inflammatory states. Intercellular communication analysis revealed monocytes as dominant ligand-receptor signaling hubs. This study provides the first comprehensive single-cell atlas of the DNCB-induced AD model, revealing immune dysregulation, epithelial remodeling, and stromal reprogramming. Notably, the transcriptomic parallels with human AD validate the model’s translational relevance. Our findings establish a foundational reference for future AD research using the DNCB mouse model and offer valuable insights for interpreting drug and target discovery studies performed in this context.
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Single cell transcriptomic atlas reveals distinct immune signatures following transfusion of COVID-19 convalescent plasma in severe COVID-19.
The inflammatory responses of severe patients before and after Convalescent COVID-19 plasma (CCP) transfusion are poorly understood. To clarify the immune response and potential pro-inflammatory factors in severe patients after CCP transfusion, we performed single-cell RNA sequencing on peripheral blood mononuclear cells (PBMCs) from severe COVID-19 patients before and 24 h after CCP transfusion. At 24 h after CCP transfusion, T and B cell proportions increased modestly without significant changes in TCR/BCR diversity. Importantly, concurrent upregulation of S100A8 in both CD4 memory T cells and B cells suggests that CCP transfusion may promote an inflammatory response in these cell subsets. Cell communication analysis revealed that CCP transfusion induced selective disruption of NK cell communication with TCR-negative T cells and BCR-positive B cells. Our data suggest CCP transfusion promoted the inflammatory response and interrupt the communication between adaptive immune cells and innate immune cells in severe COVID-19.
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Structural-functional network decoupling in early stage amyotrophic lateral sclerosis reveals cell-type specific transcriptional signatures.
BACKGROUND: Amyotrophic lateral sclerosis (ALS) involves widespread brain network dysfunction, yet the molecular mechanisms linked to these alterations remain poorly understood. We investigated macroscopic structural-functional coupling abnormalities in early-stage ALS (ALS-ES) and their underlying transcriptomic signatures. METHODS: We analyzed multimodal MRI data from 73 patients with sporadic ALS-ES and 74 age- and sex-matched healthy controls. Structural-functional (SC-FC) coupling was quantified using diffusion tensor imaging and resting-state functional MRI. Machine learning models were constructed to distinguish patients from controls based on network features. Coupling alterations were spatially correlated with neurotransmitter receptor maps and gene expression profiles from the Allen Human Brain Atlas. Key transcriptomic findings were validated using independent single-cell RNA sequencing datasets. RESULTS: While structural connectivity remained largely preserved, functional connectivity was significantly reduced in the somatomotor network (SMN). This mismatch manifested as significant SC-FC network decoupling, particularly within the SMN (pFDR = 0.001). A gradient boosting machine model accurately classified patients, identifying SC-FC coupling in the left precentral gyrus as a primary statistical contributor to the classification model. Decoupling spatially correlated with 5-HT2A and mGluR5 receptor distributions. Imaging-transcriptomics linked network failure to a gene signature enriched for synaptic pathways and microglial markers. Single-cell analysis identified FMN1 as a candidate gene whose glial expression spatially associates with network decoupling. CONCLUSIONS: Early-stage ALS is characterized by significant structural-functional network decoupling, primarily in motor systems. This macroscopic failure is linked to specific microglial dysregulation, particularly FMN1 downregulation, providing a multiscale framework bridges statistical neuroimaging signatures with potential cellular pathology.
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A cross-scale multimodal framework identifies clinically actionable immunotherapy biomarkers in melanoma through bulk to single-cell and spatial transcriptomics integration.
BACKGROUND: Melanoma, a type of skin cancer that can spread to other parts of the body, currently lacks highly precise individualized treatment options. METHODS: We performed multi-omics integration on The Cancer Genome Atlas Skin Cutaneous Melanoma (TCGA-SKCM) cohort to identify melanoma molecular subtypes. The identified genes were validated in independent meta cohorts from GEO, followed by transcriptome-wide association study (TWAS) validation using Genotype-Tissue Expression (GTEx) and UK Biobank datasets. Additionally, we analyzed machine learning-driven signature (CMLS) development, tumor microenvironment characteristics, immunotherapy response, and potential therapeutic targets. Finally, single-cell and spatial transcriptomics provided further biological insights and the pathomechanisms. RESULT: Our study identified two distinct molecular subtypes of SKCM using multimodal data integration with the MOVICS package: Cancer Subtype 1 (CS1) and CS2. CS2 showed a better prognosis and was enriched in immune-suppressive pathways such as WNT–β signaling, while CS1 exhibited higher activation of the PI3K pathway and DNA repair mechanisms, along with greater tumor invasiveness. TWAS analysis results combined the findings from TCGA-SKCM and the meta-cohort, identifying six significant prognostic-related genes (SPRGs). The CMLS prognostic model, based on SPRGs (CAP2, SELL, and LAPTM5 as risk factors and GZMA, FCER1G, and LYZ as protective factors), stratified patients into high-group (poorer survival) and low-risk groups. Single-cell and spatial transcriptomic analyses further validated CMLS prognostic results, highlighting distinct tumor microenvironment interactions and progression trajectories. CONCLUSION: Identifications of molecular subtypes and CMLS represent a valuable tool for early prediction of patient prognosis and for screening potential candidates likely to benefit from immunotherapy, with broad implications for clinical practice foundation for personalized therapies.
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Single-cell atlas of B cell heterogeneity in lacrimal IgG4-related disorders: Unraveling the transition from inflammatory exhaustion to clonal malignancy.
This study analyzed B-cell heterogeneity in lacrimal gland tissues from 4 patients with IgG4-related ophthalmic disease (IgG4-ROD) and 2 patients with IgG4-positive MALT lymphoma using single-cell transcriptome sequencing (scRNA-seq). The results revealed that while the B-cell differentiation trajectories have similarities between the two diseases, critical differences were evident. IgG4-ROD was predominantly composed of naïve B cells, with memory B cells mainly being the central memory type. These cells were enriched in hormone/innate immunity pathways, and the plasma cells exhibited features of functional exhaustion. Conversely, MALT lymphoma was dominated by memory B cells, particularly enriched in terminally differentiated subtypes, with aberrant activation of oncogenic pathways (BCR/NF-κB). In MALT lymphoma, naïve B cells showed upregulated expression of immunoglobulin genes (IGHG3/IGHG4) and abnormal activation of EBV/BCR/T-cell differentiation pathways, despite having suppressed basal metabolism. Germinal center-like B cells in MALT lymphoma revealed upregulated gene expression enriched in T-cell activation and PD-1/PD-L1 pathways. Plasma cells in MALT lymphoma displayed monoclonal expansion (high expression of IGHG2/IGHG3/IGHG4) and enhanced antibody secretion. Therefore, MALT lymphoma is characterized by abnormal activation and malignant transformation of B cells, whereas IgG4-ROD manifests as functional exhaustion and metabolic suppression. The differentiation state of memory B cells may represent a critical juncture for malignant transformation.
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Active eosinophils regulate host defence and immune responses in colitis.
In the past decade, single-cell transcriptomics has helped to uncover new cell types and states and led to the construction of a cellular compendium of health and disease. Despite this progress, some difficult-to-sequence cells remain absent from tissue atlases. Eosinophils-elusive granulocytes that are implicated in a plethora of human pathologies1-5-are among these uncharted cell types. The heterogeneity of eosinophils and the gene programs that underpin their pleiotropic functions remain poorly understood. Here we provide a comprehensive single-cell transcriptomic profiling of mouse eosinophils. We identify an active and a basal population of intestinal eosinophils, which differ in their transcriptome, surface proteome and spatial localization. By means of a genome-wide CRISPR inhibition screen and functional assays, we reveal a mechanism by which interleukin-33 (IL-33) and interferon-γ (IFNγ) induce the accumulation of active eosinophils in the inflamed colon. Active eosinophils are endowed with bactericidal and T cell regulatory activity, and express the co-stimulatory molecules CD80 and PD-L1. Notably, active eosinophils are enriched in the lamina propria of a small cohort of patients with inflammatory bowel disease, and are closely associated with CD4+ T cells. Our findings provide insights into the biology of eosinophils and highlight the crucial contribution of this cell type to intestinal homeostasis, immune regulation and host defence. Furthermore, we lay a framework for the characterization of eosinophils in human gastrointestinal diseases.