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Single-cell transcriptomic atlas of shrimp hepatopancreas reveals an endoplasmic reticulum stress-dependent immune response to Vibrio parahaemolyticus infection.
Innate immunity represents the sole immune defense system of crustaceans. Single-cell RNA sequencing (scRNA-Seq) has greatly advanced the exploration of invertebrate immune mechanisms, enabling a more detailed understanding of immune responses and their underlying molecular pathways. In this study, we employed single-cell nuclear sequencing (snRNA-Seq) to characterize the cellular atlas of the hepatopancreas in the whiteleg shrimp Litopenaeus vannamei in response to Vibrio parahaemolyticus infection. We captured over 20,000 high-quality cells and classified them into five distinct cell types (B, F, E, M, and R cells). Approximately 1400 to 2800 differentially expressed genes (DEGs) were identified in each of the five cell types. Although R cells exhibited the highest number of DEGs in response to bacterial infection, a substantial proportion of DEGs (approximately 33%) were shared across all five cell types. Further analysis revealed that these common DEGs were primarily enriched in endoplasmic reticulum (ER) stress and cell death-related processes. Concurrently, pseudotime trajectory analysis identified a cluster of DEGs highly associated with the antibacterial response, which showed a close relationship with integrin molecules. Finally, protein-level assessment (Western blot and immunohistochemistry) confirmed the presence and activation of ER stress, protein ubiquitination, apoptosis, and autophagy in hepatopancreatic cells during bacterial infection. In summary, this study enhances our understanding of antibacterial immunity in crustaceans and suggests potential evolutionary parallels of ER stress-induced immunomodulation, a finding that is consistent with stress-associated immune regulatory patterns reported in diverse taxa.
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Transcriptome-based classification in mice with ASD-risk mutations.
Autism spectrum disorder (ASD) is a neurodevelopmental condition with a strong genetic component. Large-scale human genetic studies have identified >1200 ASD-risk genes. We report a sex-balanced atlas of 1008 prefrontal RNA sequencing (RNA-seq) profiles from 17 mouse lines carrying ASD-risk mutations. Our analysis identified two opposing transcriptomic states. The two groups differed in sex bias, regional specificity, developmental stability, cell type remodeling, and responses to fluoxetine and lithium. Single-nucleus RNA-seq revealed broader cell type remodeling in group 1 than in group 2, and cell type-specific modules showed reciprocal associations that mirrored bulk transcriptomic signatures. The framework classifies independent mouse lines and identifies subgroups with conserved synaptic directionality, supporting molecular stratification.
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Spatiotemporal interplay between epithelial and mesenchymal cells drives human dentinogenesis.
Tooth dentin, secreted by odontoblasts, constitutes most of the tooth structure and provides support and sensory function. However, dentin defects are common and irreparable once they exceed a critical threshold. Human dentin develops from dental papilla (DP) cells under the guidance of the dental epithelium (DE). Here, we present a human tooth development atlas from initiation to erupted stage using single-cell RNA sequencing and spatial transcriptomics, focusing on epithelial-mesenchymal interactions. This atlas reveals that DE orchestrates DP differentiation in a WNT-NOTCH sequential activation model and identifies the key signaling molecules. DLX6-AS1+ DP cells respond to dental epithelial signals and can be isolated from adult dental pulp stem cells (DPSCs). Notably, DLX6-AS1+ DPSCs successfully generate tubular dentin in an in vivo disease model of dentin defects. This research provides valuable information on human tooth development and establishes a basis for repairing regenerative dental tissue.
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Human lung allografts experience persistent fibrogenic shift following acute cellular rejection.
RATIONALE: Acute cellular rejection (ACR) remains a significant challenge in lung transplantation, with incomplete understanding of its molecular mechanisms and pathways linking ACR to chronic lung allograft dysfunction (CLAD). OBJECTIVES: To characterize the cellular and molecular mechanisms underlying ACR in lung allografts using single cell genomics and identify potential therapeutic targets for CLAD. METHODS: Single cell RNA-sequencing of freshly collected lung tissue was performed across 8 pediatric and adult patients with ACR, Resolved ACR, and surveillance biopsies without ACR. Validation included gene microarray analysis, immunofluorescence, and single cell ATAC-seq. MEASUREMENTS AND MAIN RESULTS: Gene set enrichment analysis revealed persistent TGF-β signaling and PI3K/AKT/mTOR pathway activation in both ACR and Resolved samples, validated by immunofluorescence showing sustained elevation of mTOR activation marker phosphorylated-S6 ribosomal protein and COL3A1. Fibrogenic cells exhibited myofibroblast gene signatures via mesenchymal state transitions rather than epithelial- or endothelial-to-mesenchymal transition. Cell communication analysis showed increased Type II Interferon signaling, with Jak/Stat pathway activation in endothelial and basal cells, and reduced VE-Cadherin staining in ACR. Compositional analysis revealed increased cytotoxic, memory T cells and dendritic cells, with persistent reduction of natural killer cells in ACR and Resolved. Donor/recipient analysis revealed predominantly recipient-derived immune cells in ACR. CONCLUSIONS: Persistent TGF-β and mTOR pathway activation following histologic ACR resolution provides molecular insight into ACR-CLAD linkage and suggests mTOR inhibition and TGF-β blockade as potential therapeutic mechanisms to prevent CLAD.
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Mapping glioblastoma's isoform diversity using long-read single-cell analysis.
Glioblastoma is a highly aggressive brain tumor with poor prognosis, partly driven by extensive intratumoral heterogeneity and widespread dysregulation of RNA splicing. Alternative splicing shapes cellular identity and function and contributes to tumor progression and treatment resistance. While single-cell RNA sequencing has revealed diverse cellular states within glioblastoma, conventional short-read approaches cannot resolve full-length isoforms. Here, we apply single-cell long-read RNA sequencing to construct an isoform-level atlas of glioblastoma. By capturing full-length transcripts at single-cell resolution, hundreds of isoforms with differential transcript usage across distinct tumor cell populations are identified. We develop a framework to prioritize tumor-restricted isoforms and identify surface-intracellular target pairs in seven patients, suggesting opportunities for dual-specific ligand-based therapies. Furthermore, 6524 isoforms absent from existing annotations are discovered, including 179 that are tumor-specific. Peptides derived from these isoforms show strong predicted binding to major histocompatibility complex class I molecules, highlighting their potential as neoantigens.
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CDState Resolves Malignant Cell Heterogeneity from Bulk Tumor RNA Sequencing Data.
UNLABELLED: Intratumor transcriptional heterogeneity (ITTH), defined as the coexistence of diverse cell states within a single tumor, complicates cancer treatment and contributes to variable therapeutic responses. Although single-cell RNA sequencing (scRNA-seq) can resolve this complexity, its cost and technical demands limit large-scale use. Bulk RNA-seq provides a scalable alternative but requires computational methods to deconvolve bulk transcriptomes into distinct cell states. Existing supervised approaches rely on accurate reference data, which are lacking for many cancer types, whereas unsupervised methods are not tailored to capture heterogeneity within the malignant compartment. To address these limitations, we developed CDState, an unsupervised deconvolution method based on nonnegative matrix factorization with a sum-to-one constraint and a cosine similarity-based optimization, which infers malignant cell states using bulk RNA-seq data. CDState demonstrated robustness using pseudobulk scRNA-seq datasets from five cancer types, outperforming existing unsupervised methods in estimating both state-specific gene expression and cell proportions. Applied to 33 cancer types from The Cancer Genome Atlas, CDState revealed recurrent gene programs, including epithelial-mesenchymal transition, MYC targets, and oxidative phosphorylation, as major contributors to malignant ITTH. The malignant state proportions were linked to clinical features, including patient survival and therapeutic response. Finally, mutations and copy-number alterations in genes such as TP53, KRAS, PIK3CA, SOX2, and SATB1 were identified as potential genetic drivers of malignant cell ITTH across cancer types. This study demonstrates the utility of CDState for characterization of malignant cell states from bulk RNA-seq data, establishing a framework for investigating malignant cell ITTH in large-scale cancer atlases. SIGNIFICANCE: CDState leverages bulk RNA sequencing to resolve malignant states, revealing recurrent patterns of tumor heterogeneity that may help interpret outcomes and guide future biomarker development.
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Integrating spatial and single-cell transcriptomics analysis reveals MYCN-UBE2C-TFRC signaling endows ferroptosis resistance in neuroectodermal tumors.
MYCN amplification is a recurrent, high-risk molecular hallmark across diverse tumors, most notably neuroectodermal malignancies. Although MYCN-driven tumors uniformly exhibit robust intrinsic resistance to ferroptosis, the mechanistic link between MYCN and the ferroptotic pathway remains undefined. Here, we charted the genomic and epigenomic landscape of neuroectodermal tumors by combining single-cell RNA-seq, spatial transcriptomics (ST), CUT&Tag, and deep-coverage mass spectrometry proteomics. This integrative atlas identified UBE2C as a spatially resolved, MYCN-controlled driver gene. MYCN occupies the UBE2C promoter and potently transactivates its transcription, thereby accelerating tumor progression in vitro and in vivo. Re-expression of UBE2C fully rescued the proliferative arrest triggered by MYCN depletion, confirming its essential function downstream of MYCN. Proteomic interrogation of the UBE2C interactome further revealed that the tumor suppressor TFRC is a previously unknown ubiquitination substrate of UBE2C. Mechanistically, the polyubiquitination and proteasomal degradation of TFRC by UBE2C reduces iron influx and effectively shields cancer cells from ferroptosis. Clinically, genetic silencing of UBE2C induces ferroptosis and sensitizes tumor cells to the ferroptosis inducer erastin, revealing a therapeutically exploitable vulnerability in MYCN-amplified malignancies. Our study reveals a previously unrecognized MYCN-UBE2C-TFRC-ferroptosis regulatory axis that drives neuroectodermal tumor growth. These findings establish a mechanistic rationale for combining UBE2C silencing and ferroptosis induction as a precision therapeutic strategy against MYCN-amplified tumors.
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ScRNA-Seq Reveals a Distinct Osteogenic Progenitor of Alveolar Bone.
The metabolism and remodeling of alveolar bone are the most active among the whole skeletal system, which is related to the biological characteristics and heterogeneity of the bone mesenchymal stromal cells (MSCs). However, there is a lack of systematic description of the heterogeneity of MSC-derived osteoblastic lineage cells as well as their distinct osteogenic differentiation trajectory of alveolar bone. In this study, we constructed a single-cell atlas of the mouse alveolar bone cells through single-cell RNA sequencing (scRNA-seq). Remarkably, by comparing the cell compositions between the alveolar bone and long bone, we uncovered a previously undescribed cell population that exhibits a high expression of protocadherin Fat4 (Fat4+ cells) and is specifically enriched around alveolar bone marrow cavities. ScRNA-seq analysis indicated that Fat4+ cells may initiate a distinct osteogenic differentiation trajectory in the alveolar bone. By isolating and cultivating Fat4+ cells in vitro, we demonstrated that they possess colony-forming, osteogenic, and adipogenic capabilities. Moreover, FAT4 knockdown could significantly inhibit the osteogenic differentiation of alveolar bone MSCs. Furthermore, we revealed that the Fat4+ cells exhibit a core transcriptional signature consisting of several key transcription factors, such as SOX6, which are involved in osteogenesis, and further demonstrated that SOX6 is required for the efficient osteogenic differentiation of the Fat4+ cells. Collectively, our high-resolution single-cell atlas of the alveolar bone reveals a distinct osteogenic progenitor that may contribute to the unique physiological characteristics of alveolar bone.
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A spatiotemporal atlas of orchiectomy-induced androgen deprivation-mediated modulation of cellular composition and gene expression in the mouse prostate.
Androgen deprivation therapy (ADT) remains a cornerstone in the treatment of prostate cancer (PCa), yet most tumors eventually develop resistance. Murine models are widely used to study PCa progression and ADT response, but a detailed understanding of the prostate's biological response to androgen deprivation in these models is lacking. Here, we present a spatiotemporal analysis of cellular and transcriptional dynamics in the mouse prostate following orchiectomy (ORX)-induced androgen deprivation with a focus on non-epithelial components. We observed progressive involution across all prostate lobes (dorsal, ventral, lateral, and anterior) and distinct lobe-specific temporal gene expression changes post-ORX. Immune cell infiltration markedly increased over time, highlighting a shift in the prostate's cellular landscape. Single-cell RNA sequencing uncovered a previously undescribed fibroblast subtype-termed ORX-induced fibroblast (OIF)-characterized by high expression of Wnt2, Rorb, and Wif1, with distinct spatial localization. Pathway analysis revealed upregulation of amide and peptide binding functions, alongside suppression of peptidase and endopeptidase activity. Furthermore, dynamic changes in ligand-receptor interactions across lobes underscored the evolving intercellular communication in the post-ORX prostate. By integrating spatial transcriptomics with single-cell profiling, our study generates a high-resolution atlas of the murine prostate's response to androgen deprivation. These findings provide a foundational resource for interpreting ADT responses in preclinical models of PCa.
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Single-cell multiomic and spatial landscape of the primate pineal gland reveals circadian and melatonin regulatory architecture.
The mammalian pineal gland maintains normal circadian rhythms and homeostasis by secreting melatonin. However, the lack of a single-cell-resolved regulatory map limits our understanding of how these neuroendocrine functions are orchestrated. Here, we constructed a multiomics atlas of the pineal gland from Macaca fascicularis by integrating snRNA-seq, snATAC-seq, and spatial transcriptomics. We identified pinealocytes as the predominant cell type, alongside six glial and vascular lineages. Chromatin accessibility analysis delineated cell-type-specific regions enriched for melatonin synthesis and phototransduction genes. Notably, we resolved a dual-layer regulatory architecture: While melatonin synthesis programs are robustly organized, circadian clock regulators exhibit a distinct, sparse spatial pattern. Coexpression networks further identified core modules and regulatory hubs-including CRX/OTX2, LHX4, and RORA-that integrate these circadian and light-responsive signals. Cell-cell communication analysis identified signaling axes, such as PTN-ALK/SDC2, RA-RORB, and NRG1-ERBB4, that potentially coordinate this spatial functional organization. Integrating genetic traits showed that sleep and neuropsychiatric risk variants preferentially map to these pineal regulatory modules. Specifically, sleep-associated loci converged on MEIS1-linked elements, while bipolar disorder-associated loci highlighted candidate genes of RDH12 and SDK2. Overall, this study reveals the cellular diversity and spatial regulatory logic of the primate pineal gland, providing a physiological foundation for investigating circadian and neuroendocrine regulation in healthy and disease models.