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TrkB-dependent regulation of molecular signaling across septal cell types.
The lateral septum (LS), a GABAergic structure located in the basal forebrain, is implicated in social behavior, learning and memory. We previously demonstrated that expression of tropomyosin kinase receptor B (TrkB) in LS neurons is required for social novelty recognition. To better understand molecular mechanisms by which TrkB signaling controls behavior, we locally knocked down TrkB in LS and used bulk RNA-sequencing to identify changes in gene expression downstream of TrkB. TrkB knockdown induces upregulation of genes associated with inflammation and immune responses, and downregulation of genes associated with synaptic signaling and plasticity. Next, we generated one of the first atlases of molecular profiles for LS cell types using single nucleus RNA-sequencing (snRNA-seq). We identified markers for the septum broadly, and the LS specifically, as well as for all neuronal cell types. We then investigated whether the differentially expressed genes (DEGs) induced by TrkB knockdown map to specific LS cell types. Enrichment testing identified that downregulated DEGs are broadly expressed across neuronal clusters. Enrichment analyses of these DEGs demonstrated that downregulated genes are uniquely expressed in the LS, and associated with either synaptic plasticity or neurodevelopmental disorders. Upregulated genes are enriched in LS microglia, associated with immune response and inflammation, and linked to both neurodegenerative disease and neuropsychiatric disorders. In addition, many of these genes are implicated in regulating social behaviors. In summary, the findings implicate TrkB signaling in the LS as a critical regulator of gene networks associated with psychiatric disorders that display social deficits, including schizophrenia and autism, and with neurodegenerative diseases, including Alzheimer's.
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Epithelial and stromal remodeling in murine Crohn's disease-like ileitis.
BACKGROUND AND AIMS: Inflammatory bowel disease is characterized by progressive epithelial, immune, and stromal dysfunction. Human datasets yield important insights yet are inherently descriptive, requiring animal models for in vivo mechanistic interrogation. The SAMP1/YitFc (SAMP) mouse model develops spontaneous Crohn's disease (CD)-like ileitis while allowing controlled manipulation of pathophysiologic pathways. To understand cell-specific disease-associated transcriptional changes, we defined the single-nucleus transcriptomes of inflamed SAMP ilea using single-nucleus RNA-sequencing (snRNA-seq). METHODS: We performed whole-ileum snRNA-seq on SAMP (n=4) and control AKR/J (n=3) mice using the gut-optimized CitraPrep protocol, generating 58,349 high-quality nuclei across epithelial, immune, and stromal lineages. We corroborated SAMP-associated changes with immunofluorescent staining, Western blotting, spatial transcriptomic, and human single-cell RNA-sequencing data. RESULTS: We observed a primary type 2 immune phenotype in SAMP compared to AKR mice, but most transcriptional changes occurred in stromal and epithelial, not immune, cells. Stromal remodeling included increased fibroblast-derived Igf1. In SAMP epithelium, expansion of tuft cells and emergence of SAMP-specific Pcsk6+ crypt enterocytes were observed and confirmed in human CD patients. Finally, we identified cross-compartmental changes in cell-cell signaling, including enterocyte-to-type 3 innate lymphoid cell (ILC3) communication and enhanced global Igf1 signaling. These features recapitulate known, as well as novel, characteristics of CD and extend our understanding of disease-associated multicellular networks. CONCLUSION: This atlas of ileitis-prone SAMP mice provides a high-resolution resource for dissecting conserved and novel mechanisms of inflammation and tissue remodeling. Herein, we uncover disease-associated transcriptional changes conserved in human CD, presenting a translational platform for future mechanistic and therapeutic studies.
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Exploration of the prognostic prediction value of the PANoptosis-based risk score and its correlation with tumor immunity in lung adenocarcinoma.
Lung adenocarcinoma (LUAD) is a common cancer with high mortality worldwide. PANoptosis is a novel inflammatory programmed cell death modality with the characteristics of pyroptosis, apoptosis and necroptosis. It is necessary to explore PANoptosis-related genes in LUAD patients and offer evidence for prognosis prediction and therapeutic strategies. Single-cell RNA sequencing data and RNA expression profiles of LUAD patients from The Cancer Genome Atlas and Gene Expression Omnibus databases are used to screen PANoptosis-related differential genes for the construction of a risk model. Fifteen PANoptosis-related markers with prognostic value were identified by Least Absolute Shrinkage and Selection Operator (LASSO)-Cox regression analysis. Kaplan-Meier analysis and receiver operating characteristic curve analysis further demonstrated the significant predictive capability. Immune infiltration, Single Nucleotide Variants (SNV) mutations, and clinical drug susceptibility were analyzed. In conclusion, a risk model of 15 PANoptosis-related genes has significant value in prognostic prediction for LUAD and has potential to direct clinical therapeutic strategies during the treatment.
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The effect of sevoflurane exposure on cell-type-specific changes in the prefrontal cortex in young mice.
Sevoflurane, the predominant pediatric anesthetic, has been linked to neurotoxicity in young mice, although the underlying mechanisms remain unclear. This study focuses on investigating the impact of neonatal sevoflurane exposure on cell-type-specific alterations in the prefrontal cortex (PFC) of young mice. Neonatal mice were subjected to either control treatment (60% oxygen balanced with nitrogen) or sevoflurane anesthesia (3% sevoflurane in 60% oxygen balanced with nitrogen) for 2 hours on postnatal days (PNDs) 6, 8, and 10. Behavioral tests and single-nucleus RNA sequencing (snRNA-seq) of the PFC were conducted from PNDs 31 to 37. Mechanistic exploration included clustering analysis, identification of differentially expressed genes (DEGs), enrichment analyses, single-cell trajectory analysis, and genome-wide association studies (GWAS). Sevoflurane anesthesia resulted in sociability and cognition impairments in mice. Novel specific marker genes identified 8 distinct cell types in the PFC. Most DEGs between the control and sevoflurane groups were unique to specific cell types. Re-defining 15 glutamatergic neuron subclusters based on layer identity revealed their altered expression profiles. Notably, sevoflurane disrupted the trajectory from oligodendrocyte precursor cells (OPCs) to oligodendrocytes (OLs). Validation of disease-relevant candidate genes across the main cell types demonstrated their association with social dysfunction and working memory impairment. Behavioral results and snRNA-seq collectively elucidated the cellular atlas in the PFC of young male mice, providing a foundation for further mechanistic studies on developmental neurotoxicity induced by anesthesia.
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Single-cell atlas of human gingiva unveils a NETs-related neutrophil subpopulation regulating periodontal immunity.
INTRODUCTION: Exaggerated neutrophil recruitment and activation are the major features of pathological alterations in periodontitis, in which neutrophil extracellular traps (NETs) are considered to be responsible for inflammatory periodontal lesions. Despite the critical role of NETs in the development and progression of periodontitis, their specific functions and mechanisms remain unclear. OBJECTIVES: To demonstrate the important functions and specific mechanisms of NETs involved in periodontal immunopathology. METHODS: We performed single-cell RNA sequencing on gingival tissues from both healthy individuals and patients diagnosed with periodontitis. High-dimensional weighted gene co-expression network analysis and pseudotime analysis were then applied to characterize the heterogeneity of neutrophils. Animal models of periodontitis were treated with NETs inhibitors to investigate the effects of NETs in severe periodontitis. Additionally, we established a periodontitis prediction model based on NETs-related genes using six types of machine learning methods. Cell-cell communication analysis was used to identify ligand-receptor pairs among the major cell groups within the immune microenvironment. RESULTS: We constructed a single-cell atlas of the periodontal microenvironment and obtained nine major cell populations. We further identified a NETs-related subgroup (NrNeu) in neutrophils. An in vivo inhibition experiment confirmed the involvement of NETs in gingival inflammatory infiltration and alveolar bone absorption in severe periodontitis. We further screened three key NETs-related genes (PTGS2, MME and SLC2A3) and verified that they have the potential to predict periodontitis. Moreover, our findings revealed that gingival fibroblasts had the most interactions with NrNeu and that they might facilitate the production of NETs through the MIF-CD74/CXCR4 axis in periodontitis. CONCLUSION: This study highlights the pathogenic role of NETs in periodontal immunity and elucidates the specific regulatory relationship by which gingival fibroblasts activate NETs, which provides new insights into the clinical diagnosis and treatment of periodontitis.
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Single-cell RNA sequencing reveals the protective role of renal Cx3cr1+ macrophages in cisplatin-induced acute kidney injury.
Acute kidney injury (AKI) is a common and often fatal condition characterized by tubular epithelial cell necrosis and immune cell infiltration. The macrophage (MФ) plays multiple roles in kidney injury and repair after AKI. However, the classification and function of MФ subsets involved in AKI remain poorly understood. In this study, kidney bulk-sequencing showed the injury pattern (day 0 to day 3) to repair pattern (day 4 to day 7) after cisplatin-induced AKI (Cis-AKI). Single-cell RNA sequencing of Cis-AKI mouse kidneys dissected the transcriptome heterogeneity of renal MФs, and depletion and adoptive transfer experiments were used to explore the functional distinction of MФ subsets. The single-cell atlas identified four MФ subsets with distinct transcriptomic profiles (Mo-MФ, Mki67+MФ, Cd74+MФ, Cx3cr1+MФ). The dynamic proportion change of MФ subsets from progression to regression analyses revealed that Mo-MФ, defined as recruit-MФ in this study, was primarily distributed in the progression stage, whereas the other MФ subsets, defined as resident-MФ, were dominant in the non-pathological condition and regression stage. By depletion and adoptive transfer experiments, our results confirmed that the Cx3cr1+MФ subset plays a crucial role in the protection against Cis-AKI. Further cell coculture experiments revealed that the tyrosine-protein kinase receptor UFO (AXL)-growth arrest-specific protein 6 (GAS6) ligand-receptor pair is involved in regulating the efferocytosis of apoptotic renal tubular epithelial cells by Cx3cr1+MФs, representing one of the molecular mechanisms in promoting kidney repair. In conclusion, our study dissected the heterogeneity of renal macrophage subsets during Cis-AKI, and the discovery of the protective Cx3cr1+MФ subset may provide new therapeutic targets for AKI intervention.
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A cell atlas of the larval Aedes aegypti ventral nerve cord.
Mosquito-borne diseases account for nearly 1 million human deaths annually, yet we have a limited understanding of developmental events that influence host-seeking behavior and pathogen transmission in mosquitoes. Mosquito-borne pathogens are transmitted during blood meals, hence adult mosquito behavior and physiology have been intensely studied. However, events during larval development shape adult traits, larvae respond to many of the same sensory cues as adults, and larvae are susceptible to infection by many of the same disease-causing agents as adults. Hence, a better understanding of larval physiology will directly inform our understanding of physiological processes in adults. Here, we use single cell RNA sequencing (scRNA-seq) to provide a comprehensive view of cellular composition in the Aedes aegypti larval ventral nerve cord (VNC), a central hub of sensory inputs and motor outputs which additionally controls multiple aspects of larval physiology. We identify more than 35 VNC cell types defined in part by neurotransmitter and neuropeptide expression. We also explore diversity among monoaminergic and peptidergic neurons that likely control key elements of larval physiology and developmental timing, and identify neuroblasts and immature neurons, providing a view of neuronal differentiation in the VNC. Finally, we find that larval cell composition, number, and position are preserved in the adult abdominal VNC, suggesting studies of larval VNC form and function will likely directly inform our understanding adult mosquito physiology. Altogether, these studies provide a framework for targeted analysis of VNC development and neuronal function in Aedes aegypti larvae.
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Comparative single-cell transcriptional and proteomic atlas of clinical-grade injectable mesenchymal source tissues.
Bone marrow aspirate concentrate (BMAC) and adipose-derived stromal vascular fraction (ADSVF) are the most marketed stem cell therapies to treat a variety of conditions in the general population and elite athletes. Both tissues have been used interchangeably clinically even though their detailed composition, heterogeneity, and mechanisms of action have neither been rigorously inventoried nor compared. This lack of information has prevented investigations into ideal dosages and has facilitated anecdata and misinformation. Here, we analyzed single-cell transcriptomes, proteomes, and flow cytometry profiles from paired clinical-grade BMAC and ADSVF. This comparative transcriptional atlas challenges the prevalent notion that there is one therapeutic cell type present in both tissues. We also provide data of surface markers that may enable isolation and investigation of cell (sub)populations. Furthermore, the proteome atlas highlights intertissue and interpatient heterogeneity of injected proteins with potentially regenerative or immunomodulatory capacities. An interactive webtool is available online.
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A single-cell-resolution spatial transcriptomic atlas decodes wheat spike development and yield potential.
The molecular regulatory mechanisms underlying spike development critically influence wheat (Triticum aestivum) grain yield but remain incompletely understood. Using spatial transcriptomic analysis at single-cell resolution, we comprehensively mapped the spatiotemporal transcriptomes across five key stages of wheat spike development. Our approach enabled the identification and annotation of nine distinct cell types, revealing the spatiotemporal distribution of hormonal and metabolic signaling pathways across multiple cell populations. Notably, we observed variations in biosynthesis and signaling responses among key phytohormones, particularly cytokinin and auxin. We demonstrated that the rachis cell population plays a crucial role in nutrient and energy supply during spike morphogenesis. The pseudotime and RNA velocity analyses revealed cell populations with distinct differentiation states, highlighting the potential influence of spikelet primordium base (SPB) cells on lateral organ development and grain number determination. By integrating single-nucleus RNA sequencing from the W3.5 stage, gene regulatory relationships, and GWAS data from public databases, we constructed a co-expression regulatory network for wheat spike development and identified a key gene module that regulates multiple spike-related traits. Subsequent investigations characterized heterogeneous subpopulations of SPB cells and identified a novel gene cluster that substantially regulates grain number per spike. Based on spatial transcriptomics data, we have developed a publicly accessible online platform that allows users to interactively query and visualize spatiotemporal gene expression patterns during wheat spike development. Collectively, our study provides a comprehensive molecular framework for early spike development in wheat, offering valuable genetic resources and public data for functional genomics research. These data and knowledge may have significant implications for breeding efforts to optimize spike architecture and enhance wheat's grain yield potential.
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Multi-omics integration uncovers key transcriptional regulators in triple-negative breast cancer spatial heterogeneity.
BACKGROUND: Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer characterized by a lack of hormone receptors, making it challenging to treat. METHODS: We generated a comprehensive spatial cell atlas of TNBC using a multi-omics integration approach that combined single-cell RNA sequencing (scRNA-seq) with spatial transcriptomics. This integration allowed us to characterize the spatial microenvironment and map the cell-type-specific distributions in TNBC tissues. RESULTS: Our analysis revealed significant heterogeneity in cell types and spatial distribution, with normal regions enriched in insulin resistance functions, whereas cancerous regions displayed diverse cell populations, including immune cells, cancer-associated fibroblasts (CAFs), and mesenchymal cells. By constructing transcription factor (TF) regulatory networks, we identified TFF3, RARG, GRHL1, RORC, and KLF5 as critical regulators of epithelial cells, whereas EMX2, TWIST1, TWIST2, NFATC4, and HOXC6 were found to play essential roles in mesenchymal cells. Immunohistochemical validation supported the involvement of these TFs in TNBC. Further analysis of receptor-ligand interactions highlighted the roles of KNG1_BDKRB2 and NRG1_ERBB4 signaling in promoting tumor aggression, suggesting potential therapeutic targets. GO enrichment analysis revealed overlapping pathways between epithelial and mesenchymal cells, focusing on migration, signaling, and development, indicating that the shared regulatory mechanisms contribute to cancer progression. CONCLUSION: Our findings provide new insights into the TNBC microenvironment, emphasizing the complex spatial interactions between different cell types and highlighting key regulatory pathways that could be targeted for future therapeutic interventions. This spatial cell atlas lays the foundation for further exploration of tumor microenvironment dynamics and precision oncology approaches.