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Single-cell analysis reveals novel clonally expanded monocytes associated with IL1β-IL1R2 pair in acute inflammatory demyelinating polyneuropathy.
Guillain-Barré syndrome (GBS) is an autoimmune disorder wherein the composition and gene expression patterns of peripheral blood immune cells change significantly. It is triggered by antigens with similar epitopes to Schwann cells that stimulate a maladaptive immune response against peripheral nerves. However, an atlas for peripheral blood immune cells in patients with GBS has not yet been constructed. This is a monocentric, prospective study. We collected 5 acute inflammatory demyelinating polyneuropathy (AIDP) patients and 3 healthy controls hospitalized in the First Affiliated Hospital of Harbin Medical University from December 2020 to May 2021, 3 AIDP patients were in the peak stage and 2 were in the convalescent stage. We performed single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells (PBMCs) from these patients. Furthermore, we performed cell clustering, cell annotation, cell-cell communication, differentially expressed genes (DEGs) identification and pseudotime trajectory analysis. Our study identified a novel clonally expanded CD14+ CD163+ monocyte subtype in the peripheral blood of patients with AIDP, and it was enriched in cellular response to IL1 and chemokine signaling pathways. Furthermore, we observed increased IL1β-IL1R2 cell-cell communication between CD14+ and CD16+ monocytes. In short, by analyzing the single-cell landscape of the PBMCs in patients with AIDP we hope to widen our understanding of the composition of peripheral immune cells in patients with GBS and provide a theoretical basis for future studies.
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Single-cell and spatial atlas of glioblastoma heterogeneity: characterizing the PCLAF+ subtype and YEATS4's oncogenic role.
BACKGROUND: Glioblastoma (GBM) was considered the most aggressive type of primary brain tumor, marked by poor clinical outcomes and a high tendency to relapse. The therapeutic efficacy of GBM was significantly compromised by tumor heterogeneity, dysregulated metabolic pathways, the formation of an immunosuppressive microenvironment, and treatment resistance. Therefore, multi-dimensional therapeutic strategies targeting GBM-specific molecular features, its intrinsic properties, and microenvironmental regulatory networks were considered to potentially provide new breakthroughs for overcoming treatment resistance in GBM. METHODS: We analyzed single-cell RNA sequencing (scRNA-seq) data processed with the Seurat package to accurately identify cell types. Spatial transcriptomics integrated Multimodal Intersection Analysis, TransferData, and Robust Cell Type Decomposition techniques to characterize the spatial distribution patterns of key cell subtypes. CellChat was employed to assess intercellular communication networks. Furthermore, in vitro experiments confirmed the main regulatory role of YEATS4 (key transcription factor of C2 PCLAF+ subtype) in GBM malignant progression. RESULTS: Through scRNA-seq, we identified the C2 PCLAF+ subtype in GBM and analyzed its molecular characteristics and functional role in tumor progression. This subtype exhibited a unique malignant phenotype, marked by significant proliferative activity, characteristic metabolic reprogramming, and dysregulated cell death regulation mechanisms. Spatial transcriptomics revealed its preferential localization within specific tumor niches. Furthermore, the C2 PCLAF+ subtype established a specific interaction with fibroblasts through the MDK-LRP1 ligand-receptor pair. Critically, silencing YEATS4 in vitro significantly inhibited GBM malignancy. Additionally, the prognostic risk score model based on the C2 PCLAF+ subtype demonstrated significant clinical translational value. CONCLUSION: Our study systematically elucidated the malignant characteristics of the C2 PCLAF+ subtype and its molecular mechanisms driving GBM progression. This subtype promoted therapeutic resistance through unique metabolic reprogramming, MDK-LRP1-mediated microenvironmental interactions, and immunosuppressive properties. YEATS4 knockdown effectively suppressed malignant tumor behaviors, highlighting its therapeutic potential. These findings provided novel targeted intervention strategies to address GBM heterogeneity and treatment resistance, offering promising avenues for overcoming current therapeutic limitations.
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Single-cell transcriptomic analysis identifies vascular smooth muscle cell transcriptional programs associated with human carotid plaque remodeling.
BACKGROUND: Vascular smooth muscle cells (VSMCs) contribute to plaque structure and exhibit diverse transcriptional programs in human atherosclerosis. Although human plaque single-cell studies have established substantial VSMC heterogeneity, an important unresolved question is whether discovery-defined programs remain recognizable across independent patients and sequencing platforms without forced integration, and whether those programs retain associations with plaque instability. We therefore focused on program-level reproducibility, inferred regulatory activity, continuous expression organization, and rupture-associated variation. METHODS: We used three public human carotid plaque transcriptomic datasets in nonredundant analytical roles rather than merging all single-cell cohorts into a single atlas. GSE253903, a 10x Genomics single-cell cohort, was used for broad plaque mapping and focused VSMC characterization. SCENIC and transcriptional-continuum analyses were restricted to finalized VSMCs. Discovery signatures and assignment rules were frozen before independent assessment in the Smart-seq2 dataset GSE260657, with uncertain cells permitted to remain unassigned. GSE120521 supported exploratory paired comparison between relatively stable and visibly ruptured plaque regions. RESULTS: Quality control retained 46,209 cells from 12 patients in GSE253903, including 3,784 primary VSMCs after removal of immune-like contaminants. Five descriptive VSMC programs were identified: canonical contractile, extracellular-matrix-associated/fibromyocyte-like, DLX-osteomodulated, stress-responsive, and interferon-associated. VSMC-restricted SCENIC analysis showed higher inferred ATF3, JUND, and CREB5 regulon activity in the stress-responsive program and higher TEAD1, KLF2, and XBP1 activity in the DLX-osteomodulated program. Pseudotime analysis described two transcriptional continua with shared canonical contractile, stress-responsive, and extracellular-matrix-associated organization. In GSE260657, 842 of 1,483 VSMC-enriched cells were confidently projected, while 641 remained unassigned. Six of seven symptomatic-versus-asymptomatic program effects had concordant directions across the single-cell datasets, although no GSE260657 module reached a false-discovery rate below 0.05. In four paired plaques, ruptured regions showed lower contractile scores and higher osteogenic, foam-cell-like, and proliferation scores. qPCR analysis of an independent paired plaque cohort provided orthogonal tissue-level RNA support for selected remodeling-associated gene patterns. CONCLUSION: Human carotid plaque VSMCs display heterogeneous transcriptional programs with program-associated inferred regulon activity and continuous expression organization. An uncertainty-aware, cross-platform assessment supported partial conservation of these programs and linked selected remodeling patterns to plaque instability. This framework is intended to complement, rather than replace, spatial and mechanistic studies by identifying reproducible program-level features that can be prioritized for localization and functional testing.
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Single-cell sequencing combined with urinary multi-omics analysis reveals that the non-invasive biomarker PRDX5 regulates bladder cancer progression through ferroptosis signaling.
OBJECTIVE: This study aimed to elucidate the expression profile and biological implications of peroxidase 5 (PRDX5) in bladder cancer (BC), specifically investigating its influence on BC progression through modulation of reactive oxygen species (ROS) levels and activation of ferroptosis pathways. METHODS: We employed urine proteomics data and transcriptomic information from the Cancer Genome Atlas (TCGA) to identify differentially expressed genes in BC tissues, focusing on PRDX5. Using single-cell RNA sequencing (scRNA-seq), we assessed PRDX5 distribution across various cell types in the tumor microenvironment. We conducted in vitro experiments to analyze the impact of PRDX5 on BC cell proliferation, migration, and invasion, while exploring its mechanisms of modulating ROS levels and ferroptosis. In vivo experiments were performed to observe PRDX5's influence on ferroptosis signaling in tissue contexts. RESULTS: We found significant upregulation of PRDX5 in BC tissues, with scRNA-seq revealing its enrichment in bladder epithelial cells, correlating with disease advancement and established BC markers. In vitro analyses showed that overexpressed PRDX5 enhanced proliferation, migration, and invasion of BC cells, while PRDX5 knockout produced opposing effects. Additionally, PRDX5 modulated ROS levels and impacted ferroptosis pathways. In vivo experiments confirmed that PRDX5 knockout inhibited tumor growth and activated ferroptosis signaling pathways in tissues. CONCLUSION: Our study highlights the elevated expression of PRDX5 in BC and its role in promoting tumor progression through regulation of ROS levels and ferroptosis. PRDX5 may serve as a promising target for BC treatment, supporting further exploration of its potential in clinical applications.
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Beyond polarization: single-cell atlas unveils macrophage heterogeneity and neuro-immune crosstalk in bone regeneration.
Bone regeneration is a complex and carefully orchestrated physiological process of bone formation. Immune cells, especially macrophages, play a key role in MSC recruitment, osteoblast differentiation and osteoclast formation. However, the traditional concept of macrophage polarization is inadequate to match its functional diversity and mechanistic complexity. A comprehensive analysis and definition of macrophage heterogeneity in the bone regeneration niche is urgently needed. We analyzed single-cell RNA-seq (scRNA-seq) data of 8148 cells in the bone defect area using multiple methods and focused on macrophages infiltrating the bone regeneration microenvironment. Based on the corresponding scRNA-seq data, we systematically revealed eight heterogeneous subpopulations of macrophages. These subpopulations function as defense responses (DF-macrophages), fibrosis (FB-macrophages), osteogenesis/regeneration (OB-macrophages), bone resorption (OC-macrophages), and programmed death (PD-macrophages). Among them, the OB- and OC-macrophages has the potential to be regulated by neural signals because of their high frequency of G protein-coupled receptor genes (Gprs). Exogenous nerve growth factor (NGF) supplement effectively activated neural reaction and accelerated bone repair combined with inflammation resolution in vivo. Further bulk RNA-seq analysis provided evidence of significant enhancement of anti-inflammatory, regenerative and bone metabolism related genes and functions in macrophages upon exogenous NGF stimulation. In vitro experiments also confirmed the anti-inflammatory of the macrophage treated by the secretion of the neural cells stimulated by NGF. Our study provides evidence for revealing the functional phenotype of macrophages in the bone regeneration environment and provide evidence for the acceptance of neural regulation.
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Single cell RNA sequencing of 13 human tissues identify cell types and receptors of human coronaviruses.
The new coronavirus (SARS-CoV-2) outbreak from December 2019 in Wuhan, Hubei, China, has been declared a global public health emergency. Angiotensin I converting enzyme 2 (ACE2), is the host receptor by SARS-CoV-2 to infect human cells. Although ACE2 is reported to be expressed in lung, liver, stomach, ileum, kidney and colon, its expressing levels are rather low, especially in the lung. SARS-CoV-2 may use co-receptors/auxiliary proteins as ACE2 partner to facilitate the virus entry. To identify the potential candidates, we explored the single cell gene expression atlas including 119 cell types of 13 human tissues and analyzed the single cell co-expression spectrum of 51 reported RNA virus receptors and 400 other membrane proteins. Consistent with other recent reports, we confirmed that ACE2 was mainly expressed in lung AT2, liver cholangiocyte, colon colonocytes, esophagus keratinocytes, ileum ECs, rectum ECs, stomach epithelial cells, and kidney proximal tubules. Intriguingly, we found that the candidate co-receptors, manifesting the most similar expression patterns with ACE2 across 13 human tissues, are all peptidases, including ANPEP, DPP4 and ENPEP. Among them, ANPEP and DPP4 are the known receptors for human CoVs, suggesting ENPEP as another potential receptor for human CoVs. We also conducted "CellPhoneDB" analysis to understand the cell crosstalk between CoV-targets and their surrounding cells across different tissues. We found that macrophages frequently communicate with the CoVs targets through chemokine and phagocytosis signaling, highlighting the importance of tissue macrophages in immune defense and immune pathogenesis.
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Six Immune Associated Genes Construct Prognostic Model Evaluate Low-Grade Glioma.
BACKGROUND: The immunotherapy of Glioma has always been a research hotspot. Although tumor associated microglia/macrophages (TAMs) proves to be important in glioma progression and drug resistance, our knowledge about how TAMs influence glioma remains unclear. The relationship between glioma and TAMs still needs further study. METHODS: We collected the data of TAMs in glioma from NCBI Gene Expression Omnibus (GEO) that included 20 glioma samples and 15 control samples from four datasets. Six genes were screened from the Differential Expression Gene through Gene ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, protein-protein interaction (PPI) network and single-cell sequencing analysis. A risk score was then constructed based on the six genes and patients' overall survival rates of 669 patients from The Cancer Genome Atlas (TCGA). The efficacy of the risk score in prognosis and prediction was verified in Chinese Glioma Genome Atlas (CGGA). RESULTS: Six genes, including CD163, FPR3, LPAR5, P2ry12, PLAUR, SIGLEC1, that participate in signal transduction and plasma membrane were selected. Half of them, like CD163, FPR3, SIGLEC1, were mainly expression in M2 macrophages. FPR3 and SIGLEC1 were high expression genes in glioma associated with grades and IDH status. The overall survival rates of the high risk score group was significantly lower than that of the low risk score group, especially in LGG. CONCLUSION: Joint usage of the 6 candidate genes may be an effective method to diagnose and evaluate the prognosis of glioma, especially in Low-grade glioma (LGG).
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A single-cell survey of cellular hierarchy in acute myeloid leukemia.
BACKGROUND: Acute myeloid leukemia (AML) is a fatal hematopoietic malignancy and has a prognosis that varies with its genetic complexity. However, there has been no appropriate integrative analysis on the hierarchy of different AML subtypes. METHODS: Using Microwell-seq, a high-throughput single-cell mRNA sequencing platform, we analyzed the cellular hierarchy of bone marrow samples from 40 patients and 3 healthy donors. We also used single-cell single-molecule real-time (SMRT) sequencing to investigate the clonal heterogeneity of AML cells. RESULTS: From the integrative analysis of 191727 AML cells, we established a single-cell AML landscape and identified an AML progenitor cell cluster with novel AML markers. Patients with ribosomal protein high progenitor cells had a low remission rate. We deduced two types of AML with diverse clinical outcomes. We traced mitochondrial mutations in the AML landscape by combining Microwell-seq with SMRT sequencing. We propose the existence of a phenotypic "cancer attractor" that might help to define a common phenotype for AML progenitor cells. Finally, we explored the potential drug targets by making comparisons between the AML landscape and the Human Cell Landscape. CONCLUSIONS: We identified a key AML progenitor cell cluster. A high ribosomal protein gene level indicates the poor prognosis. We deduced two types of AML and explored the potential drug targets. Our results suggest the existence of a cancer attractor.
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Cellular diversity of the developing chick trigeminal ganglion at single-cell resolution.
BACKGROUND: The trigeminal ganglion (TG) integrates sensory input from the face and jaw and is derived from two embryonic cell populations: neural crest and cranial placode. These populations interact during TG development to coordinate specification, differentiation, and organization, but the molecular characteristics of the heterogeneous cell populations within the developing TG remain poorly defined. RESULTS: We performed single-cell RNA-sequencing (scRNA-seq) of chick TG at HH17, generating a high-resolution dataset of ~87,000 cells representing diverse neuronal and non-neuronal populations. Subclustering and RNA velocity analysis of Isl1+ neuroblasts resolved distinct developmental trajectories associated with neural crest- and cranial placode-derived populations converging toward neuronal differentiation. A Sox10+ neural crest-associated population progressively acquired neuronal characteristics, while a distinct placode-associated trajectory exhibited loss of epithelial gene expression during neuronal maturation. We additionally identified lineage-enriched long non-coding RNAs (lncRNAs), including MIR137HG, which was strongly enriched in Isl1+ neuroblasts and spatially validated across TG development. CONCLUSIONS: Our study provides a single-cell atlas of the developing chick TG that resolves transcriptional heterogeneity and developmental states within its neural crest- and placode-derived populations. These data identify candidate molecular signatures associated with sensory neuronal differentiation and provide a resource for investigating the mechanisms governing trigeminal gangliogenesis.
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Dysregulated arginine metabolism is associated with pro-tumor neutrophil polarization in liver cancer.
BACKGROUND: Liver hepatocellular carcinoma (LIHC) is a leading cause of cancer-related mortality, with an immunosuppressive tumor microenvironment (TME) contributing to therapeutic resistance. Although neutrophils are recognized as key regulators of LIHC progression, their functional heterogeneity and metabolic drivers are not yet fully understood. METHODS: We integrated bulk RNA sequencing (RNA-seq) data from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) database (GSE39791) alongside scRNA-seq data from GSE149614 and GSE290925. Neutrophils were annotated based on specific marker genes (FCGR3B, CSF3R) and classified into three metabolic states: high arginine state (HAS), intermediate arginine state (DTAS), and low arginine state (LAS) using arginine metabolism-related gene sets. Differentiation trajectories were reconstructed via CytoTRACE and monocle2. Intercellular communication was analyzed using CellChat, while machine learning, incorporating seven different algorithms, was applied to identify key regulatory genes. RESULTS: scRNA-seq analysis revealed three distinct neutrophil subgroups: high (HAS), intermediate (DTAS), and low (LAS) arginine metabolism states. The proportion of LAS neutrophils was significantly enriched in tumor tissues compared to normal tissues (p < 0.001). Trajectory analysis indicated that LAS neutrophils exhibited a less differentiated state. From this landscape, ATP11B and PADI4 were identified as key genes, with PADI4 expression being approximately 3-fold higher in HAS compared to LAS neutrophils. Functional studies demonstrated that silencing PADI4 in LIHC cell lines inhibited cell proliferation by approximately 50% at 96 hours, increased apoptosis by 2-fold, and reduced cell invasion by 50%. CONCLUSIONS: Arginine metabolism shapes neutrophil polarization in the LIHC TME. Targeting metabolic pathways may provide new therapeutic strategies to modulate the immune landscape and improve patient outcomes.