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Single-cell RNA sequencing reveals the Müller subtypes and inner blood-retinal barrier regulatory network in early diabetic retinopathy.
As the basic pathological changes of diabetic retinopathy (DR), the destruction of the blood-retina barrier (BRB) and vascular leakage have attracted extensive attention. Without timely intervention, BRB damage will eventually lead to serious visual impairment. However, due to the delicate structure and complex function of the BRB, the mechanism underlying damage to the BRB in DR has not been fully clarified. Here, we used single-cell RNA sequencing (RNA-seq) technology to analyze 35,910 cells from the retina of healthy and streptozotocin (STZ)-induced diabetic rats, focusing on the degeneration of the main cells constituting the rat BRB in DR and the new definition of two subpopulations of Müller cells at the cell level, Ctxn3 +Müller and Ctxn3 -Müller cells. We analyzed the characteristics and significant differences between the two groups of Müller cells and emphasized the importance of the Ctxn3 +Müller subgroup in diseases. In endothelial cells, we found possible mechanisms of self-protection and adhesion and recruitment to pericytes. In addition, we constructed a communication network between endothelial cells, pericytes, and Müller subsets and clarified the complex regulatory relationship between cells. In summary, we constructed an atlas of the iBRB in the early stage of DR and elucidate the degeneration of its constituent cells and Müller cells and the regulatory relationship between them, providing a series of potential targets for the early treatment of DR.
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Human subcutaneous and visceral adipocyte atlases uncover classical and nonclassical adipocytes and depot-specific patterns.
Human adipose depots are functionally distinct. Yet, recent single-nucleus RNA sequencing (snRNA-seq) analyses largely uncovered overlapping or similar cell-type landscapes. We hypothesized that adipocyte subtypes, differentiation trajectories and/or intercellular communication patterns could illuminate this depot similarity-difference gap. For this, we performed snRNA-seq of human subcutaneous or visceral adipose tissues (five or ten samples, respectively). Of 27,665 adipocyte nuclei in both depots, most were 'classical', namely enriched in lipid metabolism pathways. However, we also observed 'nonclassical' adipocyte subtypes, enriched in immune-related, extracellular matrix deposition (fibrosis), vascularization or angiogenesis or ribosomal and mitochondrial processes. Pseudo-temporal analysis showed a developmental trajectory from adipose progenitor cells to classical adipocytes via nonclassical adipocytes, suggesting that the classical state stems from loss, rather than gain, of specialized functions. Last, intercellular communication routes were consistent with the different inflammatory tone of the two depots. Jointly, these findings provide a high-resolution view into the contribution of cellular composition, differentiation and intercellular communication patterns to human fat depot differences.
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Single-cell landscape reveals active cell subtypes and their interaction in the tumor microenvironment of gastric cancer.
Background: Gastric cancer remains the third most common cause of cancer-related death worldwide. The development of novel therapeutic strategies for gastric cancer requires a deep understanding of the tumor cells and microenvironment of gastric cancer. Methods: We performed the single-cell RNA sequencing (scRNA-seq) on nine untreated non-metastatic gastric cancer patients. The transcriptomic atlas and ligand-receptor-based intercellular communication networks of the single cells were characterized. Results: Here, we profiled the transcriptomes of 47,304 cells from nine patients with gastric cancer. Tregs cells were significantly enriched in the gastric tumor tissues with increased expression of immune suppression related genes, which suggest a more immunosuppressive microenvironment. We also observed the absence of separate exhausted CD8+ T cell cluster, and the low expression level of exhaustion markers PDCD1, CTLA4, HAVCR2, LAG-3, and TIGIT in those specific cells. These may serve as molecular-level evidence for the limited benefit of immunotherapy among gastric cancer patients. In addition, we found ACKR1 specifically expressed in tumor endothelial cells, associated with poor prognosis in the cohort data and potentially provided a novel target of gastric cancer treatment. Furthermore, the tight interaction between endothelial cells and fibroblast implied the important roles of fibroblast in tumor angiogenesis and the maintenance of tumor vasculature. Conclusions: In conclusion, this single-cell atlas provide understanding the cellular heterogeneity from molecular level in gastric cancer and will serve as a valuable resource for developing innovative early and companion diagnostics, as well as discovering novel targeted therapies for gastric cancer.
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Pan-cancer analysis and single-cell analysis identifies the CENPN as a biomarker for survival prognosis and immunotherapy.
BACKGROUND: Centromere protein N (CENPN), located on chromosome 16q23.2, encodes vital nucleosome-associated complexes that are essential for dynamic assembly processes. CENPN plays a pivotal role in regulating cell proliferation and cell cycle progression by influencing mitotic events. Despite its potential importance, the precise functional role and regulatory mechanisms of CENPN in diverse malignancies remain largely unexplored. This study aimed to elucidate the role of CENPN in human cancers and evaluate its prognostic significance. METHODS: Investigate the role of CENPN in various malignancies, we leveraged data from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases. We employed a comprehensive suite of web platforms and software tools for data analysis, including R, Cytoscape, an integrated repository portal for tumor-immune system interactions (TISIDB), CBio Cancer Genomics Portal (cBioPortal), Search Tool for the Retrieval of Interaction Gene/Proteins (STRING), Gene Set Cancer Analysis (GSCALite), and a cancer single-cell state atlas (CancerSEA). RESULTS: The findings demonstrated that CENPN expression was elevated in the majority of cancer types and differentially expressed across molecular and immune subtypes. Functional enrichment analysis in multiple tumors also identified possible pathways of CENPN involvement in tumorigenesis. Its expression positively correlated with Th2 and Tcm cells in most cancers. It is also correlated with genetic markers of immunomodulators in various cancers. CONCLUSIONS: Overall, CENPN expression is closely related to cancers and has the potential to act as a cancer biomarker.
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A transcriptomic and epigenomic cell atlas of the mouse primary motor cortex.
Single-cell transcriptomics can provide quantitative molecular signatures for large, unbiased samples of the diverse cell types in the brain1-3. With the proliferation of multi-omics datasets, a major challenge is to validate and integrate results into a biological understanding of cell-type organization. Here we generated transcriptomes and epigenomes from more than 500,000 individual cells in the mouse primary motor cortex, a structure that has an evolutionarily conserved role in locomotion. We developed computational and statistical methods to integrate multimodal data and quantitatively validate cell-type reproducibility. The resulting reference atlas-containing over 56 neuronal cell types that are highly replicable across analysis methods, sequencing technologies and modalities-is a comprehensive molecular and genomic account of the diverse neuronal and non-neuronal cell types in the mouse primary motor cortex. The atlas includes a population of excitatory neurons that resemble pyramidal cells in layer 4 in other cortical regions4. We further discovered thousands of concordant marker genes and gene regulatory elements for these cell types. Our results highlight the complex molecular regulation of cell types in the brain and will directly enable the design of reagents to target specific cell types in the mouse primary motor cortex for functional analysis.
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SPP1+ neutrophil and exhausted CD8⁺ T cells infiltration predicting the early recurrence of hepatocellular carcinoma patients after R0 resection.
BACKGROUND: Early recurrence of liver cancer is significantly associated with poor prognosis. Further dissection of the cellular heterogeneity in the tumor microenvironment (TME) of patients at high risk of early recurrence after liver cancer surgery is highly necessary. METHODS: This study integrated clinical data, single-cell RNA sequencing (scRNA-seq), spatial transcriptomics, and bulk RNA-seq data to reveal and verify a TME characteristic associated with high risk of early recurrence after liver cancer surgery. RESULTS: Clinical analysis of 402 patients identified neutrophil-to-lymphocyte ratio ≥3, alpha-fetoprotein ≥400 ng/mL, and microvascular invasion as independent predictors of early recurrence. scRNA-seq of 28 hepatocellular carcinoma (HCC) samples revealed nine neutrophil subtypes, with SPP1⁺ neutrophils (enriched in TNFα/NF-κB, hypoxia, and TGF-β pathways) and exhausted CD8⁺ T cells (expressing PD-1 and CTLA-4) significantly infiltrating the TME of patients with early recurrence. These findings were corroborated in an independent validation cohort comprising scRNA-seq data from 17 HCC tissues and 7 matched peripheral blood samples. Spatial analysis demonstrated their co-localization at tumor margins, forming an immunosuppressive barrier. Ligand-receptor interaction analysis highlighted SPP1-CD44, TGFB1-TGFBR, and TNF-TNFRSF axes as key mediators of neutrophil-T cell crosstalk, inducing T cell dysfunction. Validation in The Cancer Genome Atlas-Liver Hepatocellular Carcinoma cohort comprising 365 patients confirmed that high infiltration of SPP1⁺ neutrophils and exhausted CD8⁺ T cells was significantly correlated with shorter recurrence-free (P < 0.0001) and overall survival (P < 0.0001). CONCLUSIONS: This study shows that the infiltration of SPP1⁺ neutrophils and exhausted CD8⁺ T cells is associated with a high risk of early recurrence in HCC. SPP1⁺ neutrophils may serve as key mediator of immune suppression through spatial interactions with exhausted CD8⁺ T cells, suggesting that they could be potential therapeutic targets to mitigate early recurrence in HCC.
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m6A related metabolic genes in breast cancer and their relationship with prognosis.
Breast cancer (BC) is the most prevalent malignancy among women, with incidence rates rising annually. N6-methyladenosine (m6A) modification has been recognized as a key regulator in the onset and progression of BC. Nevertheless, the role of m6A-associated metabolic genes (mMGs) in BC regulation remains insufficiently understood. In this study, we first analyzed and clustered single-cell transcriptomic (scRNA-seq) data from the peripheral blood of BC patients. Differentially expressed genes (DEGs) across various cell populations were intersected with mMGs to identify differentially expressed mMGs (DEmMGs). The AUCell algorithm was employed to score DEmMGs across cell populations, followed by subgroup clustering of high-scoring cell types. Additionally, DEGs from BC and control transcriptomic (RNA-seq) data in The Cancer Genome Atlas (TCGA) were intersected with DEmMGs. BC subtypes were identified based on the expression levels of overlapping genes, and differences in survival rates and immune microenvironment characteristics were examined across subtypes. A BC risk model was constructed using Lasso-Cox regression, and variations in prognosis, tumor mutational burden, immune cell infiltration, and drug sensitivity were explored. Finally, real-time quantitative PCR (qRT-PCR) and Western blot (WB) were used to validate the identified prognostic genes. NDUFAB1, VDAC1, TYMP, UGDH, ATP6AP1, and ALDH2 showed consistent and significant expression differences between the BC and control groups. This study's identification of key prognostic genes and the development of a risk model offer potential new targets for therapeutic intervention and clinical management of BC.
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Protocol for generating and characterizing Matrigel-free prostate cancer patient-derived organoids.
Here, we present a protocol for the generation of prostate cancer patient-derived organoids (PCa PDOs) in Matrigel-free conditions. We describe steps for sample selection, pathological resection, and tissue dissociation. We then detail procedures for the generation, maintenance, and characterization of the PCa PDOs. Finally, we provide guidance for the processing of PDOs for single-cell RNA sequencing (scRNA-seq) analysis and using the prostate PDO single-cell atlas (PPScA) for both novice and advanced bioinformatic users. For complete details on the use and execution of this protocol, please refer to Dolgos et al.1.
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Characterization of immature ovarian teratomas through single-cell transcriptome.
INTRODUCTION: Immature ovarian teratomas are a type of malignant germ cell tumor composed of complicated cell types and are characterized by pathological features of immature neuroectodermal tubules/rosettes. However, there is a lack of understanding of patient-derived immature ovarian teratomas (PDT) at the single cell level. Moreover, whether stem cell lines derived from immature teratomas (CDT) can be used as models for research on PDT remains to be elucidated. METHODS: Single-cell RNA sequencing (scRNA-seq) and subsequent bioinformatic analysis was performed on three patient-derived immature ovarian teratomas (PDT) samples to reveal the heterogeneity, evolution trajectory, and cell communication within the tumor microenvironment of PDT. Validations were conducted in additional seven samples through multiplex immunofluorescence. RESULT: A total of qualified 22,153 cells were obtained and divided into 28 clusters, which can match to the scRNA-seq annotation of CDT as well as human fetal Cell Atlas, but with higher heterogeneity and more prolific cell-cell crosstalk. Radial glia cells (tagged by SOX2) and immature neuron (tagged by DCX) exhibited mutually exclusive expression and differentiated along distinct evolutionary trajectory from cycling neural progenitors. Proportions of these neuroectodermal cell subtypes may play important roles in PDT through contributing to the internal heterogeneity of PDTs. Moreover, the immune cells in PDTs were infiltrated rather than teratoma-derived, with more abundant macrophage in immature neuron than those in radial glia cells, and the infiltrated macrophage subtypes (i.e., M1 and M2) were significantly correlated to clinical grade. Overall, suppressed evolution process and transcriptome regulation in neuroectodermal cells, reduced cell-cell crosstalk, higher M1/M2 proportion ratio, and enhanced T cell effects in tumor microenvironment are enriched in patients with favorable prognosis. DISCUSSION: This study provides a comprehensive profile of PDT at the single cell level, shedding light on the heterogeneity and evolution of neuroectodermal cells within PDTs and the role of immune cells within the tumor microenvironment. Also, our findings highlight the potential usage of CDTs as a model for research on PDT.
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Deciphering maternal-fetal cross-talk in the human placenta during parturition using single-cell RNA sequencing.
Labor is a complex physiological process requiring a well-orchestrated dialogue between the mother and fetus. However, the cellular contributions and communications that facilitate maternal-fetal cross-talk in labor have not been fully elucidated. Here, single-cell RNA sequencing (scRNA-seq) was applied to decipher maternal-fetal signaling in the human placenta during term labor. First, a single-cell atlas of the human placenta was established, demonstrating that maternal and fetal cell types underwent changes in transcriptomic activity during labor. Cell types most affected by labor were fetal stromal and maternal decidual cells in the chorioamniotic membranes (CAMs) and maternal and fetal myeloid cells in the placenta. Cell-cell interaction analyses showed that CAM and placental cell types participated in labor-driven maternal and fetal signaling, including the collagen, C-X-C motif ligand (CXCL), tumor necrosis factor (TNF), galectin, and interleukin-6 (IL-6) pathways. Integration of scRNA-seq data with publicly available bulk transcriptomic data showed that placenta-derived scRNA-seq signatures could be monitored in the maternal circulation throughout gestation and in labor. Moreover, comparative analysis revealed that placenta-derived signatures in term labor were mirrored by those in spontaneous preterm labor and birth. Furthermore, we demonstrated that early in gestation, labor-specific, placenta-derived signatures could be detected in the circulation of women destined to undergo spontaneous preterm birth, with either intact or prelabor ruptured membranes. Collectively, our findings provide insight into the maternal-fetal cross-talk of human parturition and suggest that placenta-derived single-cell signatures can aid in the development of noninvasive biomarkers for the prediction of preterm birth.