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Single-cell atlas of human pediatric liver reveals age-related hepatic gene signatures.
BACKGROUND: The liver plays a critical role in metabolism and immune function, yet the contributions of its heterogeneous cell types to these processes remain unclear. While most liver studies focus on adults, pediatric liver diseases often present differently, underscoring the need for age-specific research. METHODS: To better understand cellular drivers of childhood liver diseases, we generated single-cell RNA-sequencing maps of the normal pediatric liver and used this map to examine disease-related populations in biopsies from pediatric patients with intestinal failure-associated liver disease (IFALD). RESULTS: The normal pediatric liver map consists of 42,660 cells from 9 donors under 17 years of age. Compared with normal adult liver (26,372 cells; 7 donors, age 26-69), pediatric livers exhibited differences in myeloid populations. Specifically, pediatric Kupffer-like cells (MARCO+C1QA+VSIG4+) exhibited higher expression of immune activation genes, including CCL4, CCL3, and IL1B. In vitro stimulation confirmed more IL-1β-secreting myeloid cells in pediatric versus adult livers, supporting these findings. Using the pediatric atlas as a reference, we analyzed 3 IFALD biopsies (11,969 cells; 3 donors, under 9 y of age) and identified increased expression of fibrosis-associated genes (eg, LY96) in Kupffer-like cells. In addition, mesenchymal cells in IFALD showed fibrotic gene modules resembling adult liver cells more than healthy pediatric cells. These signatures, undetectable when comparing IFALD to adult liver alone, highlight the value of a pediatric map. CONCLUSION: Taken together, our healthy pediatric liver atlas reveals distinct age-related signatures and provides a background against which to interpret pediatric liver disease data.
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Identifying temporal and spatial patterns of variation from multimodal data using MEFISTO.
Factor analysis is a widely used method for dimensionality reduction in genome biology, with applications from personalized health to single-cell biology. Existing factor analysis models assume independence of the observed samples, an assumption that fails in spatio-temporal profiling studies. Here we present MEFISTO, a flexible and versatile toolbox for modeling high-dimensional data when spatial or temporal dependencies between the samples are known. MEFISTO maintains the established benefits of factor analysis for multimodal data, but enables the performance of spatio-temporally informed dimensionality reduction, interpolation, and separation of smooth from non-smooth patterns of variation. Moreover, MEFISTO can integrate multiple related datasets by simultaneously identifying and aligning the underlying patterns of variation in a data-driven manner. To illustrate MEFISTO, we apply the model to different datasets with spatial or temporal resolution, including an evolutionary atlas of organ development, a longitudinal microbiome study, a single-cell multi-omics atlas of mouse gastrulation and spatially resolved transcriptomics.
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Dynamic remodelling of epithelial plasticity in colorectal cancer from single-cell and spatially resolved perspectives.
BACKGROUND: Epithelial compartments play a central role in the progression and metastasis of colorectal cancer (CRC), yet the mechanisms underlying their transcriptional reprogramming across disease stages remain incompletely understood. METHODS: We constructed comprehensive single-cell and spatial transcriptomic atlases encompassing normal colorectal tissue, primary CRC, and liver metastases (LMs), profiling over 200,000 high-quality cells. Specific coexpression modules and transcriptional regulators were identified and spatially mapped. Additionally, the clinical and functional roles of SCAND1 were investigated using western blot, RT-qPCR, and immunohistochemistry in clinical samples, as well as functional assays in CRC cell lines. RESULTS: Distinct coexpression modules were selectively enriched in normal epithelial cells and associated with vesicle transport, ion homeostasis, and barrier function, whereas LM-specific modules were linked to Wnt signalling, ribosome biogenesis, and cell cycle processes. High-CNV epithelial cells exhibited progressive activation of key transcription factors such as CEBPB, E2F, and the AP-1 family, with concurrent suppression of ARGLU1 and MTNR2L8, indicating coordinated remodelling of transcriptional and metabolic programs during metastasis. These changes were spatially validated and correlated with alterations in epithelial composition within the tumour core. Consistently, multiplex immunofluorescence (mIHC) confirmed the expression patterns of CEBPB, ARGLU1, S100A4 and FOSL1, across normal epithelium, CRC, and LM. Notably, SCAND1 was identified as a potential therapeutic target for malignant epithelial plasticity. We demonstrated for the first time that SCAND1 expression is significantly upregulated in CRC patients and is associated with superior diagnostic and prognostic value. Functional experiments revealed that SCAND1 promotes tumour cell proliferation, inhibits apoptosis, and enhances metastatic potential. Furthermore, co-culture of SCAND1-overexpressing tumour cells with T cells showed that SCAND1 overexpression attenuates T cell–mediated cytotoxicity, supporting an additional immune-evasive role. CONCLUSIONS: Our study elucidates the molecular logic of epithelial state transitions during CRC metastasis and underscores the promise of SCAND1 as a novel biomarker and therapeutic target in colorectal cancer.
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The impact of asymmetrical gene expression on the development of spike morphology in Triticum aestivum.
Wheat yield is primarily determined by panicle density per unit area, grain count per spike, and grain weight. The proliferation of wheat spikes affects both the number of grains per spike and grain weight. However, the molecular regulatory mechanisms of wheat spike development are still largely elusive. In this study, we acquired high-quality sequencing data from 5989 cells derived from the double-ridge stage spike of a common wheat variety Jimai 22. The data revealed the presence of 10 distinct cell types, which were validated using RNA in situ hybridization and cell type-specific gene expression. The transition from promeristem to protoxylem and protophloem cells signifies the initiation of differentiation for protoxylem and primary protophloem cells within the promeristem. This process results in five distinct cellular differentiation states that correspond to the expression of 1410 genes. In wheat spikes, differential gene expression across eight developmental stages revealed seven unique expression patterns. Specifically, genes differentially expressed in stages C3, C4, C5, and C7 were identified as being uniquely active during the anther meristem, double ridge, floral meristem, and pistil primordium stages, respectively. Furthermore, the differential genes in stage C2 are likely to encompass critical genes that regulate the reproductive growth of wheat spikes, while those in stage C1 may significantly influence floret creation and development. Additionally, the transition of gene triplets between suppressed and balanced types represents a key element affecting spike differentiation. In this context, dominant gene triplets primarily fulfill functions associated with housekeeping genes. This study explores the impact of asymmetrical gene triplet expression during spike development on the regulation of wheat yield traits, utilizing the single-cell transcriptome atlas of the wheat spike. Our analysis of homologous gene asymmetrical expression throughout development, coupled with single-cell resolution, suggests this asymmetry could be a pivotal factor in cell differentiation.
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Transcriptional profiling of mouse peripheral nerves to the single-cell level to build a sciatic nerve ATlas (SNAT).
Peripheral nerves are organ-like structures containing diverse cell types to optimize function. This interactive assembly includes mostly axon-associated Schwann cells, but also endothelial cells of supporting blood vessels, immune system-associated cells, barrier-forming cells of the perineurium surrounding and protecting nerve fascicles, and connective tissue-resident cells within the intra-fascicular endoneurium and inter-fascicular epineurium. We have established transcriptional profiles of mouse sciatic nerve-inhabitant cells to foster the fundamental understanding of peripheral nerves. To achieve this goal, we have combined bulk RNA sequencing of developing sciatic nerves up to the adult with focused bulk and single-cell RNA sequencing of Schwann cells throughout postnatal development, extended by single-cell transcriptome analysis of the full sciatic nerve both perinatally and in the adult. The results were merged in the transcriptome resource Sciatic Nerve ATlas (SNAT: https://www.snat.ethz.ch). We anticipate that insights gained from our multi-layered analysis will serve as valuable interactive reference point to guide future studies.
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Human oral mucosa cell atlas reveals a stromal-neutrophil axis regulating tissue immunity.
The oral mucosa remains an understudied barrier tissue. This is a site of rich exposure to antigens and commensals, and a tissue susceptible to one of the most prevalent human inflammatory diseases, periodontitis. To aid in understanding tissue-specific pathophysiology, we compile a single-cell transcriptome atlas of human oral mucosa in healthy individuals and patients with periodontitis. We uncover the complex cellular landscape of oral mucosal tissues and identify epithelial and stromal cell populations with inflammatory signatures that promote antimicrobial defenses and neutrophil recruitment. Our findings link exaggerated stromal cell responsiveness with enhanced neutrophil and leukocyte infiltration in periodontitis. Our work provides a resource characterizing the role of tissue stroma in regulating mucosal tissue homeostasis and disease pathogenesis.
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A multi-omic single-cell landscape of perinatal mouse skin maps lineage specification and reveals shared dynamics in human fetal skin.
During the hair cycle and wound regeneration, various developmental transcriptomic features are reactivated. Consequently, studying skin development provides critical insights into both fundamental biology and skin regeneration. However, chromatin accessibility during skin development remains underexplored. To address this gap, we conducted integrated single-cell chromatin and transcriptomic analyses of developing mouse skin. Our investigation revealed key gene network axes underlying skin lineage specification. In particular, our multi-omics approach identified Mef2c+ upper fibroblasts as putative precursor cells for smooth muscle-like appendages, such as the arrector pili muscle. Furthermore, leveraging the fetal human skin atlas, we uncovered strong cross-species correlations between mouse and human skin during development. We identified an MEF2C+ fibroblast counterpart in human fetal skin and further delineated fibroblast lineages, including dermal sheath and arrector pili muscle, demonstrating that fibroblast developmental timelines are conserved between mouse and human. Together, this study establishes a robust, human-translatable foundation for future investigations into skin development and regeneration.
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Single-cell profiling reveals that SAA1+ epithelial cells promote distant metastasis of esophageal squamous cell carcinoma.
INTRODUCTION: Esophageal squamous cell carcinoma (ESCC) is one of the most common cancers globally, with significant cell heterogeneity and poor prognosis. Distant metastasis in ESCC is one of the key factors that affects the prognosis of patients. METHODS AND RESULTS: Starting with the analysis of ESCC single-cell sequencing data, we constructed a single-cell atlas of ESCC in detail and clarified the cell heterogeneity within tumor tissues. Through analysis of epithelial-mesenchymal transition (EMT) levels, gene expression, and pathway activation, we revealed the existence of a novel subpopulation of SAA1+ malignant cells in ESCC that are highly aggressive and closely associated with distant metastasis of ESCC. In vitro wound healing and transwell assays confirmed a strong invasion capacity of ESCC tumor cells with high expression of SAA1. Then, we constructed an effective and reliable prediction model based on the gene expression pattern of SAA1+ malignant cell subpopulations and confirmed that patients in the high-risk group had significantly worse prognosis than those in the low-risk group in the training cohort, internal verification cohort and external verification cohort. DISCUSSION: This manuscript contributes to exploration of the heterogeneity of ESCC tumor tissues and the search for new ESCC subpopulations with special biological functions. These results contribute to our understanding of the underlying mechanisms of distant metastasis of ESCC and thus provide a theoretical basis for improved therapies.
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The Alzheimer's Cell Atlas (TACA): A single-cell molecular map for translational therapeutics accelerator in Alzheimer's disease.
INTRODUCTION: Recent advances in generating massive single-cell/nucleus transcriptomic data have shown great potential for facilitating the identification of cell type-specific Alzheimer's disease (AD) pathobiology and drug-target discovery for therapeutic development. METHODS: We developed The Alzheimer's Cell Atlas (TACA) by compiling an AD brain cell atlas consisting of over 1.1 million cells/nuclei across 26 data sets, covering major brain regions (hippocampus, cerebellum, prefrontal cortex, and so on) and cell types (astrocyte, microglia, neuron, oligodendrocytes, and so on). We conducted nearly 1400 differential expression comparisons to identify cell type-specific molecular alterations (e.g., case vs healthy control, sex-specific, apolipoprotein E (APOE) ε4/ε4, and TREM2 mutations). Each comparison was followed by protein-protein interaction module detection, functional enrichment analysis, and omics-informed target and drug (over 700,000 perturbation profiles) screening. Over 400 cell-cell interaction analyses using 6000 ligand-receptor interactions were conducted to identify the cell-cell communication networks in AD. RESULTS: All results are integrated into TACA (https://taca.lerner.ccf.org/), a new web portal with cell type-specific, abundant transcriptomic information, and 12 interactive visualization tools for AD. DISCUSSION: We envision that TACA will be a highly valuable resource for both basic and translational research in AD, as it provides abundant information for AD pathobiology and actionable systems biology tools for drug discovery. HIGHLIGHTS: We compiled an Alzheimer's disease (AD) brain cell atlas consisting of more than 1.1 million cells/nuclei transcriptomes from 26 data sets, covering major brain regions (cortex, hippocampus, cerebellum) and cell types (e.g., neuron, oligodendrocyte, astrocyte, and microglia).We conducted over 1400 differential expression (DE) comparisons to identify cell type-specific gene expression alterations. Major comparison types are (1) AD versus healthy control; (2) sex-specific DE, (3) genotype-driven DE (i.e., apolipoprotein E [APOE] ε4/ε4 vs APOE ε3/ε3; TREM2R47H vs common variants) analysis; and (4) others. Each comparison was further followed by (1) human protein-protein interactome network module analysis, (2) pathway enrichment analysis, and (3) gene-set enrichment analysis.For drug screening, we conducted gene set enrichment analysis for all the comparisons with over 700,000 drug perturbation profiles connecting more than 10,000 human genes and 13,000 drugs/compounds.A total of over 400 analyses of cell-cell interactions against 6000 experimentally validated ligand-receptor interactions were conducted to reveal the disease-relevant cell-cell communications in AD.
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Microbiome drives age-dependent shifts in brain transcriptomic programs at the single-cell level in Drosophila.
The gut microbiome plays a critical role in brain function and the brain-gut axis, yet its cellular and molecular mechanisms remain unclear. Here, we present the first comprehensive single-cell transcriptomic atlas of brain cells from adult Drosophila melanogaster raised under axenic and microbiome-associated conditions, spanning young and old ages. Profiling 34,427 cells across 101 clusters, we annotated 56 cell types and identified cell type-specific gene signatures influenced by the microbiome. Transcriptional shifts were most pronounced in old flies, with glial cells and dopaminergic neurons among the most microbiome-responsive cell types. Differentially expressed genes (DEGs) were enriched in pathways related to mitochondrial activity, energy metabolism, and Notch signaling. We also quantified age-associated changes in the gut microbiome, observing reduced Acetobacter dominance and increased microbial diversity that corresponded with heightened brain transcriptional responses. These findings illuminate the cell type-specific impacts of the microbiome on brain gene expression and lay the groundwork for understanding the molecular underpinnings of the microbiome-gut-brain axis.