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Single-cell RNA sequencing reveals the developmental program underlying proximal-distal patterning of the human lung at the embryonic stage.
The lung is the primary respiratory organ in human, in which the proximal airway and the distal alveoli are responsible for air conduction and gas exchange, respectively. However, the regulation of proximal-distal patterning at the embryonic stage of human lung development is largely unknown. Here we investigated the early lung development of human embryos at weeks 4-8 post fertilization (Carnegie stages 12-21) using single-cell RNA sequencing, and obtained a transcriptomic atlas of 169,686 cells. We observed discernible gene expression patterns of proximal and distal epithelia at week 4, upon the initiation of lung organogenesis. Moreover, we identified novel transcriptional regulators of the patterning of proximal (e.g., THRB and EGR3) and distal (e.g., ETV1 and SOX6) epithelia. Further dissection revealed various stromal cell populations, including an early-embryonic BDNF+ population, providing a proximal-distal patterning niche with spatial specificity. In addition, we elucidated the cell fate bifurcation and maturation of airway and vascular smooth muscle progenitor cells at the early stage of lung development. Together, our study expands the scope of human lung developmental biology at early embryonic stages. The discovery of intrinsic transcriptional regulators and novel niche providers deepens the understanding of epithelial proximal-distal patterning in human lung development, opening up new avenues for regenerative medicine.
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Identification of angiogenesis-related genes signature for predicting survival and its regulatory network in glioblastoma.
Glioblastoma (GBM) is notorious for malignant neovascularization that contributes to undesirable outcome. However, its mechanisms remain unclear. This study aimed to identify prognostic angiogenesis-related genes and the potential regulatory mechanisms in GBM. RNA-sequencing data of 173 GBM patients were obtained from the Cancer Genome Atlas (TCGA) database for screening differentially expressed genes (DEGs), differentially transcription factors (DETFs), and reverse phase protein array (RPPA) chips. Differentially expressed genes from angiogenesis-related gene set were extracted for univariate Cox regression analysis to identify prognostic differentially expressed angiogenesis-related genes (PDEARGs). A risk predicting model was constructed based on 9 PDEARGs, namely MARK1, ITGA5, NMD3, HEY1, COL6A1, DKK3, SERPINA5, NRP1, PLK2, ANXA1, SLIT2, and PDPN. Glioblastoma patients were stratified into high-risk and low-risk groups according to their risk scores. GSEA and GSVA were applied to explore the possible underlying GBM angiogenesis-related pathways. CIBERSORT was employed to identify immune infiltrates in GBM. The Pearson's correlation analysis was performed to evaluate the correlations among DETFs, PDEARGs, immune cells/functions, RPPA chips, and pathways. A regulatory network centered by three PDEARGs (ANXA1, COL6A1, and PDPN) was constructed to show the potential regulatory mechanisms. External cohort of 95 GBM patients by immunohistochemistry (IHC) assay demonstrated that ANXA1, COL6A1, and PDPN were significantly upregulated in tumor tissues of high-risk GBM patients. Single-cell RNA sequencing also validated malignant cells expressed high levels of the ANXA1, COL6A1, PDPN, and key DETF (WWTR1). Our PDEARG-based risk prediction model and regulatory network identified prognostic biomarkers and provided valuable insight into future studies on angiogenesis in GBM.
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A Novel Four-Gene Signature Based on Nonsense-Mediated RNA Decay for Predicting Prognosis in Hepatocellular Carcinoma: Bioinformatics Analysis and Functional Validation.
PURPOSE: Nonsense-mediated RNA decay (NMD), a surveillance pathway for selective degradation of aberrant mRNAs, is associated with cancer progression. Its potential as a predictor for aggressive hepatocellular carcinoma (HCC) is unclear. Here, we present an innovative NMD risk model for predicting HCC prognosis. METHODS: The Cancer Genome Atlas (TCGA) data of 374 liver HCC (LIHC) and 50 normal liver samples were extracted. A risk model based on NMD-related genes was developed through least absolute shrinkage and selection operator Cox (LASSO-Cox) regression of the LIHC-TCGA data. Prognostic validation was done using GSE54236, GSE116174, and GSE76427 data. Univariate and multivariate Cox regression analyses were conducted to assess the prognostic value of the model. We also constructed nomograms for survival prediction. Tumor immune infiltration was evaluated using the CIBERSORT algorithm, and the tumor cell phenotype was assessed. Finally, mouse experiments verified UPF3B knockdown effects on HCC tumor characteristics. RESULTS: We developed a risk model based on four NMD-related genes (PABPC1, RPL8, SMG5, and UPF3B) and validated it using GSE54236, GSE116174, and GSE76427 data. The model effectively distinguished high- and low-risk groups corresponding to unfavorable and favorable HCC outcomes. Its prognostic prediction accuracy was confirmed through time-dependent ROC analysis, and clinical-use nomograms with calibration curves were developed. Single-cell RNA sequencing results indicated significantly higher expression of SMG5 and UPF3B in tumor cells. Knockdown of SMG5 and UPF3B inhibited HCC cell proliferation, invasion, and migration, while affecting cell-cycle progression and apoptosis. In vivo, UPF3B knockdown delayed tumor growth and increased immune cell infiltration. CONCLUSION: Our NMD-related gene-based risk model can help identify therapeutic targets and biomarkers for HCC. Additionally, it assists clinicians in predicting the prognosis of HCC patients.
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Development of stemness-related signature to optimize prognosis prediction and identify XMD8-85 as a novel therapeutic compound for glioma.
Glioma is a highly invasive and aggressive type of brain cancer with poor treatment response. Stemness-related transcription factors form a regulatory network that sustains the malignant phenotype of gliomas. We conducted an integrated analysis of stemness-related transcription factors using The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) datasets, established the characteristics of stemness-related transcription factors, including Octamer-Binding Protein 4 (OCT4), Meis Homeobox 1 (MEIS1), E2F Transcription Factor 1 (E2F1), Transcription Factor CP2 Like 1 (TFCP2L1), and RUNX Family Transcription Factor 1 (RUNX1). The characteristic of stemness-related transcription factors was identified as an independent prognostic factor for glioma patients. Patients in the high-risk group have a worse prognosis than those in the low-risk group. The glioma microenvironment in the high-risk group exhibited a more active immune status. Single-cell level analysis revealed that stem cell-like cells exhibited stronger intercellular communication than glioma cells. Meanwhile, patients in different risk stratification exhibited varying sensitivities to immunotherapy and small molecule drug therapy. XMD8-85 was more effective in the high-risk group, and its antitumor effects were validated both in vivo and in vitro. Our results indicate that this prognostic feature will assist clinicians in predicting the prognosis of glioma patients, guiding immunotherapy and personalized treatment, as well as the potential clinical application of XMD8-85 in glioma treatment, and helping to develop effective treatment strategies.
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The role of CD47 in immune escape of colon cancer and its correlation with heterogeneity of tumor immune microenvironment.
BACKGROUND: Cluster of differentiation 47 (CD47), a transmembrane protein, plays a critical role in regulating cellular functions and maintaining immune homeostasis. Its expression has been shown to influence cancer prognosis. In this study, we investigated the role of CD47 in tumor progression in colon adenocarcinoma (COAD) and evaluated its potential as a target for immunotherapy. MATERIALS AND METHODS: We analyzed surgical samples from 96 COAD patients. Immunohistochemical analysis was performed on 90 samples, while the remaining 6 were subjected to multiplex immunofluorescence. To explore the association between CD47 expression and clinicopathological characteristics, we integrated transcriptome data from The Cancer Genome Atlas and the Gene Expression Omnibus using R software. The Tumor Immune Estimation Resource and Kaplan-Meier plotter were utilized to assess the relationship between CD47 expression, patient prognosis, and immune infiltration. Furthermore, the single-cell Tumor Immune System Interaction Database was used to examine the correlation between CD47 expression and the tumor microenvironment (TME). All included patients gave oral and written informed consent. The study was approved by the Ethics Committee of 3201 Hospital (full name: Medical Ethics Committee of 3201 Hospital). RESULTS: CD47 was found to be overexpressed in various tumors, including COAD. Higher CD47 expression was significantly associated with more advanced tumor stages, including TNM staging, T staging, and N staging (P < 0.05). A robust correlation was observed between CD47 expression and immune cell infiltration in COAD. Patients with elevated CD47 expression tended to have longer disease-free intervals, although this benefit was diminished in cases with high infiltration of M1 macrophages. The immunosuppressive function of CD47 primarily acted through the CD47/SIRPα pathway. Additionally, distinct cellular compositions and distributions were identified between primary and metastatic COAD, underscoring the heterogeneity of the TME. CD47 also influenced the TME by modulating cytokine and cytokine receptor interactions. CONCLUSION: CD47 represents a promising prognostic biomarker and a potential target for immunotherapy in COAD. These findings provide new insights into therapeutic strategies aimed at modulating the TME and improving patient outcomes.
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Comprehensive profiling of migratory primordial germ cells reveals niche-specific differences in non-canonical Wnt and Nodal-Lefty signaling in anterior vs posterior migrants.
Mammalian primordial germ cells (PGCs) migrate asynchronously through the embryonic hindgut and dorsal mesentery to reach the gonads. We previously found that interaction with different somatic niches regulates mouse PGC proliferation along the migration route. To characterize transcriptional heterogeneity of migrating PGCs and their niches, we performed single-cell RNA sequencing of 13,262 mouse PGCs and 7868 surrounding somatic cells during migration (E9.5, E10.5, E11.5) and in anterior vs posterior locations to enrich for leading and lagging migrants. Analysis of PGCs by position revealed dynamic gene expression changes between faster or earlier migrants in the anterior and slower or later migrants in the posterior at E9.5; these differences include migration-associated actin polymerization machinery and epigenetic reprogramming-associated genes. We furthermore identified changes in signaling with various somatic niches, notably strengthened interactions with hindgut epithelium via non-canonical WNT (ncWNT) in posterior PGCs compared to anterior. Reanalysis of a previously published dataset suggests that ncWNT signaling from the hindgut epithelium to early migratory PGCs is conserved in humans. Trajectory inference methods identified putative differentiation trajectories linking cell states across timepoints and from posterior to anterior in our mouse dataset. At E9.5, we mainly observed differences in cell adhesion and actin cytoskeletal dynamics between E9.5 posterior and anterior migrants. At E10.5, we observed divergent gene expression patterns between putative differentiation trajectories from posterior to anterior, including Nodal signaling response genes Lefty1, Lefty2, and Pycr2 and reprogramming factors Dnmt1, Prc1, and Tet1. At E10.5, we experimentally validated anterior migrant-specific Lefty1/2 upregulation via whole-mount immunofluorescence staining for LEFTY1/2 and phosphorylated SMAD2/3, suggesting that elevated autocrine Nodal signaling in migrating PGCs occurs as they near the gonadal ridges. Together, this positional and temporal atlas of mouse PGCs supports the idea that niche interactions along the migratory route elicit changes in proliferation, actin dynamics, pluripotency, and epigenetic reprogramming.
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CEBPB as a candidate mediator of DEGDB-induced tumor-associated phenotypes in colorectal cancer cells.
OBJECTIVE: To investigate the effects of exposure to diethylene glycol dibenzoate (DEGDB) on malignant progression in colorectal cancer (CRC) cells and to identify a prioritized candidate gene. METHODS: PubChem, SwissADME, ADMETlab 3.0, and ProTox 3.0 were used to characterize the chemical structure and predict the physicochemical and toxicological properties of DEGDB. DEGDB-related targets were retrieved from the Comparative Toxicogenomics Database, STITCH, and SwissTargetPrediction and integrated with differentially expressed genes identified in the GSE39582 and GSE44076 datasets. Functional enrichment analysis and reverse transcription quantitative polymerase chain reaction were used to prioritize CEBPB. Using the GSE132465 single-cell ribonucleic acid (RNA) sequencing dataset, we characterized the cell type-specific expression of CEBPB, intercellular communication, pseudotemporal dynamics, and associated regulatory networks. In silico perturbation analysis was performed to predict transcriptional changes after CEBPB knockout. In HCT116 and SW620 cells, cell proliferation, colony formation, Transwell migration, and wound-healing assays were used to evaluate the effects of DEGDB exposure and CEBPB knockdown. The prognostic relevance of CEBPB was assessed in patients with stage I-II colon adenocarcinoma from The Cancer Genome Atlas (TCGA), and molecular docking was used to predict potential interactions between DEGDB and candidate proteins. RESULTS: A total of 35 DEGDB-related genes and 908 CRC-associated differentially expressed genes were identified, yielding five overlapping candidate genes: CEBPB, SCD, DGAT2, IGF2, and PPARG. DEGDB treatment consistently increased CEBPB messenger RNA expression in both cell lines, with a comparatively large magnitude of change; therefore, CEBPB was selected as the prioritized candidate gene. Single-cell analysis showed that CEBPB expression was higher in tumor-derived epithelial cells than in normal-derived epithelial cells and increased progressively along the pseudotime trajectory. In silico knockout analysis suggested that CEBPB deletion could substantially alter transcriptional regulatory networks in CRC-associated cells. DEGDB treatment upregulated CEBPB and enhanced CRC cell proliferation, colony formation, migration, and wound closure; these effects were attenuated by CEBPB-targeting small interfering RNA. In the early-stage colon adenocarcinoma cohort, high CEBPB expression was associated with worse overall survival. Molecular docking predicted potential interactions between DEGDB and the candidate proteins. CONCLUSIONS: Under the in vitro exposure conditions used in this study, DEGDB significantly promoted malignant phenotypes in CRC cells, whereas CEBPB knockdown effectively attenuated these effects. Collectively, these findings indicate that CEBPB may partially mediate DEGDB-induced malignant behavior in CRC cells and may serve as a candidate regulator for subsequent mechanistic studies and population-based exposure and risk assessment.
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Zonal endothelial cell heterogeneity underlies murine renal vascular development.
The renal vasculature consists of highly specialized blood vessels with distinct physiological functions. Defining their transcriptional signatures and tracing their developmental ontogeny has thus far been challenging due to a lack of regionally specific endothelial biomarkers. Here, we performed single nuclear RNA sequencing (snucRNA-Seq) to interrogate the transcriptional heterogeneity of embryonic renal endothelial cells (ECs). We identified ten endothelial subtypes, and validated regionally restricted expression of novel marker genes of glomeruli, arteries, vasa recta, and immature capillary subtypes using multiplex RNAscope. We also define previously uncharacterized and heterogeneous molecular signatures of the immature renal vasculature, including putative endothelial progenitors. We interrogate biological characteristics of immature EC types using a variety of in vivo tools. Lineage tracing of Esm1-expressing cells reveals the previously unrecognized multi-origin and multi-clonal endothelial tip cell contribution to the glomerular vasculature. Together, this study provides a validated, tool-focused developmental atlas of the murine renal vasculature and elucidates novel cellular mechanisms of nephron vascularization.
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APOE4 impairs myelination via cholesterol dysregulation in oligodendrocytes.
APOE4 is the strongest genetic risk factor for Alzheimer's disease1-3. However, the effects of APOE4 on the human brain are not fully understood, limiting opportunities to develop targeted therapeutics for individuals carrying APOE4 and other risk factors for Alzheimer's disease4-8. Here, to gain more comprehensive insights into the impact of APOE4 on the human brain, we performed single-cell transcriptomics profiling of post-mortem human brains from APOE4 carriers compared with non-carriers. This revealed that APOE4 is associated with widespread gene expression changes across all cell types of the human brain. Consistent with the biological function of APOE2-6, APOE4 significantly altered signalling pathways associated with cholesterol homeostasis and transport. Confirming these findings with histological and lipidomic analysis of the post-mortem human brain, induced pluripotent stem-cell-derived cells and targeted-replacement mice, we show that cholesterol is aberrantly deposited in oligodendrocytes-myelinating cells that are responsible for insulating and promoting the electrical activity of neurons. We show that altered cholesterol localization in the APOE4 brain coincides with reduced myelination. Pharmacologically facilitating cholesterol transport increases axonal myelination and improves learning and memory in APOE4 mice. We provide a single-cell atlas describing the transcriptional effects of APOE4 on the aging human brain and establish a functional link between APOE4, cholesterol, myelination and memory, offering therapeutic opportunities for Alzheimer's disease.
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Effect of Sortilin1 on promoting angiogenesis and systemic metastasis in hepatocellular carcinoma via the Notch signaling pathway and CD133.
Hepatocellular carcinoma (HCC) is known to be lethal disease. However, its prognosis remains poor, primarily because the precise oncogenic mechanisms underlying HCC progression remain elusive, thus hampering effective treatment. Here, we aimed to identify the potential oncogenes in HCC and elucidate the underlying mechanisms of their action. To identify potential candidate genes, an integrative analysis of eight publicly available genomic datasets was performed, and the functional implications of the identified genes were assessed in vitro and in vivo. Sortilin 1 (SORT1) was identified as a potential candidate oncogene in HCC, and its overexpression in HCC cells was confirmed by analyzing spatial transcriptomic and single-cell data. Silencing SORT1 in Huh-7 and Hep3B cells significantly reduced HCC progression in vitro and in vivo. Functional analyses of oncogenic pathways revealed that SORT1 expression regulated the Notch signaling pathway activation and CD133 expression. Furthermore, analysis of epigenetic regulation of the candidate gene and its clinical implications using The Cancer Genome Atlas Liver Hepatocellular Carcinoma (TCGA LIHC) and our HCC cohort (AJOU_HCC cohort) data demonstrated an inverse correlation between the methylation status of the SORT1 promoter region, specifically at the cg16988986 site, and SORT1 mRNA expression, indicating the epigenetic regulation of SORT1 in HCC. In addition, the distinct methylation status of cg16988986 was significantly associated with patient survival. In conclusion, SORT1 plays a pivotal role in HCC by activating the Notch signaling pathway and increasing CD133 expression. These findings suggest SORT1 as a promising therapeutic target for HCC.