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Cell atlas of the developing human meninges reveals a dura-like nature of meningiomas.
The vertebrate central nervous system is enveloped by the meninges, consisting of the pia, arachnoid and dura layers. The arachnoid is hypothesized to give rise to the most common primary intracranial tumours, meningiomas. However, supporting molecular evidence is lacking. There are no effective medical therapies to treat meningiomas that are resistant to local interventions, encumbered by our limited understanding of their cellular origin. Here, to advance our understanding of meningioma biology, we generated a comprehensive reference single-cell and spatial transcriptomic atlas of human fetal meninges at postconceptional weeks 5-13. We found that the meningeal layers develop concurrently, and identified an inner CDH1-positive dura layer expressing tight-junction genes consistent with barrier function. Comparing meningiomas with fetal meninges, we show that, transcriptionally, meningioma cells resemble dura-lineage cells, and that common meningioma driver genes were expressed in the dura lineage. This raises the hypothesis that meningiomas could originate from dura-lineage cells.
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Multilayer regulation underlies the functional precision and evolutionary potential of the olfactory system.
Sensory neurons must be reproducibly specified to permit accurate neural representation of external signals but also able to change during evolution. We studied this paradox in the Drosophila olfactory system by establishing a single-cell transcriptomic atlas of all developing antennal sensory lineages, including latent neural populations that normally undergo programmed cell death (PCD). This atlas reveals that transcriptional control is robust, but imperfect, in defining selective sensory receptor expression. A second layer of precision is afforded by the intersection of expression of functionally-interacting receptor subunits. A third layer is defined by stereotyped PCD patterning, which masks promiscuous receptor expression in neurons fated to die and removes "empty" neurons lacking receptors. Like receptor choice, PCD is under lineage-specific transcriptional control; promiscuity in this regulation leads to previously-unappreciated heterogeneity in neuronal numbers. Thus, functional precision in the mature olfactory system belies developmental imprecision that might facilitate the evolution of sensory pathways.
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Single-Cell Transcriptome Decoding Umbilical Cord-Derived Mesenchymal Stem Cell Heterogeneity Reveals a Unique IL1R1HighPDGFRAHigh Ultroser-G-MSC With Osteogenesis and Chondrogenesis Signatures.
The heterogeneity of human umbilical cord mesenchymal stem cells (hUC-MSCs) is culturing-dependent, resulting in functional non-uniformness. To achieve the best clinical benefit, a comprehensive understanding of the origin of the heterogeneity in different culture systems can identify functional subgroups to direct the precise application of hUC-MSCs. Here, we create a single-cell transcriptome atlas of hUC-MSC in different culture systems for the identification of a subgroup of Ultroser-G-MSCs with high osteogenic and chondrogenic potentials featured by high expressions of IL1R1 and PDGFRA. Further experimental validations surprisingly reveal that IL1R1highPDGFRAhigh Ultroser-G-MSCs possess advantages over "traditional" hUC-MSCs in the treatments of modeled osteoarthritis, leading to a cell-cell communication network centered in Clusters 0 and 2. Moreover, we found that Wnt5 signaling is the key pathway for the dynamic transformation of osteogenic and chondrogenic phenotypes in hUC-MSC. Overall, the present study paves the way for the clarification of heterogenetic nature of hUC-MSC in different culture systems for the selection of optimal MSC types to achieve the precision on clinical treatments.
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Single-cell transcriptome delineating asymmetric dynamics of CD4+ T and CD8+ T cell lineage commitment in human prenatal thymus.
INTRODUCTION: The thymus provides a specialized microenvironment for T cell development and selection, yet the cellular heterogeneity and molecular dynamics that govern human prenatal thymopoiesis remain incompletely characterized. METHODS: We constructed an integrative single-cell atlas of human prenatal thymocytes from 7 to 23 post-conception weeks by combining five published datasets. Selection intermediates were classified based on coreceptor expression patterns. Pseudotime analysis, regulon profiling, metabolic analysis, and cell-cell communication modeling were applied to characterize developmental dynamics. RESULTS: We identified three transitional populations, Sel. int. DP, Sel. int. CD4, and Sel. int. CD8, positioned between DP and single-positive stages. Critically, our findings reveal that CD4/CD8 lineage commitment in the developing human thymus is not a single event, but an asymmetric, multi-stage dynamic process. This asymmetry manifests in three distinct dimensions. First, at the signaling level, Sel. int. CD4 cells exhibit enriched TCR and cytokine signaling activities compared to their Sel. int. CD8 counterparts. Second, at the temporal level, CD4 lineage traits emerge coincident with cellular activation, whereas CD8 lineage characteristics appear only after activation subsides. Third, at the microenvironmental level, Sel. int. CD8 and CD8+ T cells display the most extensive interaction networks with thymic stromal cells. Pseudotime analysis delineated two developmental paths branching at the Sel. int. DP stage toward the CD4+ and CD8+ lineages, revealing four distinct gene expression patterns encompassing activation, viral response, differentiation, and apoptotic programs. DISCUSSION: Collectively, this atlas provides a comprehensive resource for understanding the asymmetric, multi-stage dynamics of human prenatal T cell development and the cellular crosstalk that orchestrates CD4/CD8 lineage commitment.
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Single-cell transcriptomic atlas-guided NRG3-ERBB4 axis enhances the efficacy of chemo-immunotherapy during induction phase in high-risk neuroblastoma.
Chemo-immunotherapy (CI) administered during the induction phase markedly ameliorates immune responses and improves clinical efficacy in patients with high-risk neuroblastoma (NB), yet the underlying translational mechanisms remain poorly defined. Single-cell transcriptomic analysis revealed selective activation of the NRG3-ERBB4 axis in pretreatment tumor specimens from high-risk NB patients, accompanied by augmented cytotoxic programs in CD8+ T cells and natural killer cells. During induction therapy, chemotherapy alone suppressed NRG3 and ERBB4 expression, whereas their levels were significantly upregulated upon the addition of naxitamab and positively correlated with NB-reactive immune responses. Functional assays further confirmed that NB cells exposed to CI activated NRG3-ERBB4 signaling, which in turn induced the upregulation of GZMB and GNLY in effector lymphocytes. Integrated analysis of bulk RNA sequencing and lipidomics further demonstrated that the NRG3-ERBB4 rewired ganglioside metabolism to limit its intratumoral accumulation, thereby restoring tumor-reactive immune surveillance. Collectively, these findings delineate an NRG3-ERBB4 axis-centered tumor-immune crosstalk that operates across pretreatment, chemotherapy, and CI, uncovering a previously unrecognized mechanism underlying naxitamab-mediated immune activation. Our results also support ERBB4 as a promising predictive biomarker and therapeutic target to optimize CI strategies for high-risk NB.
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Single-cell and spatial transcriptomics reveal SPRR2A+ epithelial-MMP1+ fibroblast interactions as key drivers of Esophageal Squamous Cell Carcinoma progression.
Esophageal squamous-cell carcinoma is a highly prevalent and lethal malignancy, and its tumor ecosystem is complex and poorly understood; therefore, how malignant epithelial states cooperate with stromal fibroblasts to drive tumor progression remains unclear. Here, we constructed a comprehensive single-cell atlas of primary ESCC tumors, which enabled the subsequent identification of thirteen epithelial subpopulations and seven fibroblast subtypes with distinct functional roles and spatial niches. Further trajectory analysis revealed that progenitor-like PLA2G2A+ fibroblasts differentiate hierarchically into tumor-promoting ACTA2+ and MMP1+ subtypes. Notably, SPRR2A+ epithelial cells and MMP1+ fibroblasts exhibited pronounced spatial co-localization, which may imply reciprocal signaling via TGFB1 and IL6, contributing to the observed extracellular matrix remodeling and malignant behavior. Moreover, functional experiments confirmed that SPRR2A promotes ESCC cell migration and invasion. Altogether, our study characterizes a coordinated epithelial-fibroblast corsstalk and a defined fibroblast differentiation hierarchy, offering new mechanistic insights into the ESCC pro-tumorigenic niche.
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Atlas of cell types and regulatory elements underlying human facial diversity.
Human genetic diversity generates an astonishing variety of facial shapes, and craniofacial anomalies rank among the most common birth defects. Identifying the cellular mechanisms that mediate the genome's influence on facial variation remains a challenge. Here we created a multimodal facial atlas across embryonic weeks 6-11, providing single-cell transcriptomics, chromatin accessibility and spatial transcriptomics, all at single-cell resolution. We characterized 56 cell states, mapping mesenchymal subtypes and their gene-enhancer cis-regulatory landscapes in space and time. Gene expression associations with facial traits were strongest in early mesenchymal progenitor cells, gradually becoming more region restricted. Autocorrelation analysis revealed patterning genes that define spatial neighborhoods of mesenchyme, potentially explaining trait specificity of their nearby variants. Enhancers of key pathology-related genes were found to be likely vehicles for generating facial variation in modern human populations. One such enhancer, linked to PAX1 expression, appears to be important for normal skeletal development in mice. Finally, facial effects inferred from the genome-wide association study, cell signaling interaction analysis and validation in mice revealed that peripheral nerves fine-tune maxilla shape during embryonic development. Together, these data offer new insights into the mechanisms underlying human phenotypic individuality and yield a multimodal atlas useful for studying craniofacial development and abnormalities.
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Single-nucleus transcriptomic atlas of postnatal camel liver development identifies candidate adaptive features.
BACKGROUND: Camels possess distinctive physiological traits related to metabolism and environmental resilience, highlighting the need to characterize liver cellular composition in this species. RESULTS: We used single-nucleus RNA sequencing to generate a developmental atlas of the Bactrian camel (Camelus bactrianus) liver using one individual from each of the newborn, weaning, and adult stages, analyzing 57,036 cells and identifying 19 cell types, including hepatocytes, liver sinusoidal endothelial cells (LSECs), and immune cells. We identified a unique subtype of HGFAC+ LSECs that was not observed in the available cattle or human datasets, characterized by high expression of hepatocyte growth factor activator (HGFAC), which is known to activate hepatocyte growth factor (HGF). Hepatocyte pseudotime ordering was consistent with a putative transition from proliferation-associated states toward metabolically annotated states. In the samples collected in this study, Kupffer cells were more represented in the newborn sample, whereas T-cell subsets were more represented in the adult sample. Exploratory cross-species mapping indicated shared transcriptional features between several adult camel and cattle immune cells. CONCLUSIONS: These results suggest liver biochemical features that may contribute to camel resilience to arid conditions, providing a resource for further studies of camel liver biology and livestock adaptation to harsh environments.
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Charting the single-cell and spatial landscape of IDH-wild-type glioblastoma with GBmap.
BACKGROUND: Glioblastoma (GB), particularly IDH-wild type, is the most aggressive brain malignancy with a dismal prognosis. Despite advances in molecular profiling, the complexity of its tumor microenvironment and spatial organization remains poorly understood. This study aimed to create a comprehensive single-cell and spatial atlas of GB to unravel its cellular heterogeneity, spatial architecture, and clinical relevance. METHODS: We integrated single-cell RNA sequencing data from 26 datasets, encompassing over 1.1 million cells from 240 patients, to construct GBmap, a harmonized single-cell atlas. High-resolution spatial transcriptomics was employed to map the spatial organization of GB tissues. We developed the Tumor Structure Score (TSS) to quantify tumor organization and correlated it with patient outcomes. RESULTS: We showcase the applications of GBmap for reference mapping, transfer learning, and biological discoveries. GBmap revealed extensive cellular heterogeneity, identifying rare populations such as tumor-associated neutrophils and homeostatic microglia. Spatial analysis uncovered 7 distinct tumor niches, with hypoxia-dependent niches strongly associated with poor prognosis. The TSS demonstrated that highly organized tumors, characterized by well-defined vasculature and hypoxic niches, correlated with worse survival outcomes. CONCLUSIONS: This study provides a comprehensive resource for understanding glioblastoma heterogeneity and spatial organization. GBmap and the TSS provide an integrative view of tumor architecture in GB, highlighting hypoxia-driven niches that may represent avenues for further investigation. Our resource can facilitate exploratory analyses and hypothesis generation to better understand disease progression.
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A Single Cell Atlas of the COPD Lung Identifies Inflammatory Reprogramming in Fibroblasts.
BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterized by persistent inflammation, structural remodeling, and irreversible airflow limitation, but the cellular mechanisms that sustain chronic inflammatory remodeling remain poorly understood. METHODS: We integrated newly generated single cell transcriptomic data with publicly available datasets, comprising 6 healthy controls and 10 patients with COPD. Gene expression programs, intercellular communication, pseudotime trajectories, and transcription factor regulatory networks were assessed to define fibroblast associated changes in COPD lung tissue. RESULTS: Fibroblasts exhibited the strongest outgoing signaling activity among lung parenchymal cells and showed the greatest increase in outgoing signaling in COPD. Across multiple fibroblast subpopulations, fibroblasts from COPD lungs acquired a shared proinflammatory and immunoregulatory state associated with inflammatory activation, tissue injury, and fibrotic remodeling. This state was characterized by increased expression of inflammatory mediators and enhanced potential to promote immune cell recruitment and activation. Regulatory analyses further suggested that this inflammatory program was accompanied by extensive remodeling of transcription factor networks in fibroblasts. CONCLUSION: These findings identify fibroblasts as key immunoregulatory cells in COPD lung tissue and suggest that fibroblast associated inflammatory programs may contribute to the maintenance of chronic inflammatory remodeling. Fibroblast centered inflammatory pathways may represent potential targets for future mechanistic and translational studies.