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Single cell atlas of developing mouse dental germs reveals populations of CD24+ and Plac8+ odontogenic cells.
The spatiotemporal relationships in high-resolution during odontogenesis remain poorly understood. We report a cell lineage and atlas of developing mouse teeth. We performed a large-scale (92,688 cells) single cell RNA sequencing, tracing the cell trajectories during odontogenesis from embryonic days 10.5 to 16.5. Combined with an assay for transposase-accessible chromatin with high-throughput sequencing, our results suggest that mesenchymal cells show the specific transcriptome profiles to distinguish the tooth types. Subsequently, we identified key gene regulatory networks in teeth and bone formation and uncovered spatiotemporal patterns of odontogenic mesenchymal cells. CD24+ and Plac8+ cells from the mesenchyme at the bell stage were distributed in the upper half and preodontoblast layer of the dental papilla, respectively, which could individually induce nonodontogenic epithelia to form tooth-like structures. Specifically, the Plac8+ tissue we discovered is the smallest piece with the most homogenous cells that could induce tooth regeneration to date. Our work reveals previously unknown heterogeneity and spatiotemporal patterns of tooth germs that may lead to tooth regeneration for regenerative dentistry.
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Multi-omics data reveal that SAA1 + fibroblasts exacerbate periodontitis by regulating macrophage inflammation and chemotaxis.
BACKGROUND: Traditional techniques are limited in their ability to analyze the complex interaction mechanisms among multiple cell types within the periodontal microenvironment, thereby restricting the development of targeted therapies for periodontitis (PD). Utilizing multiomics technologies to investigate the interaction networks of key cell clusters can systematically uncover regulatory mechanisms and identify critical therapeutic targets. METHODS: Through integrative analysis of single-cell RNA sequencing (scRNA-seq), spatial transcriptomics, and bulk transcriptome datasets from periodontal tissues, we systematically characterized the spatial architecture and intercellular communication networks within the inflammatory periodontal microenvironment, identifying a functionally serum amyloid A1 + fibroblasts (SAA1 + Fib) that critically drives disease progression. Combined bioinformatics and functional validations (in vitro and in vivo) revealed the proinflammatory role of SAA1 + Fib, demonstrating their unique transcriptional profile and mechanistic contributions to periodontal inflammation. RESULTS: This study successfully constructed a single-cell transcriptome atlas comprising 65,979 periodontal tissue cells and identified an SAA1 + fibroblast subpopulation with key functions. Cell communication analysis revealed that this subpopulation mediates the infiltration of myeloid cells, such as macrophages, to the lesion site by secreting chemokine-related signaling molecules, including members of the SAA, CXCL, and CSF families. Animal experiments confirmed a significant increase in SAA1 expression levels in both the gingival tissue and peripheral blood of periodontitis model mice. Gene function studies indicated that SAA1 knockout resulted in reduced migration ability and enhanced proliferation activity of L929 cells, while significantly decreasing the secretion of inflammatory factors such as IL-6 and TNF-α. In a co-culture system of L929 cells and RAW264.7 cells, SAA1 knockout not only diminished the chemotactic effect of fibroblasts on macrophages but also suppressed the secretion of inflammatory factors and inhibited M1 polarization of macrophages. Mechanistic studies indicated that these effects were likely mediated by the suppression of NF-κB signaling pathway activity in RAW264.7 cells. CONCLUSION: We elucidated the pro-inflammatory properties of SAA1 + Fib and their role in promoting macrophage infiltration, targeting SAA1 offers a new approach for the treatment of PD.
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Molecular and Chromatin Accessibility Programs Underlying Epithelial Injury and Impaired Regeneration in Neonatal Necrotizing Enterocolitis.
BACKGROUND & AIMS: Neonatal necrotizing enterocolitis (NEC) is a severe gastrointestinal disorder with high mortality, characterized by epithelial cell injury and compromised epithelial repair. The mechanisms underlying defective epithelial regeneration remain poorly understood despite advances in single-cell omics. Addressing these challenges is essential for elucidating the pathogenesis of NEC and identifying therapeutic targets to restore epithelial regeneration and replace the damaged epithelial layer. METHODS: Using a well-established neonatal mouse model of NEC induced by formula feeding, hypoxia, and lipopolysaccharide, we applied an integrated multi-omics framework to map epithelial injury at transcriptomic, chromatin accessibility, and spatial levels. These included bulk RNA sequencing, single-nucleus RNA sequencing (snRNA-seq), single-nucleus assay for transposase-accessible chromatin sequencing (snATAC-seq), and multiplexed error-robust fluorescence in situ hybridization (MERFISH) for spatial transcriptomics. Complementary in vitro experiments and in vivo mouse models were utilized to evaluate NEC phenotypes, intestinal tissue morphology, and organoid formation. RESULTS: Changes in cell type composition, transcriptional network remodeling, and chromatin accessibility were observed in the small intestine of neonatal mice with NEC. Chromatin accessibility significantly changed in epithelial cells, highlighting their pivotal roles in NEC. A marked reduction in intestinal stem cells (ISCs) and transit-amplifying cells, along with an increased proportion of enteroendocrine cells, indicates disrupted epithelial regeneration and functional differentiation. These changes correlated with disrupted WNT signaling and stem cell maintenance genes (eg, Lgr5, Smoc2, Axin2) and activation of inflammatory and hypoxia-related pathways (eg, Il6, Tnfα). The epigenetic regulator Ezh2 was identified as a critical factor in maintaining LGR5+ ISCs and epithelial homeostasis. Knockdown of Ezh2 reduced stemness and proliferation-related gene expression and exacerbated inflammation. Reactivation of WNT signaling restored Ezh2 and Lgr5 expression, improving intestinal regeneration. CONCLUSIONS: This study provides a comprehensive multi-omics atlas of epithelial injury in experimental NEC and reveals Ezh2 as a key regulator of LGR5+ ISC identity and regeneration. By integrating chromatin, transcriptomic, and spatial information, our findings highlight previously unrecognized mechanisms of ISC failure in NEC and support therapeutic strategies targeting Ezh2 and WNT signaling to restore epithelial integrity.
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Cross-talk of m6A methylation modification and the tumor microenvironment composition in esophageal cancer.
BACKGROUND: Esophageal cancer (EC) remains a significant clinical challenge, characterized by its aggressive nature and poor prognosis. Current therapeutic strategies, including targeted therapies, have limitations due to the complex interplay between tumor heterogeneity and the tumor microenvironment (TME). However, the specific contributions of N6-methyladenosine (m6A) methylation to the TME in EC are yet to be fully elucidated. METHODS: Through comprehensive bioinformatics analyses, a detailed examination of m6A regulators were conducted in EC using datasets from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). Single-cell RNA sequencing (scRNA-seq) and a consensus clustering algorithm was employed to classify m6A modification patterns and analyze their relationships with immune cell infiltration and clinical outcomes. Additionally, an m6A scoring system was developed based on principal component analysis to assess the prognostic value of identified m6A modification patterns. RESULTS: The findings revealed two distinct m6A modification clusters associated with divergent TME characteristics and immune infiltration profiles. Patients exhibiting the immune-inflamed phenotype (m6A cluster B) demonstrated significantly improved survival compared to those with the immune-excluded phenotype (m6A cluster A). Notably, m6A scores correlated positively with immune cell presence and related with adverse prognostic outcomes, indicating their potential as predictive biomarkers for immunotherapy responses. A low m6A score indicated a better response to immunotherapy. CONCLUSION: This study highlights the critical role of m6A methylation in shaping the TME and influencing immune dynamics in EC. The m6A score developed herein provides a novel quantitative tool for predicting tumor behavior and treatment efficacy, paving the way for more personalized immunotherapeutic strategies in clinical practice. This scoring system illustrates a strong correlation of EC with TME immune cell composition, suggesting potential as a biomarker for targeted therapeutic strategies for EC.
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Transcriptomic profiles of single-cell autophagy-related genes (ATGs) in lung diseases.
Autophagy related genes (ATGs) play essential roles in maintaining cellular functions, although biological and pathological alterations of ATG phenotypes remain poorly understood. To address this knowledge gap, we utilized the single-cell sequencing technology to elucidate the transcriptomic atlas of ATGs in lung diseases, with a focus on lung epithelium and lymphocytes. This study conducted a comprehensive investigation into RNA profiles of ATGs in the lung tissues obtained from healthy subjects and patients with different lung diseases through single-cell RNA sequencing (scRNA-seq), including COVID-19 related acute lung damage, idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD), systemic sclerosis (SSC), and lung adenocarcinoma (LUAD). Our findings revealed significant variations of ATGs expression across lung epithelial cell subsets, e.g., over-expression of MAPK8 in basal cells, ATG10 in club cells, and BCL2 in a goblet cell subset. The changes of autophagy-related pathways varied between lung epithelial and lymphocyte subsets. We identified the disease-associated changes in ATG expression, including significant alterations in BCL2, BCL2L1, PRKCD, and PRKCQ in inflammatory lung diseases (COPD and IPF), and MAP2K7, MAPK3, and RHEB in lung cancer (LUAD), as compared to normal lung tissues. Key ligand-receptor pairs (e.g., CD6-ALCAM, CD99-CD99) and signaling pathways (e.g., APP, CD74) might serve as biomarkers for lung diseases. To evaluate ATGs responses to external challenges, we examined ATGs expression in different epithelial cell lines exposed to cigarette smoking extract (CSE), lysophosphatidylcholine (lysoPC), lipopolysaccharide (LPS), and cholesterol at various doses and durations. Notable changes were observed in CFLAR, EIF2S1, PPP2CA, and PPP2CB in A549 and H1299 against CSE and LPS. The heterogeneity of ATGs expression was dependent on cell subsets, pathologic conditions, and challenges, as well as varied among cellular phenotypes, functions, and behaviors, and the severity of lung diseases. In conclusion, our data might provide new insights into the roles of ATGs in epithelial biology and pulmonary disease pathogenesis, with implications for disease progression and prognosis.
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A single-cell multi-omics atlas of rice.
Cell functions across eukaryotes are driven by specific gene expression programs, which are dependent on chromatin structure1-3. Here we report a single-cell multi-omics atlas of rice, one of the world's major crops. By simultaneously profiling chromatin accessibility and RNA expression in 116,564 cells from eight organs, we identified cell-type-specific gene regulatory networks and described novel cell states, such as a 'transitional state' in floral meristems. On the basis of our network analyses, we uncovered the function of the cell-type-specific regulatory hubs RSR1, F3H and LTPL120 during rice development. Our analysis revealed correlations between cell type and agronomic traits, as well as conserved and divergent cell-type functions during evolution. In summary, this study not only offers a unique single-cell multi-omics resource for a major crop but also advances our understanding of cell-type functions and the underlying molecular programs in rice.
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scImmOmics: a manually curated resource of single-cell multi-omics immune data.
Single-cell sequencing technology has enabled the discovery and characterization of subpopulations of immune cells with unique functions, which is critical for revealing immune responses under healthy or disease conditions. Efforts have been made to collect and curate single-cell RNA sequencing (scRNA-seq) data, yet an immune-specific single-cell multi-omics atlas with harmonized metadata is still lacking. Here, we present scImmOmics (https://bio.liclab.net/scImmOmics/home), a manually curated single-cell multi-omics immune database constructed based on high-quality immune cells with known immune cell labels. Currently, scImmOmics documents >2.9 million cell-type labeled immune cells derived from seven single-cell sequencing technologies, involving 131 immune cell types, 47 tissues and 4 species. To ensure data consistency, we standardized the nomenclature of immune cell types and presented them in a hierarchical tree structure to clearly describe the lineage relationships within the immune system. scImmOmics also provides comprehensive immune regulatory information, including T-cell/B-cell receptor sequencing clonotype information, cell-specific regulatory information (e.g. gene/chromatin accessibility/protein/transcription factor states within known cell types, cell-to-cell communication and co-expression networks) and immune cell responses to cytokines. Collectively, scImmOmics is a comprehensive and valuable platform for unraveling the heterogeneity and diversity of immune cells and elucidating the specific regulatory mechanisms at the single-cell level.
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Single-cell atlas in the living fossil Yangtze sturgeon provides insight into the evolution of fish.
BACKGROUND: Fish are the largest group of vertebrates. Studying the characteristics, functions, and interactions of different fish cells is important for understanding their roles in disease and evolution. However, most single cell RNA-seq studies in fish are restricted to a few specific organs, leaving a comprehensive cell landscape that aims to characterize the heterogeneity and connections among body-wide organs largely unexplored. RESULTS: We construct a single-cell atlas from the Yangtze sturgeon, Acipenser dabryanus, containing 82,401 high-quality cells and identify 72 major cell types. We compare differentially expressed genes among enterocytes in each part of the intestines and reveal the differences in absorption function of pyloric caecum, duodenum, spiral intestine, and rectum. Best4/Otop2 cells, newly identified in human, are also found in the intestines of sturgeon, indicating that these cells originated in an ancient period. We confirm the status of Müller glia as resident stem cells in fish nervous systems. We also characterize the different immune function between mucosa- and systemic-associated tissues. We detect several unexpected types of cells in Yangtze sturgeon, confirming that sturgeon is basal to teleosts. Cross-species analysis further indicates that sturgeon might occupy an ancient evolutionary position bridging the transition from cartilaginous to bony fish. In addition, novel cell markers, transcription factors, and intercellular communications are identified and found to be associated with the biological functions of specific types of cells. CONCLUSION: We generate the cellular landscape of an ancient fish and provide a valuable resource for revealing the cellular heterogeneity and biology of vertebrates.
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NR2F6, a new immune checkpoint that acts as a potential biomarker of immunosuppression and contributes to poor clinical outcome in human glioma.
INTORODUCTION: Nuclear receptor subfamily 2 group F member 6 (NR2F6) is a promising checkpoint target for cancer immunotherapy. However, there has been no investigation of NR2F6 in glioma. Our study systematically explored the clinical characteristics and biological functions of NR2F6 in gliomas. METHODS: We extracted RNA sequencing (RNA-seq) data of 663 glioma samples from The Cancer Genome Atlas (TCGA) as the training cohort and 325 samples from the Chinese Glioma Genome Atlas (CGGA) as the validation cohort. We also confirmed the NR2F6 gene expression feature in our own cohort of 60 glioma patients. R language and GraphPad Prism softwares were mainly used for statistical analysis and graphical work. RESULTS: We found that NR2F6 was significantly related to high tumor aggressiveness and poor outcomes for glioma patients. Functional enrichment analysis demonstrated that NR2F6 was associated with many biological processes that are related to glioma progression, such as angiogenesis, and with multiple immune-related functions. Moreover, NR2F6 was found to be significantly correlated with stromal and immune infiltration in gliomas. Subsequent analysis based on Gliomas single-cell sequencing datasets showed that NR2F6 was expressed in immune cells, tumor cells, and stromal cells. Mechanistically, results suggested that NR2F6 might act as a potential immunosuppression-mediated molecule in the glioma microenvironment through multiple ways, such as the recruitment of immunosuppressive cells, secretion of immunosuppressive cytokines, M2 polarization of macrophages, in addition to combining with other immune checkpoint inhibitors. CONCLUSION: Our findings indicated that intracellular targeting of NR2F6 in both immune cells and tumor cells, as well as stromal cells, may represent a promising immunotherapeutic strategy for glioma. Stromal cells, may represent a promising immunotherapeutic strategy for glioma.
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Single-cell transcriptomic dissection of the cellular and molecular events underlying the triclosan-induced liver fibrosis in mice.
BACKGROUND: Triclosan [5-chloro-2-(2,4-dichlorophenoxy) phenol, TCS], a common antimicrobial additive in many personal care and health care products, is frequently detected in human blood and urine. Therefore, it has been considered an emerging and potentially toxic pollutant in recent years. Long-term exposure to TCS has been suggested to exert endocrine disruption effects, and promote liver fibrogenesis and tumorigenesis. This study was aimed at clarifying the underlying cellular and molecular mechanisms of hepatotoxicity effect of TCS at the initiation stage. METHODS: C57BL/6 mice were exposed to different dosages of TCS for 2 weeks and the organ toxicity was evaluated by various measurements including complete blood count, histological analysis and TCS quantification. Single cell RNA sequencing (scRNA-seq) was then carried out on TCS- or mock-treated mouse livers to delineate the TCS-induced hepatotoxicity. The acquired single-cell transcriptomic data were analyzed from different aspects including differential gene expression, transcription factor (TF) regulatory network, pseudotime trajectory, and cellular communication, to systematically dissect the molecular and cellular events after TCS exposure. To verify the TCS-induced liver fibrosis, the expression levels of key fibrogenic proteins were examined by Western blotting, immunofluorescence, Masson's trichrome and Sirius red staining. In addition, normal hepatocyte cell MIHA and hepatic stellate cell LX-2 were used as in vitro cell models to experimentally validate the effects of TCS by immunological, proteomic and metabolomic technologies. RESULTS: We established a relatively short term TCS exposure murine model and found the TCS mainly accumulated in the liver. The scRNA-seq performed on the livers of the TCS-treated and control group profiled the gene expressions of > 76,000 cells belonging to 13 major cell types. Among these types, hepatocytes and hepatic stellate cells (HSCs) were significantly increased in TCS-treated group. We found that TCS promoted fibrosis-associated proliferation of hepatocytes, in which Gata2 and Mef2c are the key driving TFs. Our data also suggested that TCS induced the proliferation and activation of HSCs, which was experimentally verified in both liver tissue and cell model. In addition, other changes including the dysfunction and capillarization of endothelial cells, an increase of fibrotic characteristics in B plasma cells, and M2 phenotype-skewing of macrophage cells, were also deduced from the scRNA-seq analysis, and these changes are likely to contribute to the progression of liver fibrosis. Lastly, the key differential ligand-receptor pairs involved in cellular communications were identified and we confirmed the role of GAS6_AXL interaction-mediated cellular communication in promoting liver fibrosis. CONCLUSIONS: TCS modulates the cellular activities and fates of several specific cell types (including hepatocytes, HSCs, endothelial cells, B cells, Kupffer cells and liver capsular macrophages) in the liver, and regulates the ligand-receptor interactions between these cells, thereby promoting the proliferation and activation of HSCs, leading to liver fibrosis. Overall, we provide the first comprehensive single-cell atlas of mouse livers in response to TCS and delineate the key cellular and molecular processes involved in TCS-induced hepatotoxicity and fibrosis.