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Single-cell analysis of angiotensin-converting enzyme II expression in human kidneys and bladders reveals a potential route of 2019 novel coronavirus infection.
BACKGROUND: Since 2019, a novel coronavirus named 2019 novel coronavirus (2019-nCoV) has emerged worldwide. Apart from fever and respiratory complications, acute kidney injury has been observed in a few patients with coronavirus disease 2019. Furthermore, according to recent findings, the virus has been detected in urine. Angiotensin-converting enzyme II (ACE2) has been proposed to serve as the receptor for the entry of 2019-nCoV, which is the same as that for the severe acute respiratory syndrome. This study aimed to investigate the possible cause of kidney damage and the potential route of 2019-nCoV infection in the urinary system. METHODS: We used both published kidney and bladder cell atlas data and new independent kidney single-cell RNA sequencing data generated in-house to evaluate ACE2 gene expression in all cell types in healthy kidneys and bladders. The Pearson correlation coefficients between ACE2 and all other genes were first generated. Then, genes with r values larger than 0.1 and P values smaller than 0.01 were deemed significant co-expression genes with ACE2. RESULTS: Our results showed the enriched expression of ACE2 in all subtypes of proximal tubule (PT) cells of the kidney. ACE2 expression was found in 5.12%, 5.80%, and 14.38% of the proximal convoluted tubule cells, PT cells, and proximal straight tubule cells, respectively, in three published kidney cell atlas datasets. In addition, ACE2 expression was also confirmed in 12.05%, 6.80%, and 10.20% of cells of the proximal convoluted tubule, PT, and proximal straight tubule, respectively, in our own two healthy kidney samples. For the analysis of public data from three bladder samples, ACE2 expression was low but detectable in bladder epithelial cells. Only 0.25% and 1.28% of intermediate cells and umbrella cells, respectively, had ACE2 expression. CONCLUSION: This study has provided bioinformatics evidence of the potential route of 2019-nCoV infection in the urinary system.
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A GPCR atlas across human microglial states in Alzheimer's disease: Insights from snRNA-seq and hiPSC models.
Microglia are the resident immune cells of the central nervous system, and their state heterogeneity is closely associated with the pathological progression of Alzheimer's disease (AD). Single-nucleus RNA sequencing (snRNA-seq) studies have identified multiple transcriptional states of microglia in human AD brain. However, the characteristics and potential functions of G protein-coupled receptors (GPCRs) across different states remain poorly systematized. This review systematically searched and reviewed snRNA-seq studies based on human brain tissue published between 2020 and 2025. By re-analyzing GPCR expression across these datasets, we focuses on characterizing the differential expression characteristics and potential functions of GPCRs in five key AD-related microglial states: disease-associated microglia, tau-associated microglia, inflammation-associated microglia, proliferation-associated microglia, and interferon-associated microglia. Furthermore, we cross-reference these findings with single-cell sequencing data from human induced pluripotent stem cell (hiPSC)-derived microglia to prioritize a conserved set of GPCRs of high interest. In summary, by integrating transcriptomic evidence from both post-mortem human brain and hiPSC models, this review not only refines the understanding of microglial heterogeneity in AD but also provides a set of candidate GPCR targets for subsequent validation and drug discovery efforts against AD.
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Mapping the tumor microenvironment in bladder cancer and exploring the prognostic genes by single-cell RNA sequencing.
Despite substantial advances in the treatment using immune checkpoint inhibitors (ICIs), the clinical expected therapeutic effect on bladder cancer has not been achieved, in which the tumor microenvironment (TME) occupies a notable position. In this research, 10X single-cell RNA-sequencing technology was conducted to analyze seven primary bladder tumor tissues (three non-muscle-invasive bladder cancer (NMIBC) and four muscle-invasive bladder cancer (MIBC)) and seven corresponding normal tissues adjacent to cancer; eight various cell types were identified in the bladder cancer (BC) TME, and a complete TME atlas in bladder cancer was made. Moreover, bladder cancer epithelial cells were further subdivided into 14 subgroups, indicating a high intra-tumoral heterogeneity. Additionally, the differences between NMIBC and MIBC were compared based on differential gene expression heatmap, copy number variation (CNV) distribution heatmap, Gene Ontology (GO) enrichment analysis, and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Weighted gene co-expression network analysis (WGCNA), protein-protein interaction (PPI) network mutual analysis, and the Kaplan-Meier survival prognosis analysis were used to identify six key genes associated with the prognosis of bladder cancer: VEGFA, ANXA1, HSP90B1, PSMA7, PRDX6, and PPP1CB. The dynamic change of the expression distribution of six genes on the pseudo-time axis was further verified by cell pseudo-time analysis.
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The Hippo-Yki pathway governs growth and cell fate in the posterior silk gland of the silkworm.
The posterior silk gland (PSG) of the silkworm (Bombyx mori) is a specialized organ that synthesizes vast quantities of silk fibroin; however, the cell-type-specific mechanisms regulating its development remain largely unclear. Leveraging our previously constructed single-cell atlas, we performed high-dimensional weighted gene coexpression network analysis (hdWGCNA). The analysis revealed a gene module strongly correlated with fibroin-synthesizing cells (FBSs) in the PSG. Pathway analysis revealed significant enrichment of the Hippo signaling pathway within this module, with its downstream transcriptional coactivator, Yorkie (Yki), being identified as a top-ranked hub gene. Strikingly, PSG-specific Yki overexpression or knockdown induced severe developmental defects from early larval stages. Transcriptomic profiling combined with cellular deconvolution demonstrated that Yki is essential for maintaining the transcriptional identity and proportional homeostasis of the FBS population. Our study establishes the Hippo-Yki pathway as a central developmental regulator that coordinates organ growth and FBS fate specification in the silk gland, offering new genetic insights into potential targets for improving silk production.
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Single-cell dissection of shoulder-derived mesenchymal stem cells reveals source-specific progenitor heterogeneity and a SIX2-driven chondrogenic program.
BACKGROUND: Mesenchymal stem cells (MSCs) within the shoulder joint serve as a critical progenitor pool for regenerating the fibrocartilaginous enthesis during rotator cuff repair. However, the chondrogenic potential of MSCs across distinct rotator cuff sites, along with the underlying molecular mechanisms, remains to be elucidated. METHODS: We performed a comparative analysis of human subacromial bursa-derived MSCs (sMSCs) and rotator cuff enthesis-derived MSCs (rMSCs). By integrating functional chondrogenic assays with longitudinal bulk and single-cell RNA sequencing, we reconstructed source-specific differentiation trajectories and identified key regulatory drivers. RESULTS: rMSCs exhibited superior chondrogenic potency compared to sMSCs. Transcriptional profiling identified a region-specific pro-chondrogenic module in rMSCs driven by the transcription factor SIX2. Single-cell atlas construction revealed that tissue origin dictates lineage fate: rMSCs were enriched for a high-potency SIX2+ progenitor population that differentiated into metabolic-active S100A2+ chondrocytes. Conversely, sMSCs were dominated by DPP4+ progenitors that preferentially bifurcated into an aberrant CXCL8+ inflammatory trajectory. Mechanistically, we demonstrated that SIX2 acted as a competency factor, coordinating early proliferative expansion with late-stage matrix assembly and, crucially, active suppression of inflammatory signaling. Accordingly, lentiviral overexpression of SIX2 in sMSCs was sufficient to rescue their chondrogenic defects and rewire their trajectory toward a regenerative phenotype. CONCLUSIONS: Our findings define the transcriptional hierarchy of shoulder-resident progenitors, identifying SIX2 as a master regulator that couples chondrogenesis with immune evasion. This establishes a molecular framework for precision cell sourcing and rational design of lineage-specific therapies.
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Comprehensive Pan-Cancer Analysis of the Prognostic Role of KLF Transcription Factor 2 (KLF2) in Human Tumors.
BACKGROUND: KLF2 is a transcription factor expressed early in mammalian development that plays a role in many processes of development and disease. Recently, increasing studies revealed that KLF2 plays a key role in the occurrence and progression of cancer. PURPOSE: The aim of this study was to explore the role of KLF2 in various tumor types using the Cancer Genome Atlas dataset. METHODS: Here, we set out to explore the role of KLF2 in 33 tumor types using TCGA (The Cancer Genome Atlas), GEO (Gene Expression Omnibus) dataset, Human Protein Atlas (HPA), UALCAN database, CancerSEA, GSCALite and several bioinformatic tools. Furthermore, we also performed immunohistochemistry and qPCR to further validate the role of KLF2 in multiple cancers and its correlation with prognosis. RESULTS: We found that KLF2 was underexpressed in most tumors and generally predicted poor OS in tumor patients. We found that amplification of KLF2 may be a risk factor for patients with OV (Ovarian serous cystadenocarcinoma). We also analyzed the abundance of checkpoints and markers of specific immune subsets including CD8+ T lymphocytes (T cells), CD4+ T cells, macrophages, and endothelial cells that significantly correlated with the expression level of KLF2 in pan-carcinoma tissues. In some cancers, KLF2 expression levels are positively correlated with gene promoter DNA methylation and drug sensitivity. In addition, we found that KLF2 is involved in single-cell level cell invasion in some cancers. In addition, KLF2 is co-expressed with several intracellular signal transduction genes involved in immune system processes. Immunohistochemistry and qPCR confirmed the low expression of KLF2 in STAD (stomach adenocarcinoma) and renal cancer. CONCLUSION: Our pan-cancer analysis provides a comprehensive overview of the oncogenic roles of KLF2 in multiple human cancers and can be regarded as a potential prognostic marker and a novel target for cancer immunotherapy.
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Identification of Hub Genes Associated With Clear Cell Renal Cell Carcinoma by Integrated Bioinformatics Analysis.
BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is a common genitourinary cancer type with a high mortality rate. Due to a diverse range of biochemical alterations and a high level of tumor heterogeneity, it is crucial to select highly validated prognostic biomarkers to be able to identify subtypes of ccRCC early and apply precision medicine approaches. METHODS: Transcriptome data of ccRCC and clinical traits of patients were obtained from the GSE126964 dataset of Gene Expression Omnibus and The Cancer Genome Atlas Kidney Renal Clear Cell Carcinoma (TCGA-KIRC) database. Weighted gene co-expression network analysis (WGCNA) and differentially expressed gene (DEG) screening were applied to detect common differentially co-expressed genes. Gene Ontology, Kyoto Encyclopedia of Genes and Genomes analysis, survival analysis, prognostic model establishment, and gene set enrichment analysis were also performed. Immunohistochemical analysis results of the expression levels of prognostic genes were obtained from The Human Protein Atlas. Single-gene RNA sequencing data were obtained from the GSE131685 and GSE171306 datasets. RESULTS: In the present study, a total of 2,492 DEGs identified between ccRCC and healthy controls were filtered, revealing 1,300 upregulated genes and 1,192 downregulated genes. Using WGCNA, the turquoise module was identified to be closely associated with ccRCC. Hub genes were identified using the maximal clique centrality algorithm. After having intersected the hub genes and the DEGs in GSE126964 and TCGA-KIRC dataset, and after performing univariate, least absolute shrinkage and selection operator, and multivariate Cox regression analyses, ALDOB, EFHD1, and ESRRG were identified as significant prognostic factors in patients diagnosed with ccRCC. Single-gene RNA sequencing analysis revealed the expression profile of ALDOB, EFHD1, and ESRRG in different cell types of ccRCC. CONCLUSIONS: The present results demonstrated that ALDOB, EFHD1, and ESRRG may act as potential targets for medical therapy and could serve as diagnostic biomarkers for ccRCC.
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The role of single cell transcriptomics for efficacy and toxicity profiling of chimeric antigen receptor (CAR) T cell therapies.
CAR T cells are genetically modified T cells that target specific epitopes. CAR T cell therapy has proven effective in difficult-to-treat B cell cancers and is now expanding into hematology and solid tumors. To date, approved CAR therapies target only two specific epitopes on cancer cells. Identifying more suitable targets is challenged by the lack of truly cancer-specific structures and the potential for on-target off-tumor toxicity. We analyzed gene expression of potential targets in single-cell data from cancer and healthy tissues. Because safety and efficacy can ultimately only be defined clinically, we selected approved and investigational targets for which clinical trail data are available. We generated atlases using >300,000 cells from 48 patients with follicular lymphoma, multiple myeloma, and B-cell acute lymphoblastic leukemia, and integrated over 3 million cells from 35 healthy tissues, harmonizing datasets from over 300 donors. To contextualize findings, we compared target expression patterns with outcome data from clinical trials, linking target profiles to efficacy and toxicity, and ranked 15 investigational targets based on their similarity to approved ones. Target expression did not significantly correlate with reported clinical toxicities in patients undergoing therapy. This may be attributed to the intricate interplay of patient-specific variables, the limited amount of metadata, and the complexity underlying toxicity. Nevertheless, our study serves as a resource for retrospective and prospective target evaluation to improve the safety and efficacy of CAR therapies.
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Molecular Characteristics and Distribution of Adult Human Corneal Immune Cell Types.
BACKGROUND: The limbus is located at a 2-mm-wide area between the bulbar conjunctiva and the cornea and has been suggested to be the niche of corneal epithelial stem cells and immune cells. Like the skin and intestines, the cornea is also an important mucosal surface, and immune cells on the cornea play critical roles in immune surveillance to ensure barrier surface homeostasis and protection from various environmental damage and infections. Single-cell RNA sequencing (scRNA-seq) analysis of protein tyrosine phosphatase receptor type C positive (PTPRC+) hematopoietic cells from the corneal limbus could provide a single cell atlas of all the immune cell subsets. METHODS: We performed single-cell RNA sequencing to generate transcriptomic profile for 804 sort-purified hematopoietic cells from the corneal limbus of three healthy donors. RESULTS: Our analysis identified a primary transcriptomic pattern for multiple immune cell subtypes, including naive T cells, antiviral effector CD8+ T cells, and innate immune cells such as IDO1+ mature regulatory dendritic cells (mregDCs), macrophages, monocytes, and basophils in the human corneal limbus. CONCLUSION: Overall, single-cell transcriptomic analysis of limbal immune cells suggested the possible contribution of these cells on the adaptive and innate immune response of the human cornea.
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Distinct single-nucleus RNA-seq changes among non-neuronal cells in ADNC, LATE-NC, and mixed pathologies.
INTRODUCTION: Limbic-predominant age-related transactive response DNA binding protein 43 kDa encephalopathy neuropathological change (LATE-NC) frequently co-occurs with Alzheimer's disease neuropathologic change (ADNC), complicating classification. Cell type-specific molecular features distinguishing LATE-NC-dominant, ADNC-dominant, and mixed LATE-NC and ADNC pathology remain incompletely characterized. METHODS: We analyzed single-nucleus RNA sequencing data from the Seattle Alzheimer's Disease Brain Cell Atlas consortium, focusing on non-neuronal cells in the middle temporal gyrus (MTG). Donors were stratified into LATE-NC dominant, ADNC dominant, and mixed LATE-NC and ADNC. Differential expression and gene set enrichment analyses were performed across glial and vascular cell supertypes. RESULTS: Distinct transcriptional patterns differentiated pathologies. Astrocytes, microglia, and oligodendrocytes exhibited differential expression between LATE-NC- and ADNC-dominant cases. Representative genes and pathways highlighted these distinctions, with LATE-NC dominant showing enrichment in signaling and RNA regulation, ADNC dominant in mitochondrial dysfunction, and mixed pathology in translational dysregulation and lipid remodeling, suggesting a distinct biological state. DISCUSSION: Findings highlight biological heterogeneity and non-neuronal molecular features relevant to disease classification and future research. CLINICAL TRIAL REGISTRATION INFORMATION: Not applicable. This study is a secondary analysis of publicly available Seattle Alzheimer's Disease Brain Cell Atlas (SEA-AD) data.