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Tabula Sapiens: An Atlas of Single-Cell Gene Expression.
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PSMD4 promotes malignant phenotypes and is associated with angiogenesis-related signaling and immune remodeling in hepatocellular carcinoma.
BACKGROUND: Proteasome 26 S non-ATPase subunit 4 (PSMD4) is implicated in various cancers, but its role in hepatocellular carcinoma (HCC) is unclear. This study investigates PSMD4 expression, prognostic value, and functions in HCC progression, angiogenesis, and immune regulation. METHODS: TCGA-LIHC was used as the training cohort and ICGC-LIRI as an external validation cohort to assess PSMD4 expression and prognostic value. Human Protein Atlas (HPA) immunohistochemistry data were used to evaluate PSMD4 protein expression. Survival, ROC, nomogram, functional enrichment, immune infiltration, single-cell, and cell-cell communication analyses were performed. Single-cell RNA-seq data from GSE146409 were used to assess cell-type-specific PSMD4 expression and intercellular communication patterns. Spatial transcriptomics data from HRA000437 were used to visualize the spatial distribution of PSMD4 expression in HCC tissues. The biological role of PSMD4 was validated in Huh7 and HepG2 cells using qRT-PCR, CCK-8, colony formation, wound-healing, and western blot assays. RESULTS: PSMD4 was significantly upregulated in HCC in both TCGA-LIHC and ICGC-LIRI cohorts, with positive protein expression confirmed by HPA immunohistochemistry. High PSMD4 expression was associated with poorer overall survival and showed moderate predictive performance for survival outcomes. Enrichment analyses linked PSMD4 to cell-cycle progression, DNA replication, genomic instability, and angiogenesis-related pathways. Single-cell analysis indicated that PSMD4 was mainly enriched in malignant hepatocytes and SPP1⁺ tumor-associated fibroblasts, while spatial transcriptomics analysis showed that PSMD4 expression was concentrated in tumor-dense regions. PSMD4 knockdown inhibited HCC cell proliferation, colony formation, and migration, and reduced VEGFA, RAF1, and MEK1/2 expression. Moreover, high PSMD4 expression was associated with decreased antitumor immune infiltration and suppression of immune activation-related genes. CONCLUSION: PSMD4 is upregulated in HCC and is associated with unfavorable prognosis. Functional assays suggest that PSMD4 contributes to malignant phenotypes and angiogenesis-related signaling in HCC cells, while computational immune analyses indicate an association between high PSMD4 expression and an immunosuppressive immune landscape. These findings suggest that PSMD4 may serve as a potential prognostic biomarker and candidate therapeutic target in HCC.
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Predicting gene regulatory networks from cell atlases.
Recent single-cell RNA-sequencing atlases have surveyed and identified major cell types across different mouse tissues. Here, we computationally reconstruct gene regulatory networks from three major mouse cell atlases to capture functional regulators critical for cell identity, while accounting for a variety of technical differences, including sampled tissues, sequencing depth, and author assigned cell type labels. Extracting the regulatory crosstalk from mouse atlases, we identify and distinguish global regulons active in multiple cell types from specialised cell type-specific regulons. We demonstrate that regulon activities accurately distinguish individual cell types, despite differences between individual atlases. We generate an integrated network that further uncovers regulon modules with coordinated activities critical for cell types, and validate modules using available experimental data. Inferring regulatory networks during myeloid differentiation from wild-type and Irf8 KO cells, we uncover functional contribution of Irf8 regulon activity and composition towards monocyte lineage. Our analysis provides an avenue to further extract and integrate the regulatory crosstalk from single-cell expression data.
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Spatial transcriptomics in neuroscience.
The brain is one of the most complex living tissue types and is composed of an exceptional diversity of cell types displaying unique functional connectivity. Single-cell RNA sequencing (scRNA-seq) can be used to efficiently map the molecular identities of the various cell types in the brain by providing the transcriptomic profiles of individual cells isolated from the tissue. However, the lack of spatial context in scRNA-seq prevents a comprehensive understanding of how different configurations of cell types give rise to specific functions in individual brain regions and how each distinct cell is connected to form a functional unit. To understand how the various cell types contribute to specific brain functions, it is crucial to correlate the identities of individual cells obtained through scRNA-seq with their spatial information in intact tissue. Spatial transcriptomics (ST) can resolve the complex spatial organization of cell types in the brain and their connectivity. Various ST tools developed during the past decade based on imaging and sequencing technology have permitted the creation of functional atlases of the brain and have pulled the properties of neural circuits into ever-sharper focus. In this review, we present a summary of several ST tools and their applications in neuroscience and discuss the unprecedented insights these tools have made possible.
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Nephronectin is required to maintain right lung lobar separation during embryonic development.
Nephronectin (NPNT) is a basement membrane (BM) protein and high-affinity ligand of integrin α8β1 that is required for kidney morphogenesis in mice. In the lung, NPNT also localizes to BMs, but its potential role in pulmonary development has not been investigated. Mice with a floxed Npnt allele were used to generate global knockouts (KOs). Staged embryos were obtained by timed matings of heterozygotes and lungs were isolated for analysis. Although primary and secondary lung bud formation was normal in KO embryos, fusion of right lung lobes, primarily the medial and caudal, was first detected at E13.5 and persisted into adulthood. The lung parenchyma of KO mice was indistinguishable from wild-type (WT) and lobe fusion did not alter respiratory mechanics in adult KO mice. Interrogation of an existing single-cell RNA-seq atlas of embryonic and adult mouse lungs identified Npnt transcripts in mesothelial cells at E12.5 and into the early postnatal period, but not in adult lungs. KO embryonic lungs exhibited increased expression of laminin α5 and deposition of collagen IV in the mesothelial BM, accompanied by abnormalities in collagen fibrils in the adjacent stroma. Cranial and accessory lobes extracted from KO embryonic lungs fused ex vivo when cultured in juxtaposition, with the area of fusion showing loss of the mesothelial marker Wilms tumor 1. Because a similar pattern of lobe fusion was previously observed in integrin α8 KO embryos, our results suggest that NPNT signaling through integrin α8, likely in the visceral pleura, maintains right lung lobe separation during embryogenesis.
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Clump sequencing exposes the spatial expression programs of intestinal secretory cells.
Single-cell RNA sequencing combined with spatial information on landmark genes enables reconstruction of spatially-resolved tissue cell atlases. However, such approaches are challenging for rare cell types, since their mRNA contents are diluted in the spatial transcriptomics bulk measurements used for landmark gene detection. In the small intestine, enterocytes, the most common cell type, exhibit zonated expression programs along the crypt-villus axis, but zonation patterns of rare cell types such as goblet and tuft cells remain uncharacterized. Here, we present ClumpSeq, an approach for sequencing small clumps of attached cells. By inferring the crypt-villus location of each clump from enterocyte landmark genes, we establish spatial atlases for all epithelial cell types in the small intestine. We identify elevated expression of immune-modulatory genes in villus tip goblet and tuft cells and heterogeneous migration patterns of enteroendocrine cells. ClumpSeq can be applied for reconstructing spatial atlases of rare cell types in other tissues and tumors.
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CD38⁺ endothelial remodeling marks spatially patterned vasculopathy in rapidly advancing periodontitis and peri-implantitis.
Oral inflammatory diseases affect nearly half of all humans, yet mechanisms underlying rapidly-destructive inflammation remain poorly understood. We compared peri-implantitis with moderate- and high-grade periodontitis using integrated microbial and single-cell sequencing (>967,169-cells; single-cell RNA-seq, spatial proteotranscriptomics). Laser capture microdissection with compartmental microbiome analysis revealed reduced bacterial load and diversity in peri-implantitis. Expansion of the Human Periodontal Atlas with peri-implantitis single-cell RNA-seq data (36-samples; 121,395 cells) identified CD34+ vascular endothelial cell (VEC) rarefaction and oxidative stress, hypoxia, and NAD⁺ metabolism-associated transcriptional programs enriched in a TNFRSF6B⁺/ICAM1⁺ post-capillary venule (PC-VEC) subpopulation. NAD⁺-consuming ectoenzyme CD38 was selectively enriched and orthogonally confirmed by spatial transcriptomics (6-samples; 283,377-cells) and proteomics (23-samples; 562,397-cells). Spatial neighborhood analyses demonstrated CD38⁺-high PC-VEC expansion, closer proximity, and higher IL16-CD4 T cell signaling in peri-implantitis. Matched high-grade periodontitis biopsies confirmed spatially restricted CD38⁺-VECs despite similar microbial burden, identifying endothelial vasculopathy underlying rapidly advancing oral inflammation and a potential therapeutic axis.
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LiverSCA: A comprehensive and user-friendly cell atlas in human hepatocellular carcinoma.
We developed a cell atlas named LiverSCA on human liver cancer single-cell RNA sequencing data. It has a user-friendly web interface and comprehensive functionalities aiming to help researchers to make easy access to cellular and molecular landscapes of the tumor microenvironment in liver cancer. LiverSCA includes a complete analytical pipeline that allow mechanistic exploration on a wide variety of functionalities, such as cell clustering, cell annotation, identification of differentially expressed genes, functional enrichment analysis, analysis of cellular crosstalk, and pseudo-time trajectory analysis. Notably, our intuitive web interface allows users, particularly wet-lab researchers, to easily explore and undertake data discovery, without the need to handle any of the raw data.
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A unified developmental timeline of pigmented ocular tissues in the mouse eye.
Pigmented tissues of the vertebrate eye are essential for optical performance, metabolic support, and tissue homeostasis, yet their coordinated development has been difficult to study because melanin interferes with histological and immunohistochemical analyses. Here, we apply a gentle hydrogen peroxide based bleaching method compatible with IHC for Rpe65, Rhodopsin, ZO-1, Cralbp/Rlbp1, S100b, and Cd34, and examined Dct/Tyrp2 expression, to generate a unified developmental atlas of all pigmented tissues in the mouse eye. We also re-analyzed published single-cell RNA-seq datasets from developing and adult mouse eyes to examine gene expression patterns across pigmented ocular tissues. Using daily samples from embryonic day 14.5 (E14.5) through postnatal day 14 (P14), we tracked the emergence and maturation of pigmented cell populations in the retinal pigment epithelium (RPE), choroid, ciliary body, and iris. The RPE, the earliest tissue to synthesize melanin, does not acquire continuous Rpe65 expression, apical-basal polarity, or full morphological maturity until eyelid opening. Neural crest-derived melanocytes in the choroid, ciliary body and iris undergo distinct maturation phases marked by early Dct expression, subsequent melanin synthesis, and late induction of S100b. In the innermost layer of the future iris epithelium, early Dct expression precedes postnatal pigmentation. Notably, we observe a coordinated burst of melanogenesis across multiple ocular and periocular tissues immediately after birth, suggesting regulation by systemic developmental transitions rather than light exposure. Together, these findings establish a comprehensive timeline for the maturation of pigmented ocular tissues, providing a clearer framework for studying eye development and disease.
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CD13 identifies S100A4+ immunosuppressive monocytes and predicts temozolomide benefit in glioblastoma.
BACKGROUND: Glioblastoma (GBM) is an immunologically "cold" tumor in which S100A4-driven immunosuppressive myeloid cells promote progression and resistance. However, the specific immune subpopulation that intrinsically expresses S100A4 and the corresponding cell surface targets remain poorly defined. MATERIALS AND METHODS: S100A4 expression was profiled across immune subsets in healthy human bone marrow and peripheral blood by flow cytometry. TCGA GBM datasets were used to identify S100A4-correlated surface markers, and CD13 (encoded by ANPEP) was validated across the Human Protein Atlas, Immgen, GEO and single-cell RNA-seq datasets. The functional link between CD13, S100A4, and TGFβ was assessed by network analysis and correlation. Drug response analysis was conducted using GEPIA 3 platform. RESULTS: Monocytes were the predominant S100A4-expressing population in both bone marrow and peripheral blood. CD13 emerged as the surface marker most significantly correlated with S100A4 in GBM. CD13+ monocytes co-expressed high levels of S100A4 and were transcriptionally positioned between monocytic and granulocytic lineages. These cells displayed a strong association with TGFβ signaling, suggesting a CD13-TGFβ-S100A4 immunosuppressive axis. Notably, temozolomide conferred a significant survival benefit specifically in CD13-high GBM patients. CONCLUSIONS: CD13 marks S100A4-high immunosuppressive monocytes in GBM and represents an accessible surface target for monitoring and potentially depleting this pathogenic population. The CD13-S100A4-TGFβ axis and the predictive value of CD13 for temozolomide response offer a translational framework for advancing GBM immunotherapy.