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A Cellular atlas of the human fallopian tube reveals the metamorphosis of secretory epithelial cells during the menstrual cycle and menopause.
UNLABELLED: The fallopian tube, connecting the uterus with the ovary, is a dynamic organ that undergoes cyclical changes and is the site of several diseases, including serous cancer. Here, we use single-cell technologies to construct a comprehensive cell map of healthy pre-menopausal fallopian tubes, capturing the impact of the menstrual cycle and menopause on different fallopian tube cells at the molecular level. The comparative analysis between pre- and post-menopausal fallopian tubes reveals substantial shifts in cellular abundance and gene expression patterns, highlighting the physiological changes associated with menopause. Further investigations into menstrual cycle phases illuminate distinct molecular states in secretory epithelial cells caused by hormonal fluctuations. The markers we identified characterizing secretory epithelial cells provide a valuable tool for classifying ovarian cancer subtypes. GRAPHICAL SUMMARY: Graphical summary of results. During the proliferative phase (estrogen high ) of the menstrual cycle, SE2 cells (OVGP1 + ) dominate the fallopian tube (FT) epithelium, while SE1 cells (OVGP1 - ) dominate the epithelium during the secretory phase. Though estrogen levels decrease during menopause, SE post-cells (OVGP1 + , CXCL2 + ) make up most of the FT epithelium.
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A prenatal skin atlas reveals immune regulation of human skin morphogenesis.
Human prenatal skin is populated by innate immune cells, including macrophages, but whether they act solely in immunity or have additional functions in morphogenesis is unclear. Here we assembled a comprehensive multi-omics reference atlas of prenatal human skin (7-17 post-conception weeks), combining single-cell and spatial transcriptomics data, to characterize the microanatomical tissue niches of the skin. This atlas revealed that crosstalk between non-immune and immune cells underpins the formation of hair follicles, is implicated in scarless wound healing and is crucial for skin angiogenesis. We systematically compared a hair-bearing skin organoid (SkO) model derived from human embryonic stem cells and induced pluripotent stem cells to prenatal and adult skin1. The SkO model closely recapitulated in vivo skin epidermal and dermal cell types during hair follicle development and expression of genes implicated in the pathogenesis of genetic hair and skin disorders. However, the SkO model lacked immune cells and had markedly reduced endothelial cell heterogeneity and quantity. Our in vivo prenatal skin cell atlas indicated that macrophages and macrophage-derived growth factors have a role in driving endothelial development. Indeed, vascular network remodelling was enhanced following transfer of autologous macrophages derived from induced pluripotent stem cells into SkO cultures. Innate immune cells are therefore key players in skin morphogenesis beyond their conventional role in immunity, a function they achieve through crosstalk with non-immune cells.
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Mapping gene activity of Arabidopsis root hairs.
BACKGROUND: Quantitative information on gene activity at single cell-type resolution is essential for the understanding of how cells work and interact. Root hairs, or trichoblasts, tubular-shaped outgrowths of specialized cells in the epidermis, represent an ideal model for cell fate acquisition and differentiation in plants. RESULTS: Here, we provide an atlas of gene and protein expression in Arabidopsis root hair cells, generated by paired-end RNA sequencing and LC/MS-MS analysis of protoplasts from plants containing a pEXP7-GFP reporter construct. In total, transcripts of 23,034 genes were detected in root hairs. High-resolution proteome analysis led to the reliable identification of 2,447 proteins, 129 of which were differentially expressed between root hairs and non-root hair tissue. Dissection of pre-mRNA splicing patterns showed that all types of alternative splicing were cell type-dependent, and less complex in EXP7-expressing cells when compared to non-root hair cells. Intron retention was repressed in several transcripts functionally related to root hair morphogenesis, indicative of a cell type-specific control of gene expression by alternative splicing of pre-mRNA. Concordance between mRNA and protein expression was generally high, but in many cases mRNA expression was not predictive for protein abundance. CONCLUSIONS: The integrated analysis shows that gene activity in root hairs is dictated by orchestrated, multilayered regulatory mechanisms that allow for a cell type-specific composition of functional components.
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Single-cell transcriptomic atlas reveals distinct immunological responses between COVID-19 vaccine and natural SARS-CoV-2 infection.
To control the ongoing coronavirus disease-2019 (COVID-19) pandemic, CoronaVac (Sinovac), an inactivated vaccine, has been granted emergency use authorization by many countries. However, the underlying mechanisms of the inactivated COVID-19 vaccine-induced immune response remain unclear, and little is known about its features compared to (Severe acute respiratory syndrome coronavirus 2) SARS-CoV-2 infection. Here, we implemented single-cell RNA sequencing (scRNA-seq) to profile longitudinally collected PBMCs (peripheral blood mononuclear cells) in six individuals immunized with CoronaVac and compared these to the profiles of COVID-19 infected patients from a Single Cell Consortium. Both inactivated vaccines and SARS-CoV-2 infection altered the proportion of different immune cell types, caused B cell activation and differentiation, and induced the expression of genes associated with antibody production in the plasma. The inactivated vaccine and SARS-COV-2 infection also caused alterations in peripheral immune activity such as interferon response, inflammatory cytokine expression, innate immune cell apoptosis and migration, effector T cell exhaustion and cytotoxicity, however, the magnitude of change was greater in COVID-19 patients, especially those with severe disease, than in immunized individuals. Further analyses revealed a distinct peripheral immune cell phenotype associated with CoronaVac immunization (HLA class II upregulation and IL21R upregulation in naïve B cells) versus SARS-CoV-2 infection (HLA class II downregulation and IL21R downregulation in naïve B cells from severe disease individuals). There were also differences in the expression of important genes associated with proinflammatory cytokines and thrombosis. In conclusion, this study provides a single-cell atlas of the systemic immune response to CoronaVac immunization and revealed distinct immune responses between inactivated vaccines and SARS-CoV-2 infection.
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Multi-omic profiling of follicular lymphoma reveals changes in tissue architecture and enhanced stromal remodeling in high-risk patients.
Follicular lymphoma (FL) is a generally incurable malignancy that evolves from developmentally blocked germinal center (GC) B cells. To promote survival and immune escape, tumor B cells undergo significant genetic changes and extensively remodel the lymphoid microenvironment. Dynamic interactions between tumor B cells and the tumor microenvironment (TME) are hypothesized to contribute to the broad spectrum of clinical behaviors observed among FL patients. Despite the urgent need, existing clinical tools do not reliably predict disease behavior. Using a multi-modal strategy, we examined cell-intrinsic and -extrinsic factors governing progression and therapeutic outcomes in FL patients enrolled onto a prospective clinical trial. By leveraging the strengths of each platform, we identify several tumor-specific features and microenvironmental patterns enriched in individuals who experience early relapse, the most high-risk FL patients. These features include stromal desmoplasia and changes to the follicular growth pattern present 20 months before first progression and first relapse.
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Adrenomedullin orchestrates treatment resistance in hepatocellular carcinoma via immune microenvironment remodeling.
BACKGROUND: Hepatocellular carcinoma (HCC) displays marked cellular heterogeneity and immune microenvironment complexity that fundamentally influence transcatheter arterial chemoembolization (TACE) treatment responses and patient outcomes. Deciphering the molecular architecture underlying therapy resistance remains essential for advancing precision oncology in HCC management. METHODS: We integrated four single-cell RNA sequencing cohorts with bulk transcriptomic datasets and longitudinal clinical annotations from The Cancer Genome Atlas Liver Hepatocellular Carcinoma database and Gene Expression Omnibus repositories to perform multidimensional analyses. Computational frameworks including single-cell Phenotype Associated Score (scPAS), high-dimensional weighted gene co-expression network analysis (hdWGCNA), and Single-Cell Regulatory Network Inference and Clustering (SCENIC) were deployed to identify resistance-linked cellular subpopulations and pivotal regulatory modules. Functional validation employed adrenomedullin (ADM)-depleted Huh7 cellular models and xenograft tumor-bearing mouse systems, with mechanistic interrogation via Western immunoblotting, quantitative reverse transcription polymerase chain reaction, and Kaplan-Meier survival estimation to confirm ADM biological functions and clinical relevance. RESULTS: We identified a TACE-resistant malignant cell subset (scPAS+) characterized by pronounced activation of glycolytic, hypoxic, and epithelial-mesenchymal transition pathways alongside overexpression of resistance-conferring genes including LINC00221, hexokinase 2, and alpha-fetoprotein. This cellular phenotype demonstrated robust associations with TACE non-responsiveness, sorafenib cross-resistance, and abbreviated patient survival. Patient stratification based on scPAS + signature genes delineated two distinct molecular subgroups: the scPAS + -enriched cohort exhibited marked TACE refractoriness, elevated sorafenib failure rates, immunosuppressive microenvironmental architecture, and diminished 5-year survival probability. Mechanistic investigations established ADM as a critical driver orchestrating this resistance phenotype. ADM depletion attenuated Huh7 cell proliferative capacity, migratory potential, and invasive behavior, reduced xenograft tumor burden in murine models, and substantially potentiated sorafenib antitumor efficacy. CONCLUSION: This study delineates an ADM-driven TACE-resistant HCC cellular subtype (scPAS+) that functions simultaneously as a prognostic biomarker and actionable therapeutic target for circumventing treatment resistance.
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Cellular and Molecular Atlas of Peripheral Blood Mononuclear Cells from a Pregnant Woman After Recovery from COVID-19.
OBJECTIVE: This study aimed to investigate the immune response of a pregnant woman who recovered from the coronavirus disease 2019 (COVID_RS) by using single-cell transcriptomic profiling of peripheral blood mononuclear cells (PBMCs) and to analyze the properties of different immune cell subsets. METHODS: PBMCs were collected from the COVID_RS patient at 28 weeks of gestation, before a cesarean section. The PBMCs were then analyzed using single-cell RNA sequencing. The transcriptional profiles of myeloid, T, and natural killer (NK) cell subsets were systematically analyzed and compared with those of healthy pregnant controls from a published single-cell RNA sequencing data set. RESULTS: We identified major cell types such as T cells, B cells, NK cells, and myeloid cells in the PBMCs of our COVID_RS patient. The increase of myeloid and B cells and decrease of T cells and NK cells in the PBMCs in this patient were quite distinct compared with that in the control subjects. After reclustering and Augur analysis, we found that CD16 monocytes and mucosal-associated invariant T (MAIT) cells were mostly affected within different myeloid, T, and NK cell subtypes in our COVID_RS patient. The proportion of CD16 monocytes in the total myeloid population was increased, and the frequency of MAIT cells in the total T and NK cells was significantly decreased in the COVID-RS patient. We also observed significant enrichment of gene sets related to antigen processing and presentation, T-cell activation, T-cell differentiation, and tumor necrosis factor superfamily cytokine production in CD16 monocytes, and enrichment of gene sets related to antigen processing and presentation, response to type II interferon, and response to virus in MAIT cells. CONCLUSION: Our study provides a single-cell resolution atlas of the immune gene expression patterns in PBMCs from a COVID_RS patient. Our findings suggest that CD16-positive monocytes and MAIT cells likely play crucial roles in the maternal immune response against severe acute respiratory syndrome coronavirus 2 infection. These results contribute to a better understanding of the maternal immune response to severe acute respiratory syndrome coronavirus 2 infection and may have implications for the development of effective treatments and preventive strategies for the coronavirus disease 2019 in pregnant women.
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Comprehensive analysis to identify PUS7 as a prognostic biomarker from pan-cancer analysis to osteosarcoma validation.
AIM: Pseudouridylation has demonstrated the potential to control the development of numerous malignancies. PUS7(Pseudouridine Synthase 7) is one of the pseudouridine synthases, but the literature on this enzyme is limited to several cancer types. Currently, no investigation has been performed on the systematic pan-cancer analysis concerning PUS7 role in cancer diagnosis and prognosis. METHODS: Employing public databases, including The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression Project (GTEx), Human Protein Atlas (HPA), UALCAN and Tumor Immune Single-cell Hub (TISCH), this work investigated the PUS7 carcinogenesis in pan-cancer. Differential expression analysis, prognostic survival analysis and biological function were systematically performed. Furthermore, PUS7 potential as an osteosarcoma biomarker for diagnosis and prognosis was assessed in this study. RESULTS: The findings indicated that PUS7 was overexpressed in the majority of malignancies. High PUS7 expression contributed to the poor prognosis among 11 cancer types, including Adrenocortical Cancer (ACC), Bladder Cancer (BLCA), Liver Cancer (LIHC), Kidney Papillary Cell Carcinoma (KIRP), Mesothelioma (MESO), Lower Grade Glioma (LGG), Kidney Chromophobe (KICH), Sarcoma (SARC), osteosarcoma (OS), Pancreatic Cancer (PAAD), and Thyroid Cancer (THCA). In addition, elevated PUS7 expression was linked to advanced TNM across multiple malignancies, including ACC, BLCA, KIRP, LIHC and PAAD. The function enrichment analysis revealed that PUS7 participates in E2F targets, G2M checkpoint, ribosome biogenesis, and rRNA metabolic process. Moreover, PUS7 is also a reliable biomarker and a potential therapeutic target for osteosarcoma. CONCLUSIONS: In summary, PUS7 is a putative pan-cancer biomarker that reliably forecasts cancer patients' prognosis. In addition, this enzyme regulates the cell cycle, ribosome biogenesis, and rRNA metabolism. Most importantly, PUS7 possibly regulates osteosarcoma initiation and progression.
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Specification of neuronal subtypes in the spiral ganglion begins prior to birth in the mouse.
The afferent innervation of the cochlea is comprised of spiral ganglion neurons (SGNs), which are characterized into four subtypes (Type 1A, B, and C and Type 2). However, little is known about the factors and/or processes that determine each subtype. Here, we present a transcriptional analysis of approximately 5,500 single murine SGNs collected across four developmental time points. All four subtypes are transcriptionally identifiable prior to the onset of coordinated spontaneous activity, indicating that the initial specification process is under genetic control. Trajectory analysis indicates that SGNs initially split into two precursor types (Type 1A/2 and Type 1B/C), followed by subsequent splits to give rise to four transcriptionally distinct subtypes. Differential gene expression, pseudotime, and regulon analyses were used to identify candidate transcription factors which may regulate the subtypes specification process. These results provide insights into SGN development and comprise a transcriptional atlas of SGN maturation across the prenatal period.
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Single-cell transcriptomic atlas of blood and lung from mice infected with SARS-CoV-2 revealing distinct virulence characteristics between prototype and Omicron BA.1 strain.
The markedly reduced pathogenicity of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Omicron variant in comparison to earlier strains has raised critical questions regarding its underlying mechanisms. To elucidate the host immune responses driving these differences, we performed single-cell transcriptomic profiling of lung and blood samples from human angiotensin-converting enzyme 2 (hACE2) transgenic mice infected with either the SARS-CoV-2 prototype strain or the Omicron BA.1 variant at 5 days post-inoculation. Both strains induced a reduction in lung cell numbers, with capillary endothelial cells showing the highest number of differentially expressed genes (DEGs). Shared transcriptional responses included upregulation of chemokine (e.g. Gnaq, Lyn, Ccl5) and IL-17 signaling pathways. Notably, Omicron BA.1 infection resulted in downregulation of Txnip, a key gene involved in oxidative stress responses. Genes associated with neutrophil granules and pro-inflammatory functions (Mmp8, S100a8, S100a9) were also downregulated, whereas wound healing pathways were upregulated in immature neutrophils. Additionally, Omicron BA.1 altered gene expression associated with neutrophil migration from blood to lung, and decreased the activation of cell chemotaxis, cytokine-mediated signaling, IL-17 and NF-κB pathways in pro-inflammatory monocytes and pulmonary interstitial macrophages. These findings highlight distinct immunological signatures contributing to the attenuated pathogenicity of Omicron BA.1, particularly through the modulation of neutrophil and monocyte-macrophage responses.