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Cellular and Transcriptional Landscape of Human Hypoplastic Left Heart Syndrome.
Hypoplastic left heart syndrome (HLHS) is a congenital heart defect characterized by impaired development of the left ventricle, often managed through surgical palliation creating a single ventricle (SV). Failure of the anatomical right ventricle (RV) represents a common complication with high mortality. We used single-nucleus RNA sequencing to generate a map of the pediatric non-failing (NF) and failing (SysHF) SV. Fibroblasts and endocardial cells displayed the greatest transcriptional shifts between NF and SysHF. Notably, activated fibroblasts expanded in SysHF, and endocardial cells in NF demonstrated adaptive transcriptomic shifts absent from controls or SysHF samples. Ligand-target analysis predicted disease-state specific signaling from endocardial cells to fibroblasts: NRG3 signaling in NF and CCN2 signaling in SysHF. In silico perturbation predicted FOS, JUN, and STAT3 as regulators of fibroblast activation and endocardial adaptation. Finally, HLHS data was compared to adult human and murine RV failure to gain insight into shared pathological processes and the suitability of current animal models. These findings provide a comprehensive SV atlas and implicate cell non-autonomous signaling between endocardial cells and fibroblasts as drivers of SV systolic heart failure.
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Complementing tissue characterization by integrating transcriptome profiling from the Human Protein Atlas and from the FANTOM5 consortium.
Understanding the normal state of human tissue transcriptome profiles is essential for recognizing tissue disease states and identifying disease markers. Recently, the Human Protein Atlas and the FANTOM5 consortium have each published extensive transcriptome data for human samples using Illumina-sequenced RNA-Seq and Heliscope-sequenced CAGE. Here, we report on the first large-scale complex tissue transcriptome comparison between full-length versus 5'-capped mRNA sequencing data. Overall gene expression correlation was high between the 22 corresponding tissues analyzed (R > 0.8). For genes ubiquitously expressed across all tissues, the two data sets showed high genome-wide correlation (91% agreement), with differences observed for a small number of individual genes indicating the need to update their gene models. Among the identified single-tissue enriched genes, up to 75% showed consensus of 7-fold enrichment in the same tissue in both methods, while another 17% exhibited multiple tissue enrichment and/or high expression variety in the other data set, likely dependent on the cell type proportions included in each tissue sample. Our results show that RNA-Seq and CAGE tissue transcriptome data sets are highly complementary for improving gene model annotations and highlight biological complexities within tissue transcriptomes. Furthermore, integration with image-based protein expression data is highly advantageous for understanding expression specificities for many genes.
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Epithelial pyroptosis-induced TREM1+ macrophages activate Th17 cells to accelerate oral mucosal inflammation.
Chronic inflammation of the oral mucosa could affect daily living and even threaten systemic health. Unlike periodontitis, oral lichen planus, a common oral chronic inflammatory disease, has diverse clinical manifestations and can progress to malignancy. Hence, this study aimed to investigate the mechanism of oral chronic inflammation using single-cell RNA sequencing (scRNA-seq), spatial transcriptome, a large clinical follow-up cohort with bulk RNA sequencing, cytological experiments, and multiplex immunohistochemistry. We found that epithelial pyroptosis-induced triggering receptor expressed on myeloid cell-1 (TREM1)+ macrophages activated pathogenic T helper cell 17 via interleukin-1β, to spur the inflammatory development of oral mucosal epithelium. Besides, we established a spatiotemporal interactional online database, Oral-Gut Axis Mucosal Immune Atlas (ORGUAMIA), to uncover the extensive pro-inflammatory role of epithelial pyroptosis-induced TREM1+ macrophages in chronic digestive tract disorders. In summary, this study highlights the role of epithelial pyroptosis-induced TREM1+ macrophages accelerating mucosal epithelial inflammation and offers ORGUAMIA as a tool for researchers using scRNA-seq and spatial transcriptome without technological barriers.
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A single-cell transcriptome atlas of the adult human retina.
The retina is a specialized neural tissue that senses light and initiates image processing. Although the functional organization of specific retina cells has been well studied, the molecular profile of many cell types remains unclear in humans. To comprehensively profile the human retina, we performed single-cell RNA sequencing on 20,009 cells from three donors and compiled a reference transcriptome atlas. Using unsupervised clustering analysis, we identified 18 transcriptionally distinct cell populations representing all known neural retinal cells: rod photoreceptors, cone photoreceptors, Müller glia, bipolar cells, amacrine cells, retinal ganglion cells, horizontal cells, astrocytes, and microglia. Our data captured molecular profiles for healthy and putative early degenerating rod photoreceptors, and revealed the loss of MALAT1 expression with longer post-mortem time, which potentially suggested a novel role of MALAT1 in rod photoreceptor degeneration. We have demonstrated the use of this retina transcriptome atlas to benchmark pluripotent stem cell-derived cone photoreceptors and an adult Müller glia cell line. This work provides an important reference with unprecedented insights into the transcriptional landscape of human retinal cells, which is fundamental to understanding retinal biology and disease.
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A systems-based framework to computationally describe putative transcription factors and signaling pathways regulating glycan biosynthesis.
Glycosylation is a common posttranslational modification, and glycan biosynthesis is regulated by a set of glycogenes. The role of transcription factors (TFs) in regulating the glycogenes and related glycosylation pathways is largely unknown. In this work, we performed data mining of TF-glycogene relationships from the Cistrome Cancer database (DB), which integrates chromatin immunoprecipitation sequencing (ChIP-Seq) and RNA-Seq data to constitute regulatory relationships. In total, we observed 22,654 potentially significant TF-glycogene relationships, which include interactions involving 526 unique TFs and 341 glycogenes that span 29 the Cancer Genome Atlas (TCGA) cancer types. Here, TF-glycogene interactions appeared in clusters or so-called communities, suggesting that changes in single TF expression during both health and disease may affect multiple carbohydrate structures. Upon applying the Fisher's exact test along with glycogene pathway classification, we identified TFs that may specifically regulate the biosynthesis of individual glycan types. Integration with Reactome DB knowledge provided an avenue to relate cell-signaling pathways to TFs and cellular glycosylation state. Whereas analysis results are presented for all 29 cancer types, specific focus is placed on human luminal and basal breast cancer disease progression. Overall, the article presents a computational approach to describe TF-glycogene relationships, the starting point for experimental system-wide validation.
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Spatiotemporal single-cell analysis elucidates the cellular and molecular dynamics of human cornea aging.
BACKGROUND: The human cornea is a transparent and uniquely ordered optical-biological system. Precise coordination of its cellular mechanisms is essential to maintain its transparency and functionality. However, the spatial, cellular and molecular architecture of the human cornea and its intercellular interactions during aging have not been elucidated. METHODS: We performed single-cell RNA sequencing (scRNA-seq) and single-cell SpaTial Enhanced REsolution Omics-sequencing (scStereo-seq) analysis in corneal tissue from eight eyes of donors aged 33-88 years to elucidate the spatiotemporal cellular and molecular dynamics of human cornea aging. Immunofluorescence staining and Western blotting were performed to validate the findings. RESULTS: Spatiotemporal single-cell analysis revealed the complex cellular landscape, spatial organization and intercellular communication within the human cornea. The subpopulations of major cell types of the cornea were elucidated with precise spatial positions. In particular, we identified novel subpopulations, mapped the spatial positioning of limbal stem cells within the limbal niche, and delineated the interactions between major cell types. We observed that three basal cell subsets migrate centripetally from the peripheral to the central cornea with age, suggesting the "spatiotemporal centripetal pattern" as a novel paradigm for the age-related migration of corneal epithelial cells. Furthermore, we elucidated the age-related, region-specific molecular and functional characteristics of the corneal endothelium, demonstrating differential metabolic capacities and functional properties between the peripheral and central regions. CONCLUSIONS: As the first comprehensive spatiotemporal atlas, our work provides a valuable resource for understanding tissue homeostasis in the human cornea and advances research on corneal pathology, transplantation, senescence and regenerative medicine in the context of corneal aging.
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Multi-omics analysis reveals AFAP1L1 as a prognostic biomarker and immune-related therapeutic target in glioma.
OBJECTIVES: Actin filament-associated protein 1 like 1 (AFAP1L1) is an adaptor protein lacking enzymatic and transcriptional activity, but the AFAP1L1 gene functions as an oncogene in colorectal cancer and gastric cancers. This study aims to investigate the role of AFAP1L1 in glioma and to explore changes in AFAP1L1 expression during glioma progression. METHODS: Clinical and transcriptomic data of glioma patients were downloaded from The Cancer Genome Atlas (TCGA), the Chinese Glioma Genome Atlas (CGGA), and the Gene Expression Omnibus (GEO) databases to analyze the associations between AFAP1L1 expression and glioma prognosis, somatic mutations, immune cell infiltration, and enriched signaling pathways. Western blotting and real-time polymerase chain reaction (PCR) were used to detect AFAP1L1 messenger RNA (mRNA) and protein expression in glioma patients. RESULTS: Patients with high AFAP1L1 expression had poorer prognosis, and AFAP1L1 was identified as an independent risk factor for glioma. In addition, glioma patients with high AFAP1L1 expression exhibited lower levels of somatic mutations, including amplification of oncogenes such as epidermal growth factor receptor and deletion of tumor suppressor genes such as cyclin-dependent kinase inhibitor 2A (CDKN2A). Estimation of STromal and Immune cells in Malignant Tumours using Expression (ESTIMATE) algorithm analysis showed that AFAP1L1 expression was positively correlated with the immune microenvironment. Tumor immune dysfunction and exclusion (TIDE) analysis indicated that glioma patients with high AFAP1L1 expression responded poorly to immunotherapy. Single cell analysis showed that AFAP1L1 expression was mainly concentrated in glioma cells. Enrichment analysis suggested that AFAP1L1 was potentially associated with small guanosine triphosphatases (GTPases), hypoxia-inducible factor-1 (HIF-1), focal adhesion, and mitogen-activated protein kinase (MAPK) signaling pathways. CONCLUSIONS: AFAP1L1 is a novel biomarker indicating glioma progression and a potential therapeutic target for glioma.
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Mrc1+ macrophage-derived IGF1 mitigates crystal nephropathy by promoting renal tubule cell proliferation via the AKT/Rb signaling pathway.
Rationale: The present understanding of the cellular characteristics and communications in crystal nephropathy is limited. Here, molecular and cellular studies combined with single-cell RNA sequencing (scRNA-seq) were performed to investigate the changes in cell components and their interactions in glyoxylate-induced crystallized kidneys to provide promising treatments for crystal nephropathy. Methods: The transcriptomes of single cells from mouse kidneys treated with glyoxylate for 0, 1, 4, or 7 days were analyzed via 10× Genomics, and the single cells were clustered and characterized by the Seurat pipeline. The potential cellular interactions between specific cell types were explored by CellChat. Molecular and cellular findings related to macrophage-to-epithelium crosstalk were validated in sodium oxalate (NaOx)-induced renal tubular epithelial cell injury in vitro and in glyoxylate-induced crystal nephropathy in vivo. Results: Our established scRNA atlas of glyoxylate-induced crystalline nephropathy contained 15 cell populations with more than 40000 single cells, including relatively stable tubular cells of different segments, proliferating and injured proximal tubular cells, T cells, B cells, and myeloid and mesenchymal cells. In this study, we found that Mrc1+ macrophages, as a subtype of myeloid cells, increased in both the number and percentage within the myeloid population as crystal-induced injury progresses, and distinctly express IGF1, which induces the activation of a signal pathway to dominate a significant information flow towards injured and proliferating tubule cells. IGF1 promoted the repair of damaged tubular epithelial cells induced by NaOx in vitro, as well as the repair of damaged tubular epithelial cells and the recovery of disease outcomes in glyoxylate-induced nephrolithic mice in vivo. Conclusion: After constructing a cellular atlas of glyoxylate-induced crystal nephropathy, we found that IGF1 derived from Mrc1+ macrophages attenuated crystal nephropathy through promoting renal tubule cell proliferation via the AKT/Rb signaling pathway. These findings could lead to the identification of potential therapeutic targets for the treatment of crystal nephropathy.
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Single-cell and spatial atlas unveil tumor-specific microenvironment convergence and a prognosis-associated PLXDC1+ myofibroblast population in metastatic bladder cancer.
BACKGROUND: While single-cell technologies have advanced bladder cancer research, the microenvironment of lymph node metastases and its role in progression remain unclear. We aimed to elucidate dynamic tumor-microenvironment interactions across metastatic and primary sites, identify poor-prognosis features, and uncover novel therapeutic targets. METHODS: We profiled matched single-cell and spatial transcriptomic samples from lymph node-metastasized bladder cancer to construct a high-resolution atlas. Bioinformatic analyses were used to inferred ligand-receptor interactions, regulatory networks, and spatial co-localization. Integration with multiple prognostic cohorts revealed key cell subpopulations linked to tumor biology and poor outcomes. RESULTS: Our atlas included 32 samples, 61 cell subtypes, key ligand signals (e.g., TGFB1, OSM, IFNG), 343 transcription factors, 188 co-localization events, over 1,000 spatially validated interactions, and 21 cell niches. Tumor-driven convergence was observed across distinct microenvironments. Notably, a pericyte-like myofibroblast subtype, myoCAF_PLXDC1, was enriched in malignant tissues, associated with poor prognosis, and exhibited enhanced angiogenic but reduced chemotactic activity compared to myoCAF_CCL21. Its phenotype was linked to intracellular regulators (PRRX1 and MXD4) and extracellular signals (IFNG and TGFB1). Spatially, myoCAF_PLXDC1 co-localized with ITGA8+ endothelial cells and enriched in tumor regions. CONCLUSIONS: This study offers a comprehensive resource for lymph node-metastasized bladder cancer and identifies PLXDC1+ fibroblasts co-localized with ITGA8+ ECs as potential components of a tumor-specific vascular niche and therapeutic target.
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The immune cell atlas of human neuroblastoma.
Understanding the complete immune cell composition of human neuroblastoma (NB) is crucial for the development of immunotherapeutics. Here, we perform single-cell RNA sequencing (scRNA-seq) on 19 human NB samples coupled with multiplex immunohistochemistry, survival analysis, and comparison with normal fetal adrenal gland data. We provide a comprehensive immune cell landscape and characterize cell-state changes from normal tissue to NB. Our analysis reveals 27 immune cell subtypes, including distinct subpopulations of myeloid, NK, B, and T cells. Several different cell types demonstrate a survival benefit. In contrast to adult cancers and previous NB studies, we show an increase in inflammatory monocyte cell state when contrasting normal and tumor tissue, while no differences in cytotoxicity and exhaustion score for T cells, nor in Treg activity, are observed. Our receptor-ligand interaction analysis reveals a highly complex interactive network of the NB microenvironment from which we highlight several interactions that we suggest for future therapeutic studies.