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HISSTA: a human in situ single-cell transcriptome atlas.
MOTIVATION: Spatial transcriptomics holds great promise for revolutionizing biology and medicine by providing gene expression profiles with spatial information. Until recently, spatial resolution has been limited, but advances in high-throughput in situ imaging technologies now offer new opportunities by covering thousands of genes at a single-cell or even subcellular resolution, necessitating databases dedicated to comprehensive coverage and analysis with user-friendly intefaces. RESULTS: We introduce the HISSTA database, which facilitates the archival and analysis of in situ transcriptome data at single-cell resolution from various human tissues. We have collected and annotated spatial transcriptome data generated by MERFISH, CosMx SMI, and Xenium techniques, encompassing 112 samples and 28 million cells across 16 tissue types from 63 studies. To decipher spatial contexts, we have implemented advanced tools for cell type annotation, spatial colocalization, spatial cellular communication, and niche analyses. Notably, all datasets and annotations are interactively accessible through Vitessce, allowing users to focus on regions of interest and examine gene expression in detail. HISSTA is a unique database designed to manage the rapidly growing dataset of in situ transcriptomes at single-cell resolution. Given its comprehensive data content and advanced analysis tools with interactive visualizations, HISSTA is poised to significantly impact cancer diagnosis, precision medicine, and digital pathology. AVAILABILITY AND IMPLEMENTATION: HISSTA is freely accessible at https://kbds.re.kr/hissta/. The source code is available at https://doi.org/10.5281/zenodo.14904523.
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Overview of Gene Expression Dynamics during Human Oogenesis/Folliculogenesis.
The oocyte transcriptome follows a tightly controlled dynamic that leads the oocyte to grow and mature. This succession of distinct transcriptional states determines embryonic development prior to embryonic genome activation. However, these oocyte maternal mRNA regulatory events have yet to be decoded in humans. We reanalyzed human single-oocyte RNA-seq datasets previously published in the literature to decrypt the transcriptomic reshuffles ensuring that the oocyte is fully competent. We applied trajectory analysis (pseudotime) and a meta-analysis and uncovered the fundamental transcriptomic requirements of the oocyte at any moment of oogenesis until reaching the metaphase II stage (MII). We identified a bunch of genes showing significant variation in expression from primordial-to-antral follicle oocyte development and characterized their temporal regulation and their biological relevance. We also revealed the selective regulation of specific transcripts during the germinal vesicle-to-MII transition. Transcripts associated with energy production and mitochondrial functions were extensively downregulated, while those associated with cytoplasmic translation, histone modification, meiotic processes, and RNA processes were conserved. From the genes identified in this study, some appeared as sensitive to environmental factors such as maternal age, polycystic ovary syndrome, cryoconservation, and in vitro maturation. In the future, the atlas of transcriptomic changes described in this study will enable more precise identification of the transcripts responsible for follicular growth and oocyte maturation failures.
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Gene expression variations and allele-specific expression of two rice and their hybrid in caryopses at single-nucleus resolution.
Seeds are an indispensable part of the flowering plant life cycle and a critical determinant of agricultural production. Distinct differences in the anatomy and morphology of seeds separate monocots and dicots. Although some progress has been made with respect to understanding seed development in Arabidopsis, the transcriptomic features of monocotyledon seeds at the cellular level are much less understood. Since most important cereal crops, such as rice, maize, and wheat, are monocots, it is essential to study transcriptional differentiation and heterogeneity during seed development at a finer scale. Here, we present single-nucleus RNA sequencing (snRNA-seq) results of over three thousand nuclei from caryopses of the rice cultivars Nipponbare and 9311 and their intersubspecies F1 hybrid. A transcriptomics atlas that covers most of the cell types present during the early developmental stage of rice caryopses was successfully constructed. Additionally, novel specific marker genes were identified for each nuclear cluster in the rice caryopsis. Moreover, with a focus on rice endosperm, the differentiation trajectory of endosperm subclusters was reconstructed to reveal the developmental process. Allele-specific expression (ASE) profiling in endosperm revealed 345 genes with ASE (ASEGs). Further pairwise comparisons of the differentially expressed genes (DEGs) in each endosperm cluster among the three rice samples demonstrated transcriptional divergence. Our research reveals differentiation in rice caryopsis from the single-nucleus perspective and provides valuable resources to facilitate clarification of the molecular mechanism underlying caryopsis development in rice and other monocots.
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Identification and validation of a pyroptosis-related prognostic model for colorectal cancer based on bulk and single-cell RNA sequencing data.
BACKGROUND: Pyroptosis impacts the development of malignant tumors, yet its role in colorectal cancer (CRC) prognosis remains uncertain. AIM: To assess the prognostic significance of pyroptosis-related genes and their association with CRC immune infiltration. METHODS: Gene expression data were obtained from The Cancer Genome Atlas (TCGA) and single-cell RNA sequencing dataset GSE178341 from the Gene Expression Omnibus (GEO). Pyroptosis-related gene expression in cell clusters was analyzed, and enrichment analysis was conducted. A pyroptosis-related risk model was developed using the LASSO regression algorithm, with prediction accuracy assessed through K-M and receiver operating characteristic analyses. A nomogram predicting survival was created, and the correlation between the risk model and immune infiltration was analyzed using CIBERSORTx calculations. Finally, the differential expression of the 8 prognostic genes between CRC and normal samples was verified by analyzing TCGA-COADREAD data from the UCSC database. RESULTS: An effective pyroptosis-related risk model was constructed using 8 genes-CHMP2B, SDHB, BST2, UBE2D2, GJA1, AIM2, PDCD6IP, and SEZ6L2 (P < 0.05). Seven of these genes exhibited differential expression between CRC and normal samples based on TCGA database analysis (P < 0.05). Patients with higher risk scores demonstrated increased death risk and reduced overall survival (P < 0.05). Significant differences in immune infiltration were observed between low- and high-risk groups, correlating with pyroptosis-related gene expression. CONCLUSION: We developed a pyroptosis-related prognostic model for CRC, affirming its correlation with immune infiltration. This model may prove useful for CRC prognostic evaluation.
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Mapping the Tissue Architecture and Endothelial-PEC Network in HAML Using Single-Cell and Spatial Transcriptomics.
Hepatic angiomyolipoma (HAML) is a rare variant of perivascular epithelioid cell neoplasms (PEComas). Unlike its more common renal angiomyolipoma (RAML), the unique spatial microenvironment of HAML and its specific progression mechanisms remain poorly characterized. Here, we integrated single-nucleus RNA-sequencing and spatial transcriptomics from three sporadic HAML cases. We mapped functionally heterogeneous PEComas subpopulations and their localized tissue niches. Transcriptomic alignment and spatial colocalization demonstrated a high similarity between endothelial cells and a subset of PEComas, supporting a potential transition trajectory. Furthermore, spatial intercellular communication analysis identified an endothelial-derived PDGFD-PDGFRB axis. We propose that this paracrine signaling engages downstream Ras cascades to sustain localized autophagic flux in adjacent PEComas, potentially acting as a compensatory survival mechanism parallel to intrinsic TSC-mTOR defects. While definitive in vivo functional fate-mapping and perturbation studies are requisite, this multi-omics atlas provides a novel spatial framework for HAML pathogenesis and highlights the endothelial-PEComa signaling network as a potential therapeutic vulnerability.
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Integration mapping of cardiac fibroblast single-cell transcriptomes elucidates cellular principles of fibrosis in diverse pathologies.
Single-cell technology has allowed researchers to probe tissue complexity and dynamics at unprecedented depth in health and disease. However, the generation of high-dimensionality single-cell atlases and virtual three-dimensional tissues requires integrated reference maps that harmonize disparate experimental designs, analytical pipelines, and taxonomies. Here, we present a comprehensive single-cell transcriptome integration map of cardiac fibrosis, which underpins pathophysiology in most cardiovascular diseases. Our findings reveal similarity between cardiac fibroblast (CF) identities and dynamics in ischemic versus pressure overload models of cardiomyopathy. We also describe timelines for commitment of activated CFs to proliferation and myofibrogenesis, profibrotic and antifibrotic polarization of myofibroblasts and matrifibrocytes, and CF conservation across mouse and human healthy and diseased hearts. These insights have the potential to inform knowledge-based therapies.
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Single-cell RNA-sequencing reveals the transcriptional landscape of lacrimal gland in GVHD mouse model.
PURPOSE: To investigate the global transcriptional landscape of lacrimal gland cell populations in the GVHD mouse model. METHODS: Single-cell RNA sequencing and further bioinformatic analysis of dissociated lacrimal gland (LG) cells from the mouse model were performed. Parts of transcriptional results were confirmed by immunofluorescence staining. RESULTS: We identified 23 cell populations belonging to 11 cell types. In GVHD LG, the proportion of acinar cells, myoepithelial cells, and endothelial cells was remarkably decreased, while T cells and macrophages were significantly expanded. Gene expression analysis indicated decreased secretion function, extracellular matrix (ECM) synthesis, and increased chemokines of myoepithelial cells. A newly described epithelial population named Lrg1high epithelial cells, expressing distinct gene signatures, was exclusively identified in GVHD LG. The fibroblasts exhibited an inflammation gene pattern. The gene pattern of endothelial cells suggested an increased ability to recruit immune cells and damaged cell-cell junctions. T cells were mainly comprised of Th2 cells and effective memory CD8+ T cells. GVHD macrophages exhibited a Th2 cell-linked pattern. CONCLUSIONS: This single-cell atlas uncovered alterations of proportion and gene expression patterns of cell populations and constructed cell-cell communication networks of GVHD LG. These data may provide some new insight into understanding the development of ocular GVHD.
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Role of cancer stem cell heterogeneity in intrahepatic cholangiocarcinoma.
BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is a highly invasive bile duct cancer with poor prognosis due to frequent recurrence and limited effective treatments. Cancer stem cells (CSCs) contribute to ICC's therapeutic resistance and recurrence, driven by distinct cellular subpopulations with variable tumorigenic properties. Recent advances in single-cell RNA sequencing (scRNA-seq) have enabled a deeper exploration of cellular heterogeneity in tumors, offering insights into unique CSC subgroups that impact ICC progression and patient outcomes. This study aimed to investigate the effect of CSC heterogeneity on the prognosis of ICC. METHODS: The scRNA-seq dataset GSE142784 was retrieved from the Gene Expression Omnibus (GEO) database, and Bulk RNA-seq data were obtained from The Cancer Genome Atlas (TCGA) databases. Hallmarks and AUCell R package were adopted for analyzing the signaling pathway activity, CellChat for observing cell communication between subgroups, and SCENIC for analyzing transcription factors expression. The immune cell infiltration and drug sensitivity of the model were analyzed using the CIBERSORT algorithm and the "pRRophetic" R packages, respectively. And immunohistochemistry (IHC) tests were used to evaluate expression of transcription factors in ICC patients. RESULTS: Based on scRNA-seq data, five clusters (DLK+, CD13+, CD90+, CD133+, and other cholangiocarcinoma cells) were observed in ICC, which presented different signaling pathway activities, such as HSF1 and STAT1 were highly expressed in the CD133 cluster, and consistent with the results of IHC tests. Pathways like Notch and Wnt/β-catenin signaling transferred among above subgroups. Further, subgroups favored varied immune response and drug sensitivity, and CD133+ subgroup patients showed significantly shortened recurrence-free survival (RFS). CONCLUSIONS: Configuring the subgroup of ICC is helpful for predicting the prognosis and drug resistance in ICC and can provide new strategies for cancer treatment.
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Stress-free single-cell transcriptomic profiling and functional genomics of murine eosinophils.
Eosinophils are a class of granulocytes with pleiotropic functions in homeostasis and various human diseases. Nevertheless, they are absent from conventional single-cell RNA sequencing atlases owing to technical difficulties preventing their transcriptomic interrogation. Consequently, eosinophil heterogeneity and the gene regulatory networks underpinning their diverse functions remain poorly understood. We have developed a stress-free protocol for single-cell RNA capture from murine tissue-resident eosinophils, which revealed distinct intestinal subsets and their roles in colitis. Here we describe in detail how to enrich eosinophils from multiple tissues of residence and how to capture high-quality single-cell transcriptomes by preventing transcript degradation. By combining magnetic eosinophil enrichment with microwell-based single-cell RNA capture (BD Rhapsody), our approach minimizes shear stress and processing time. Moreover, we report how to perform genome-wide CRISPR pooled genetic screening in ex vivo-conditioned bone marrow-derived eosinophils to functionally probe pathways required for their differentiation and intestinal maturation. These protocols can be performed by any researcher with basic skills in molecular biology and flow cytometry, and can be adapted to investigate other granulocytes, such as neutrophils and mast cells, thereby offering potential insights into their roles in both homeostasis and disease pathogenesis. Single-cell transcriptomics of eosinophils can be performed in 2-3 d, while functional genomics assays may require up to 1 month.
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The evolution of facultative symbiosis in stony corals.
Most stony corals are obligate symbionts that are dependent on nutrients provided by the photosynthetic activity of dinoflagellates residing within specialized cells1. Disruption of this symbiotic consortium leads to coral bleaching and, ultimately, mortality2. However, a few coral species exhibit facultative symbiosis, allowing them to survive extended periods of bleaching3,4. Despite this resilience, the underlying biological mechanisms remain poorly understood. Here we investigate the genomic and cellular basis of facultative symbiosis in Oculina patagonica, a thermotolerant Mediterranean coral5,6. We sequenced and annotated a chromosome-scale genome of O. patagonica and built cell atlases for this species and two obligate symbiotic corals. Comparative genomic analysis revealed karyotypic and syntenic conservation across all scleractinians, with species-specific gene expansions primarily driven by tandem duplications. Single-cell transcriptomic profiling of symbiotic and naturally aposymbiotic wild specimens identified an increase in phagocytic immune cells and a metabolic shift in gastrodermal gene expression from growth-related functions to quiescent, epithelial-like states. Cross-species comparison of host cells uncovered Oculina-specific metabolic and signalling adaptations indicative of an opportunistic, dual-feeding strategy that decouples survival from symbiotic state.