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A single-nucleus and spatial transcriptomic atlas of the COVID-19 liver reveals topological, functional, and regenerative organ disruption in patients.
The molecular underpinnings of organ dysfunction in acute COVID-19 and its potential long-term sequelae are under intense investigation. To shed light on these in the context of liver function, we performed single-nucleus RNA-seq and spatial transcriptomic profiling of livers from 17 COVID-19 decedents. We identified hepatocytes positive for SARS-CoV-2 RNA with an expression phenotype resembling infected lung epithelial cells. Integrated analysis and comparisons with healthy controls revealed extensive changes in the cellular composition and expression states in COVID-19 liver, reflecting hepatocellular injury, ductular reaction, pathologic vascular expansion, and fibrogenesis. We also observed Kupffer cell proliferation and erythrocyte progenitors for the first time in a human liver single-cell atlas, resembling similar responses in liver injury in mice and in sepsis, respectively. Despite the absence of a clinical acute liver injury phenotype, endothelial cell composition was dramatically impacted in COVID-19, concomitantly with extensive alterations and profibrogenic activation of reactive cholangiocytes and mesenchymal cells. Our atlas provides novel insights into liver physiology and pathology in COVID-19 and forms a foundational resource for its investigation and understanding.
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A single-cell perspective on polyethylene microplastic toxicity: linking fibroblast reprogramming to immune microenvironment alterations in the lung.
BACKGROUND: Microplastics represent ubiquitous and persistent environmental contaminants, with growing evidence of their accumulation in human tissues including the lung. Chronic pulmonary exposure has been associated with tissue damage, fibrotic remodeling, and immune dysregulation; however, a systematic understanding of the underlying multicellular dynamics and transcriptional alterations remains limited. Polyethylene is a dominant component of airborne microplastics, yet its specific pathogenic mechanisms in the lung are poorly characterized. METHODS: We developed a rat model of chronic intranasal exposure to polyethylene microplastics (PE-MPs). Lung tissues from exposed and control animals were analyzed by histopathology and subjected to high-throughput single-cell RNA sequencing (scRNA-seq). Computational pipelines were employed to construct a comprehensive cellular atlas, characterize transcriptomic alterations, infer cellular communication, and map transcription factor regulatory networks. Cell populations were annotated based on canonical markers, and differential analyses compared PE-MPs-exposed and control groups. RESULTS: Histological analysis revealed enhanced collagen deposition and perivascular lymphocyte infiltration in PE-MPs-exposed lungs. scRNA-seq profiling of 25,625 cells delineated a remodeled cellular landscape, marked by expansion of fibroblasts and myofibroblasts alongside increased proportions of T cells, B cells, and dendritic cells, coupled with a contraction of specific epithelial and endothelial subsets. Fibroblasts exhibited an activated phenotype characterized by upregulation of extracellular matrix genes and inferred hyperactivation of TGF-β pathway transducers Smad3 and Smad4. Epithelial dysfunction was evident across populations: club cells displayed altered differentiation potential, ciliated cells showed impaired ciliogenesis, and alveolar type II cells downregulated surfactant homeostasis genes. Myeloid immune cells upregulated chemokines (Cxcl9, Cxcl10, Ccl3, Ccl4) and MHC molecules, indicating enhanced antigen-presenting capacity and chemotactic activity. Notably, Tgfb1 expression was significantly elevated in plasmacytoid dendritic cells, monocytes, macrophages, and NK/NKT cells. Ligand-receptor interaction analysis predicted heightened TGF-β1 signaling to fibroblasts and increased chemokine-mediated recruitment of immune cells, particularly plasmacytoid dendritic cells. CD123, TGF‑β1, and p‑Smad3 immunoreactivities co‑localized with Masson's trichrome‑stained collagen deposits in the perivascular spaces of small pulmonary arteries. CONCLUSION: This study provides a high-resolution single-cell transcriptomic atlas delineating the pulmonary response to chronic PE-MPs exposure. We identify a coordinated pathogenic network involving epithelial/endothelial dysfunction, immune microenvironment imbalance, and fibroblast activation via paracrine TGF-β signaling as central mechanisms driving microplastic-induced lung injury. These findings elucidate novel cellular and molecular pathways linking environmental plastic exposure to pulmonary fibrosis and immune dysregulation, offering potential targets for therapeutic intervention.
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Disturbed Flow Induces Reprogramming of Endothelial Cells to Immune-like and Foam Cells under Hypercholesterolemia during Atherogenesis.
BACKGROUND: Atherosclerosis occurs preferentially in the arteries exposed to disturbed flow (d-flow), while the stable flow (s-flow) regions are protected even under hypercholesterolemic conditions. We recently showed that d-flow alone initiates flow-induced reprogramming of endothelial cells (FIRE), including the novel concept of partial endothelial-to-immune-cell-like transition (partial EndIT), but was not validated using a genetic lineage-tracing model. Here, we tested and validated the two-hit hypothesis that d-flow is an initial instigator of partial FIRE but requires hypercholesterolemia to induce a full-blown FIRE and atherosclerotic plaque development. METHODS: Mice were treated with adeno-associated virus expressing proprotein convertase subtilisin/kexin type 9 and a Western diet to induce hypercholesterolemia and/or partial carotid ligation (PCL) surgery to expose the left common carotid artery (LCA) to d-flow. Single-cell RNA sequencing (scRNA-seq) analysis was performed using cells obtained from the intima and leftover LCAs and the control right common carotid arteries at 2 and 4 weeks post-PCL. Comprehensive immunohistochemical staining was performed on EC-specific confetti mice treated with PCL and hypercholesterolemic conditions at 4 weeks post-PCL to validate endothelial reprogramming. RESULTS: Atherosclerotic plaques developed by d-flow under hypercholesterolemia at 2 and 4 weeks post-PCL, but not by d-flow or hypercholesterolemia alone, as expected. The scRNA-seq results of 98,553 single cells from 95 mice revealed 25 cell clusters; 5 EC, 3 vascular smooth muscle cell (SMC), 5 macrophage (MΦ), and additional fibroblast, T cell, natural killer cell, dendritic cell, neutrophil, and B cell clusters. Our scRNA-seq analyses showed that d-flow under hypercholesterolemia transitioned healthy ECs to full immune-like (EndIT) and, more surprisingly, foam cells (EndFT), in addition to inflammatory and mesenchymal cells (EndMT). Further, EC-derived foam cells shared remarkably similar transcriptomic profiles with foam cells derived from SMCs and MΦs. Comprehensive lineage-tracing studies using immunohistochemical staining of canonical protein and lipid markers in the EC-specific confetti mice clearly demonstrated direct evidence supporting the novel FIRE hypothesis, including EndIT and EndFT, when d-flow was combined with hypercholesterolemia. Further, reanalysis of the publicly available human carotid plaque scRNA-seq and Perturb-seq datasets supported the FIRE hypothesis and a potential mechanistic link between the genes and FIRE. CONCLUSION: We provide evidence supporting the two-hit hypothesis: ECs in d-flow regions, such as the branching points, are partially reprogrammed, while hypercholesterolemia alone has minimal endothelial reprogramming effects. Under hypercholesterolemia, d-flow fully reprograms arterial ECs, including the novel EndIT and EndFT, in addition to inflammation and EndMT, during atherogenesis. This single-cell atlas provides a crucial roadmap for developing novel mechanistic understanding and therapeutics targeting flow-sensitive genes, proteins, and pathways of atherosclerosis.
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A single-cell time-series atlas of endothelial cell embryonic development.
Endothelial cells (ECs) are essential components of the vertebrate circulatory system; however, a comprehensive atlas characterizing how ECs acquire organ-specific transcriptomic heterogeneity has not been established. Here, we generated a time-series endothelial resource covering the entirety of mouse embryonic development, including 26 time points and 8 organs. Time-series multi-organ comparison revealed emergence timing and lineage trajectory of organotypic ECs together with organ-specific genes and pathways. Using these resources, we found that most ECs showed distinguishable organ specificity before late gestation. The organotypic EC-enriched genes were associated with vascular function in the organs. Human and mouse pulmonary ECs underwent an evolutionarily conserved transcriptional transition. Endothelial-specific knockout of Casz1, a pulmonary EC-enriched transcription factor, resulted in impaired vascular growth, disturbed pulmonary endothelial organotypic differentiation, and deficient epithelial-EC crosstalk. Our work provides a powerful endothelial resource that reveals fundamental principles of organ-specific EC differentiation and uncovers previously unknown molecular mechanisms governing lung-specific vascular development.
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Transcriptome analysis combined with single-cell analysis identified that APOC1 influences cholesterol transport by macrophages in ccRCC.
Renal cell carcinoma (RCC) is one of the most prevalent categories of cancer worldwide, accounting for approximately 2% of cancer diagnoses and cancer deaths worldwide. various immunotherapeutic strategies have emerged as key approaches to managing advanced RCC. Bioinformatics methodologies were employed to analyze the TCGA-KIRC RNA sequencing dataset, GSE105261, GSE168845, and single-cell dataset GSE121636. Various techniques, including PCR, Western blotting, migration assays, scratch wound assays, flow cytometry, and immunofluorescence staining, were utilized to elucidate the functional characteristics of the tumor. In this study, we obtained transcriptome RNA sequencing data from the Cancer Genome Atlas (TCGA) database. Using the ESTIMATE algorithm, 249 immune-related genes were identified. Additionally, single-cell RNA sequencing data were integrated to determine the immune-related genes that affect the prognosis of clear cell renal cell carcinoma (ccRCC). Eventually, a total of 42 immune-related genes (IMDGs) were identified. Subsequently, in vitro experiments confirmed that APOC1 is highly expressed in ccRCC and significantly affects the migration and proliferation of ccRCC cells. Furthermore, our findings indicate that APOC1 plays a critical role in modulating cholesterol transport within macrophages and significantly contributes to the polarization of macrophages toward the M2 phenotype.
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An MRI radiomics approach to predict survival and tumour-infiltrating macrophages in gliomas.
Preoperative MRI is one of the most important clinical results for the diagnosis and treatment of glioma patients. The objective of this study was to construct a stable and validatable preoperative T2-weighted MRI-based radiomics model for predicting the survival of gliomas. A total of 652 glioma patients across three independent cohorts were covered in this study including their preoperative T2-weighted MRI images, RNA-seq and clinical data. Radiomic features (1731) were extracted from preoperative T2-weighted MRI images of 167 gliomas (discovery cohort) collected from Beijing Tiantan Hospital and then used to develop a radiomics prediction model through a machine learning-based method. The performance of the radiomics prediction model was validated in two independent cohorts including 261 gliomas from the The Cancer Genomae Atlas database (external validation cohort) and 224 gliomas collected in the prospective study from Beijing Tiantan Hospital (prospective validation cohort). RNA-seq data of gliomas from discovery and external validation cohorts were applied to establish the relationship between biological function and the key radiomics features, which were further validated by single-cell sequencing and immunohistochemical staining. The 14 radiomic features-based prediction model was constructed from preoperative T2-weighted MRI images in the discovery cohort, and showed highly robust predictive power for overall survival of gliomas in external and prospective validation cohorts. The radiomic features in the prediction model were associated with immune response, especially tumour macrophage infiltration. The preoperative T2-weighted MRI radiomics prediction model can stably predict the survival of glioma patients and assist in preoperatively assessing the extent of macrophage infiltration in glioma tumours.
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Single-cell RNA sequencing uncovers cellular heterogeneity and the progression of heterotopic ossification of the elbow.
Heterotopic ossification of the elbow (HOE) is a complicated pathologic process characterized by extra bone formation in the elbow. Bone formation is a complex developmental process involving the differentiation of mesenchymal stem cells into osteoblasts. The aim of this study was to explore the cellular origin and progression of HOE by single-cell RNA sequencing. We identified 13 clusters of cells in HOE and further analyzed the subclusters for 4 of the main cell types. Six subclusters of osteoblasts, nine subclusters of chondrocytes, six subclusters of fibroblasts, and five subclusters of mononuclear phagocytes (MPs) were identified and analyzed. The new findings on osterix (OSX) and SOX9 expression in osteoblast subclusters and chondrocyte subclusters indicate that HOE is mediated through endochondral ossification. Further identification of the corresponding signature gene sets of distinct subclusters indicated that subclusters of osteoblasts_3, osteoblasts_4, osteoblasts_5, and osteoblasts_6 are relatively more mature during the osteoblastic progression of HOE. The trajectory analysis of the osteoblasts demonstrated that some genes were gradually downregulated, such as CRYAB, CCL3, SFRP4, WIF1, and IGFBP3, while other critical genes were upregulated, such as VCAN, IGFBP4, FSTL1, POSTN, MDK, THBS2, and ALPL, suggesting that these factors may participate in HOE progression. Cell-cell communication networks revealed extensive molecular interactions among the 13 HOE clusters. Ligand-receptor pairs for IL6, COL24A1, COL22A1, VWF, FZD6, FGF2, and NOTCH1 were identified, suggesting that multiple signaling pathways may be involved in HOE. In conclusion, this study provided the cellular atlas for HOE. We have established a greater extent of the heterogeneity of HOE cells than previously known through transcriptomic analysis at the single-cell level. We have observed gradual patterns of signature gene expression during the differentiation and maturation progression of osteoblasts from stem cells in HOE with higher resolution. The cell heterogeneity of HOE deserves further investigation to pave the way for identification of potential targets for HOE early diagnosis and therapeutic treatment.
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An Analysis Regarding the Association Between Connexins and Colorectal Cancer (CRC) Tumor Microenvironment.
BACKGROUND: Gap junctions, as one of the major ways to maintain social connections between cells, are now considered as one of the potential regulators of tumor metastasis. However, to date, studies on the relationship between gap junctions and colorectal cancer (CRC) are limited. METHODS: We synthesized connexins-coding gene expression data from public Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases. Bioinformatics analysis was performed using R software and several database resources such as MEXPRESS database, Gene Set Cancer Analysis (GSCA) database, Human Protein Atlas (HPA) database, Tumor Immune Single Cell Hub (TISCH) database, Search Tool for Retrieval of Gene Interaction Relationships (STRING), and Cytoscape software, etc., to investigate the biological mechanisms that may be involved in connexins. Immunofluorescence and immunohistochemical staining were used to validate the expression and localization of GJA4. RESULTS: We found that CRC patients can be divided into two connexin clusters and that patients in cluster C1 had shorter survival than in cluster C2. The infiltration of M1 macrophages and NK cells was lower in cluster C1, while the levels of M2 macrophages and immune checkpoints were higher, indicating an immunosuppressed state in cluster C1. In addition, the epithelial-mesenchymal transition (EMT) phenotype was significantly activated in cluster C1. We observed that GJA4 was up-regulated in colorectal cancer tissues, which was related to poor prognosis. It was mainly expressed in fibroblasts, but the expression levels in normal intestinal epithelial cells were low. Finally, we found that GJA4 was associated with M2 macrophages and may be a potential immunosuppressive factor. CONCLUSION: We found that there is a significant correlation between abnormal connexins expression and patients' prognosis, and connexins play an important role in stromal-tumor interactions. Connexins, especially GJA4, can help enhance our understanding of tumor microenvironment (TME) and may guide more effective immunotherapeutic strategies.
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Single-Cell Transcriptomic Profiling Identifies Molecular Phenotypes of Newborn Human Lung Cells.
While animal model studies have extensively defined the mechanisms controlling cell diversity in the developing mammalian lung, there exists a significant knowledge gap with regards to late-stage human lung development. The NHLBI Molecular Atlas of Lung Development Program (LungMAP) seeks to fill this gap by creating a structural, cellular and molecular atlas of the human and mouse lung. Transcriptomic profiling at the single-cell level created a cellular atlas of newborn human lungs. Frozen single-cell isolates obtained from two newborn human lungs from the LungMAP Human Tissue Core Biorepository, were captured, and library preparation was completed on the Chromium 10X system. Data was analyzed in Seurat, and cellular annotation was performed using the ToppGene functional analysis tool. Transcriptional interrogation of 5500 newborn human lung cells identified distinct clusters representing multiple populations of epithelial, endothelial, fibroblasts, pericytes, smooth muscle, immune cells and their gene signatures. Computational integration of data from newborn human cells and with 32,000 cells from postnatal days 1 through 10 mouse lungs generated by the LungMAP Cincinnati Research Center facilitated the identification of distinct cellular lineages among all the major cell types. Integration of the newborn human and mouse cellular transcriptomes also demonstrated cell type-specific differences in maturation states of newborn human lung cells. Specifically, newborn human lung matrix fibroblasts could be separated into those representative of younger cells (n = 393), or older cells (n = 158). Cells with each molecular profile were spatially resolved within newborn human lung tissue. This is the first comprehensive molecular map of the cellular landscape of neonatal human lung, including biomarkers for cells at distinct states of maturity.
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Single-nucleus transcriptomic atlas of sexually dimorphic molecular responses to sub-chronic variable stress in the mouse hippocampus.
BACKGROUND: Major depressive disorder (MDD) exhibits a higher prevalence in women, yet the underlying cellular mechanisms for this clinical disparity remain elusive. To investigate sex-specific molecular mechanisms, we profiled sex-specific molecular responses to sub-chronic stress in the mouse hippocampus at single-nucleus resolution. METHODS: Male and female C57BL/6N mice were exposed to sub-chronic variable stress (SCVS). Anhedonia was assessed via sucrose preference and novelty-suppressed feeding. We employed single-nucleus RNA sequencing (snRNA-seq) to map sex-specific hippocampal responses to sub-chronic variable stress (SCVS) in mice. RESULTS: Female mice displayed significantly exacerbated anhedonia and selective depletion of plasma serotonin (5-HT) following SCVS exposure, contrasting with minimal behavioral changes in males. Single-nucleus RNA sequencing of 31,256 hippocampal cells revealed profound sex-dimorphic transcriptional reprogramming: females exhibited a 3-fold greater number of differentially expressed genes (DEGs) than males with minimal overlap. Key mechanistic findings included: (1) Females exhibited oligodendrocyte-specific upregulation of mitochondrial genes (mt-Atp6, mt-Co3), increasing oxidative stress susceptibility. Concurrently, stress depleted their baseline oligodendrocyte predominance, potentially disrupting hippocampal synchrony underlying anhedonia.; (2) Females exhibit broad Mef2c upregulation, while males show astrocyte/cholinergic neuron NRG-1 upregulation and astrocyte Slc6a11 downregulation; (3) Females display suppressed oxytocin signaling and coordinated dampening of glutamatergic signaling, astrocytic K⁺ buffering, and cell adhesion; males exhibit dysregulated kinase/phosphatase activity. CONCLUSION: This study presents the single-nucleus atlas of hippocampal sexual dimorphism in stress response, identifying oligodendrocyte mitochondrial dysfunction, pan-cellular Mef2c upregulation, and oxytocin suppression as potential female-specific therapeutic targets for depression. Our findings reveal fundamental sex-divergent molecular adaptations to stress, providing a roadmap for novel, sex-stratified treatments for MDD.