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A single-cell transcriptome atlas of human euploid and aneuploid blastocysts.
Aneuploidy is frequently detected in early human embryos as a major cause of early pregnancy failure. However, how aneuploidy affects cellular function remains elusive. Here, we profiled the transcriptomes of 14,908 single cells from 203 human euploid and aneuploid blastocysts involving autosomal and sex chromosomes. Nearly all of the blastocysts contained four lineages. In aneuploid chromosomes, 19.5% ± 1.2% of the expressed genes showed a dosage effect, and 90 dosage-sensitive domains were identified. Aneuploidy leads to prevalent genome-wide transcriptome alterations. Common effects, including apoptosis, were identified, especially in monosomies, partially explaining the lower cell numbers in autosomal monosomies. We further identified lineage-specific effects causing unstable epiblast development in aneuploidies, which was accompanied by the downregulation of TGF-β and FGF signaling, which resulted in insufficient trophectoderm maturation. Our work provides crucial insights into the molecular basis of human aneuploid blastocysts and may shed light on the cellular interaction during blastocyst development.
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Integrative cross-species transcriptome analysis reveals earlier occurrence of myelopoiesis in pre-circulation primates compared to mice.
Hematopoiesis originates in the yolk sac, which forms prior to the establishment of blood circulation and exhibits distinct developmental processes between primates and mice. Despite increasing appreciation of yolk sac hematopoiesis for its lifelong contribution to the adult hematopoietic system and its regulatory roles in organogenesis, cross-species differences, particularly before the onset of blood circulation, remain incompletely understood. In this study, we constructed an integrative cross-species transcriptome atlas of pre-circulation hematopoiesis in humans, monkeys ( Macaca fascicularis), and mice. This analysis identified conserved populations between primates and mice, while also revealing more differentiated myeloid, erythroid, and megakaryocytic lineages in pre-circulation primates compared to mice. Specifically, SPP1-expressing macrophages were detected in primates before the onset of blood circulation but were absent in mice. Cell-cell communication analysis identified CSF1 + extraembryonic mesoderm cells as a potential supportive niche for macrophage generation, with ligand-receptor interactions between macrophages and other cell populations in the human yolk sac. Interestingly, pre-circulation SPP1 + macrophages exhibited hallmark signatures reminiscent of a macrophage subset that positively regulates hematopoietic stem cell generation. Our findings provide a valuable cross-species resource, advancing our understanding of human pre-circulation yolk sac hematopoiesis and offering a theoretical basis for the regeneration of functional blood cells.
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Application of single-cell RNA sequencing analysis of novel breast cancer phenotypes based on the activation of ferroptosis-related genes.
Ferroptosis is distinct from classic apoptotic cell death characterized by the accumulation of reactive oxygen species (ROS) and lipid peroxides on the cell membrane. Increasing findings have demonstrated that ferroptosis plays an important role in cancer development, but the exploration of ferroptosis in breast cancer is limited. In our study, we aimed to establish a ferroptosis activation-related model based on the differentially expressed genes between a group exhibiting high ferroptosis activation and a group exhibiting low ferroptosis activation. By using machine learning to establish the model, we verified the accuracy and efficiency of our model in The Cancer Genome Atlas Breast Invasive Carcinoma (TCGA-BRCA) set and gene expression omnibus (GEO) dataset. Additionally, our research innovatively utilized single-cell RNA sequencing data to systematically reveal the microenvironment in the high and low FeAS groups, which demonstrated differences between the two groups from comprehensive aspects, including the activation condition of transcription factors, cell pseudotime features, cell communication, immune infiltration, chemotherapy efficiency, and potential drug resistance. In conclusion, different ferroptosis activation levels play a vital role in influencing the outcome of breast cancer patients and altering the tumor microenvironment in different molecular aspects. By analyzing differences in ferroptosis activation levels, our risk model is characterized by a good prognostic capacity in assessing the outcome of breast cancer patients, and the risk score can be used to prompt clinical treatment to prevent potential drug resistance. By identifying the different tumor microenvironment landscapes between the high- and low-risk groups, our risk model provides molecular insight into ferroptosis in breast cancer patients.
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Identification and Functional Analysis of Transcriptome Profiles, Long Non-Coding RNAs, Single-Nucleotide Polymorphisms, and Alternative Splicing from the Oocyte to the Preimplantation Stage of Sheep by Single-Cell RNA Sequencing.
Numerous dynamic and complicated processes characterize development from the oocyte to the embryo. However, given the importance of functional transcriptome profiles, long non-coding RNAs, single-nucleotide polymorphisms, and alternative splicing during embryonic development, the effect that these features have on the blastomeres of 2-, 4-, 8-, 16-cell, and morula stages of development has not been studied. Here, we carried out experiments to identify and functionally analyze the transcriptome profiles, long non-coding RNAs, single-nucleotide polymorphisms (SNPs), and alternative splicing (AS) of cells from sheep from the oocyte to the blastocyst developmental stages. We found between the oocyte and zygote groups significantly down-regulated genes and the second-largest change in gene expression occurred between the 8- and 16-cell stages. We used various methods to construct a profile to characterize cellular and molecular features and systematically analyze the related GO and KEGG profile of cells of all stages from the oocyte to the blastocyst. This large-scale, single-cell atlas provides key cellular information and will likely assist clinical studies in improving preimplantation genetic diagnosis.
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Single-cell atlas profiling revealed cellular characteristics and dynamic changes after PD-1 blockade therapy of brain metastases from laryngeal squamous cell carcinoma.
Brain metastasis (BM) in laryngeal squamous cell carcinoma (LSCC) is uncommon but prognosis is poor. Anti-PD-1 immunotherapy benefits some advanced LSCC cases, yet its efficiency is limited by tumor complexity. We analyzed paired metastatic tumor samples from before and after immunotherapy using single-cell RNA sequencing (scRNA-seq), along with a primary LSCC dataset and bulk RNA sequencing. This identified changes post-immunotherapy and revealed differences in single-cell transcriptomes among LSCC, primBM, and neoBM. Our findings show that anti-PD-1 treatment suppresses metastasis-promoting pathways like VEGF and EMT in cancer cells, and alters immune cell functions. Notably, it upregulates T cell activation, leading to CD8 T cell exhaustion from excess heat shock proteins, notably HSPA8. However, CD8 T cell cytotoxic functions improve post-treatment. In myeloid cells, anti-PD-1 therapy enhances antigen presentation and promotes a proinflammatory shift post-metastasis. Additionally, NUPR1 is linked to BM in LSCC, and NEAT1 is a potential metastatic cancer cell cycle participant. Our study provides insights into cancer heterogeneity and the impact of PD-1 immunotherapy on metastasis, aiding precise diagnosis and prognosis.
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MICA+ Tumor Cell Upregulated Macrophage-Secreted MMP9 via PROS1-AXL Axis to Induce Tumor Immune Escape in Advanced Hepatocellular Carcinoma (HCC).
BACKGROUND: tumor-associated macrophages (TAMs) constitute a significant proportion of non-cancerous cells within the intricate tumor microenvironment (TME) of hepatocellular carcinoma (HCC). Understanding the communication between macrophages and tumor cells, as well as investigating potential signaling pathways, holds promise for enhancing therapeutic responses in HCC. METHODS: single-cell RNA-sequencing data and bulk RNA-sequencing data were derived from open source databases Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA). Through this analysis, we elucidated the interactions between MICA+ tumor cells and MMP9+ macrophages, primarily mediated via the PROS1-AXL axis in advanced HCC. Subsequently, we employed a range of experimental techniques including lentivirus infection, recombinant protein stimulation, and AXL inhibition experiments to validate these interactions and unravel the underlying mechanisms. RESULTS: we presented a single-cell atlas of advanced HCC, highlighting the expression patterns of MICA and MMP9 in tumor cells and macrophages, respectively. Activation of the interferon gamma (IFN-γ) signaling pathway was observed in MICA+ tumor cells and MMP9+ macrophages. We identified the existence of an interaction between MICA+ tumor cells and MMP9+ macrophages mediated via the PROS1-AXL axis. Additionally, we found MMP9+ macrophages had a positive correlation with M2-like macrophages. Subsequently, experiments validated that DNA damage not only induced MICA expression in tumor cells via IRF1, but also upregulated PROS1 levels in HCC cells, stimulating macrophages to secrete MMP9. Consequently, MMP9 led to the proteolysis of MICA. CONCLUSION: MICA+ HCC cells secreted PROS1, which upregulated MMP9 expression in macrophages through AXL receptors. The increased MMP9 activity resulted in the proteolytic shedding of MICA, leading to the release of soluble MICA (sMICA) and the subsequent facilitation of tumor immune escape.
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hAECs restore follicular development in premature ovarian insufficiency via IGFBP2/IGF1R-mediated intercellular communication.
BACKGROUND: Premature ovarian insufficiency (POI) is defined by ovarian dysfunction and consequent decreased fertility. While follicular depletion is an acknowledged factor, dynamic changes in follicular subpopulations and single-cell-level niche remodeling remains largely unexplored. Human amniotic epithelial cells (hAECs) represent a promising regenerative approach for restoring ovarian function; however, the underlying mechanism in promoting follicular development remains unclear. METHODS: We established a chemotherapy-induced POI mouse model and conducted single-nucleus RNA sequencing (snRNA-seq) to systematically characterize ovarian cellular heterogeneity, residual follicular development, and ovarian microenvironmental alteration. A human-derived cell projection model was established to track the distribution of transplanted hAECs. Furthermore, the functional role of IGF1R signaling in granulosa cells was validated using both in vitro culture assays and in vivo interventions. RESULTS: We identified eight distinct ovarian cell types and uncovered stage-specific injury patterns: acute chemotherapy exposure induced massive loss of granulosa cells and oocytes, while the chronic phase was characterized by fibrotic accumulation and immune infiltration. Furthermore, residual follicles exhibited aberrant development trajectories and compromised progression, primarily due to disrupted granulosa cells -oocytes communication. Notably, hAEC transplantation significantly enhanced follicle survival, partially attenuated fibrosis and promoted ovarian structural restoration. Mechanistically, hAECs-derived IGFBP2 regulated IGF1R expression in granulosa cells, thereby reactivating the Akt/FoxO3A signaling pathway and downregulating the senescence marker P21. CONCLUSIONS: This study presents a time-resolved snRNA-seq atlas capturing both acute and chronic injury phases in a chemotherapy-induced POI model, combined with a human-mouse projection approach to track transplanted hAECs in damaged ovaries. Our study establishes a novel cell-based therapeutic strategy for partial ovarian functional recovery, in which hAEC-derived IGFBP2 restores granulosa cell function and intercellular communication by regulating the IGF1R/Akt/mTOR signaling axis.
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Cell Type- and Age-Specific Expression of lncRNAs across Kidney Cell Types.
KEY POINTS: We constructed a single-cell long noncoding RNA atlas of various tissues, including normal and aged kidneys. We identified age- and cell type–specific expression changes of long noncoding RNAs in kidney cells. BACKGROUND: Accumulated evidence demonstrates that long noncoding RNAs (lncRNAs) regulate cell differentiation and homeostasis, influencing kidney aging and disease. Despite their versatility, the function of lncRNA remains poorly understood because of the lack of a reference map of lncRNA transcriptome in various cell types. METHODS: In this study, we used a targeted single-cell RNA sequencing method to enrich and characterize lncRNAs in individual cells. We applied this method to various mouse tissues, including normal and aged kidneys. RESULTS: Through tissue-specific clustering analysis, we identified cell type–specific lncRNAs that showed a high correlation with known cell-type marker genes. Furthermore, we constructed gene regulatory networks to explore the functional roles of differentially expressed lncRNAs in each cell type. In the kidney, we observed dynamic expression changes of lncRNAs during aging, with specific changes in glomerular cells. These cell type– and age-specific expression patterns of lncRNAs suggest that lncRNAs may have a potential role in regulating cellular processes, such as immune response and energy metabolism, during kidney aging. CONCLUSIONS: Our study sheds light on the comprehensive landscape of lncRNA expression and function and provides a valuable resource for future analysis of lncRNAs (https://gist-fgl.github.io/sc-lncrna-atlas/).
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The Hydractinia cell atlas reveals cellular and molecular principles of cnidarian coloniality.
Coloniality is a widespread growth form in cnidarians, tunicates, and bryozoans, among others. Colonies function as single physiological units despite their modular structure of zooids and supporting tissues. A key question is how structurally and functionally distinct colony parts are generated. In the cnidarian Hydractinia symbiolongicarpus, colonies consist of zooids (polyps) interconnected by stolons attached to the substrate. Using single-cell transcriptomics, we profiled ~200,000 Hydractinia cells, including stolons and two polyp types, identifying major cell types and their distribution across colony parts. Distinct colony parts are primarily characterised by unique combinations of shared cell types and to a lesser extent by part-specific cell types. We identified cell type-specific transcription factors (TFs) and gene sets expressed within these cell types. This suggests that cell type combinations and occasional innovations drive the evolution of coloniality in cnidarians. We uncover a novel stolon-specific cell type linked to biomineralization and chitin synthesis, potentially crucial for habitat adaptation. Additionally, we describe a new cell type mediating self/non-self recognition. In summary, the Hydractinia cell atlas provides insights into the cellular and molecular mechanisms underpinning coloniality.
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Exploring Functionally Enhanced BLP-Trained Macrophage Subpopulations in S. Aureus Infection: Underlying Mechanisms and Therapeutic Significance.
Tolerance to bacterial lipoprotein (BLP) is an evolved protective mechanism characterized by an enhanced resistance of BLP-trained macrophages to microbial infection. However, the underlying mechanisms are not fully understood, and their potential for translational clinical application needs further evaluation. In the present study, through single-cell RNA sequencing (scRNA-seq), transcriptomic profiles in both naïve and BLP-trained bone marrow-derived macrophages (BMDMs) during Staphylococcus aureus infection are analyzed, and 13 distinct BMDM subpopulations are identified. Notably, BLP-trained tolerance initiates the emergence of two novel BMDM subpopulations, C5 and C7, characterized by increased antibacterial gene expression and enhanced anti-inflammatory and antioxidative stress abilities. Moreover, BLP-trained BMDMs demonstrate activation of the NRF2 signaling pathway, thereby augmenting an antioxidative stress response and mitigating oxidative stress-induced cell damage and ferroptosis, while undergoing metabolic reprogramming characterized by enhanced glycolysis and oxidative phosphorylation pathways, together with increased anti-inflammatory metabolites. Critically, in vivo adoptive transfer of BLP-trained BMDMs protects mice against sepsis-associated lethality by attenuating systemic inflammatory response, accelerating bacterial clearance, and alleviating organ damage. Collectively, the present study presents a single-cell atlas of murine BMDMs at rest and under S. aureus infection following BLP training, which reveals novel mechanisms of BLP training-altered macrophage immunity and identifies macrophage subpopulations responsible for an enhanced resistance to infection, thus offering new preventive and therapeutic strategies for sepsis.