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StrokeTime: A comprehensive longitudinal scRNA-seq atlas of the ischemic mouse brain.
Ischemic stroke triggers profound, dynamic changes in the brain's cellular landscape. To systematically characterize these dynamics, we integrated single-cell RNA-sequencing data from 21 mouse stroke studies (103 samples; 414,359 cells) spanning multiple models and post-stroke intervals. Using a harmonized computational workflow, we constructed StrokeTime, a single-cell mouse brain atlas covering hyperacute, acute, subacute, and chronic stages post-ischemia. The atlas contains 17 major cell classes and 120 fine-grained transcriptional states within myeloid, lymphoid, vascular, epithelial, neuronal, and glial populations. Myeloid cells showed the greatest plasticity, including disease-associated microglia/macrophage programs shared across resident and infiltrating cells, whereas lymphocytes featured activation and regulatory signatures within lineage constraints. Vascular and mural cells shifted from early inflammatory and barrier-disruptive programs to later fibrotic and angiogenic states. StrokeTime delineates both convergent and cell type-specific injury responses, offering a resource for studying post-ischemic brain immunity, tissue remodeling, and benchmarking future single-cell and single-nucleus studies of cerebrovascular disease.
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Single-cell RNA sequencing reveals atlas of dairy goat testis cells.
Single-cell RNA sequencing (scRNA-seq) is useful for exploring cell heterogeneity. For large animals, however, little is known regarding spermatogonial stem cell (SSC) self-renewal regulation, especially in dairy goats. In this study, we described a high-resolution scRNA-seq atlas derived from a dairy goat. We identified six somatic cell and five spermatogenic cell subtypes. During spermatogenesis, genes with significantly changed expression were mainly enriched in the Notch, TGF-β, and Hippo signaling pathways as well as the signaling pathway involved in the regulation of stem cell pluripotency. We detected and screened specific candidate marker genes ( TKTL1 and AES) for spermatogonia. Our study provides new insights into goat spermatogenesis and the development of testicular somatic cells.
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RBMS3 promotes ferroptosis in colorectal cancer and is suppressed by M2 tumor-associated macrophages via STAT3 activation.
BACKGROUND: Colon adenocarcinoma (COAD) shows marked clinical heterogeneity, and robust biomarkers with mechanistic relevance are still needed for prognostic stratification. RBMS3 has been implicated in tumor biology, but its pan-cancer significance, prognostic value in COAD, and regulatory mechanisms remain insufficiently defined. METHODS: We performed integrated analyses of The Cancer Genome Atlas pan-cancer and COAD cohorts, followed by external validation in GEO datasets. Prognostic associations were evaluated by Cox and Kaplan-Meier analyses, and clinicopathological relevance was assessed in TCGA-COAD. A prognostic nomogram combining RBMS3 and clinical variables was constructed. Single-cell RNA-seq analysis was used to characterize RBMS3-associated functional programs. In vitro experiments in HCT116 cell and THP-1-derived M2 macrophage co-culture systems were conducted to validate ferroptosis-related effects and upstream STAT3-dependent regulation. RESULTS: RBMS3 was significantly dysregulated across multiple tumor types and showed prognostic relevance in pan-cancer analysis, with a prominent adverse survival association in COAD. GEO cohorts confirmed decreased RBMS3 expression in tumor samples relative to normal controls, and low RBMS3 expression was associated with unfavorable prognosis, supporting its tumor-suppressive prognostic role. In TCGA-COAD, RBMS3 expression correlated with T stage and pathological stage, and integration of RBMS3 with staging factors improved prognostic stratification in a nomogram model. Single-cell analysis showed enrichment of ferroptosis-related pathways in RBMS3-positive tumor cells. Functionally, RBMS3 overexpression in HCT116 cells reduced viability, decreased GPX4, increased ACSL4, and elevated intracellular Fe ion levels, indicating molecular features consistent with enhanced ferroptotic sensitivity. Mechanistically, M2 macrophages suppressed RBMS3 expression in tumor cells with concomitant STAT3 activation, while pharmacological STAT3 inhibition partially restored RBMS3 expression. CONCLUSION: RBMS3 is a clinically relevant prognostic biomarker in COAD and is linked to ferroptosis-associated tumor-cell programs. The M2 macrophage-STAT3-RBMS3 axis provides a mechanistic connection between the immune microenvironment and tumor intrinsic regulation, highlighting RBMS3 as a potential target for prognostic modeling and translational intervention in COAD.
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Integration of unpaired single cell omics data by deep transfer graph convolutional network.
The rapid advance of large-scale atlas-level single cell RNA sequences and single-cell chromatin accessibility data provide extraordinary avenues to broad and deep insight into complex biological mechanism. Leveraging the datasets and transfering labels from scRNA-seq to scATAC-seq will empower the exploration of single-cell omics data. However, the current label transfer methods have limited performance, largely due to the lower capable of preserving fine-grained cell populations and intrinsic or extrinsic heterogeneity between datasets. Here, we present a robust deep transfer model based graph convolutional network, scTGCN, which achieves versatile performance in preserving biological variation, while achieving integration hundreds of thousands cells in minutes with low memory consumption. We show that scTGCN is powerful to the integration of mouse atlas data and multimodal data generated from APSA-seq and CITE-seq. Thus, scTGCN shows high label transfer accuracy and effectively knowledge transfer across different modalities.
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Transcriptional profiling and therapeutic targeting of oxidative stress in neuroinflammation.
Oxidative stress is a central part of innate immune-induced neurodegeneration. However, the transcriptomic landscape of central nervous system (CNS) innate immune cells contributing to oxidative stress is unknown, and therapies to target their neurotoxic functions are not widely available. Here, we provide the oxidative stress innate immune cell atlas in neuroinflammatory disease and report the discovery of new druggable pathways. Transcriptional profiling of oxidative stress-producing CNS innate immune cells identified a core oxidative stress gene signature coupled to coagulation and glutathione-pathway genes shared between a microglia cluster and infiltrating macrophages. Tox-seq followed by a microglia high-throughput screen and oxidative stress gene network analysis identified the glutathione-regulating compound acivicin, with potent therapeutic effects that decrease oxidative stress and axonal damage in chronic and relapsing multiple sclerosis models. Thus, oxidative stress transcriptomics identified neurotoxic CNS innate immune populations and may enable discovery of selective neuroprotective strategies.
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CD52 mRNA expression predicts prognosis and response to immune checkpoint blockade in melanoma.
The immune-modulating protein CD52 attenuates lymphocyte function and is associated with autoimmune disorders, for example, multiple sclerosis (MS). CD52 represents a therapeutic target in MS and chronic lymphocytic leukemia (CLL). Its expression has prognostic and predictive value in CLL and is prognostic in breast cancer. Its significance in melanoma is unclear. We analyzed CD52 mRNA expression data from tumor bulk tissues of N = 445 untreated melanoma patients from The Cancer Genome Atlas (TCGA) Research Network and of N = 121 melanoma patients undergoing anti-PD-1 immune checkpoint blockade (ICB) with regard to outcome (overall survival [OS], disease control [DC], and progression-free survival [PFS]), single-cell RNA-Seq data of N = 4645 cells from N = 19 melanoma tissues, and N = 15,457 cells from normal skin provided by N = 5 donors. Higher CD52 mRNA expression was associated with favorable OS (hazard ratio (HR) = 0.820, [95% CI 0.734-0.916], p < .001) in non-ICB-treated melanoma and with PFS (HR = 0.875, [95% CI 0.775-0.989], p = .033) and DC (p = .005) in ICB-treated melanoma. CD52 expression correlated significantly with distinct immune cell subsets and correlated negatively with immune checkpoint expression in T cells. Moreover, our results suggest CD52 expression by a certain type of tissue-resident macrophages. CD52 mRNA was expressed in a small subgroup (8%) of immune checkpoint coexpressing melanoma cells. CD52 expression is associated with features of ICB response in melanoma. Concomitant ICB and anti-CD52 treatment requires critical review.
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An integrated single-cell reference atlas of the human endometrium.
The complex and dynamic cellular composition of the human endometrium remains poorly understood. Previous endometrial single-cell atlases profiled few donors and lacked consensus in defining cell types. We introduce the Human Endometrial Cell Atlas (HECA), a high-resolution single-cell reference atlas (313,527 cells) combining published and new endometrial single-cell transcriptomics datasets of 63 women with and without endometriosis. HECA assigns consensus and identifies previously unreported cell types, mapped in situ using spatial transcriptomics and validated using a new independent single-nuclei dataset (312,246 nuclei, 63 donors). In the functionalis, we identify intricate stromal-epithelial cell coordination via transforming growth factor beta (TGFβ) signaling. In the basalis, we define signaling between fibroblasts and an epithelial population expressing progenitor markers. Integration of HECA with large-scale endometriosis genome-wide association study data pinpoints decidualized stromal cells and macrophages as most likely dysregulated in endometriosis. The HECA is a valuable resource for studying endometrial physiology and disorders, and for guiding microphysiological in vitro systems development.
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Systematic characterization of the tumor microenvironment in Chinese patients with hepatocellular carcinoma highlights intratumoral B cells as a potential immunotherapy target.
Hepatocellular carcinoma (HCC) is an immunogenic malignancy, which exhibits low responsiveness to programmed cell death protein‑1 (PD‑1)/programmed death ligand‑1 (PD‑L1) antibodies. Therefore, the identification of novel immunotherapeutic targets to treat HCC is imperative. Systematic characterization of the HCC tumor microenvironment (TME) can provide novel insight into additional therapeutic approaches. In the present study, the RNA‑sequencing (RNA‑seq) data of 360 patients with HCC were integrated from The Cancer Genome Atlas to assess the expression of membrane spanning 4‑domains A1 (MS4A1; encoding CD20) in tumors and normal liver tissues. Immunofluorescence and multiplex tissue fluorescence analyses were performed and combined with flow cytometry staining to measure CD20/CD19 expression at the protein level. In addition, published single cell RNA‑seq data of CD45+ cells were derived from 16 treatment‑naïve patients from Beijing Shijitan Hospital with HCC to illustrate the characteristics of CD19+ B cells. The results indicated that the HCC TME included nuclear receptor subfamily 4 group A member 2+ (NR4A2) B cells. Patients with HCC and high density of intratumoral B cells demonstrated compromised antitumor immunity manifested by low percentages of cytotoxic CD8+ T cells and high density of regulatory T cells. Furthermore, PD‑L1 expression was significantly correlated with the B cell signature marker CD20. The present study indicated that tumor‑infiltrating B cells may play a negative role in antitumor immunity and serve as a promising target for HCC immunotherapy, alone or in combination with anti‑PD‑L1/PD‑1 antibodies.
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An integrated transcriptomic cell atlas of human neural organoids.
Human neural organoids, generated from pluripotent stem cells in vitro, are useful tools to study human brain development, evolution and disease. However, it is unclear which parts of the human brain are covered by existing protocols, and it has been difficult to quantitatively assess organoid variation and fidelity. Here we integrate 36 single-cell transcriptomic datasets spanning 26 protocols into one integrated human neural organoid cell atlas totalling more than 1.7 million cells1-26. Mapping to developing human brain references27-30 shows primary cell types and states that have been generated in vitro, and estimates transcriptomic similarity between primary and organoid counterparts across protocols. We provide a programmatic interface to browse the atlas and query new datasets, and showcase the power of the atlas to annotate organoid cell types and evaluate new organoid protocols. Finally, we show that the atlas can be used as a diverse control cohort to annotate and compare organoid models of neural disease, identifying genes and pathways that may underlie pathological mechanisms with the neural models. The human neural organoid cell atlas will be useful to assess organoid fidelity, characterize perturbed and diseased states and facilitate protocol development.
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A spatiotemporal transcriptomic atlas of mouse placentation.
The placenta, a temporary but essential organ for gestational support, undergoes intricate morphological and functional transformations throughout gestation. However, the spatiotemporal patterns of gene expression underlying placentation remain poorly understood. Utilizing Stereo-seq, we constructed a Mouse Placentation Spatiotemporal Transcriptomic Atlas (MPSTA) spanning from embryonic day (E) 7.5 to E14.5, which includes the transcriptomes of large trophoblast cells that were not captured in previous single-cell atlases. We defined four distinct strata of the ectoplacental cone, an early heterogeneous trophectoderm structure, and elucidated the spatial trajectory of trophoblast differentiation during early postimplantation stages before E9.5. Focusing on the labyrinth region, the interface of nutrient exchange in the mouse placenta, our spatiotemporal ligand-receptor interaction analysis unveiled pivotal modulators essential for trophoblast development and placental angiogenesis. We also found that paternally expressed genes are exclusively enriched in the placenta rather than in the decidual regions, including a cluster of genes enriched in endothelial cells that may function in placental angiogenesis. At the invasion front, we identified interface-specific transcription factor regulons, such as Atf3, Jun, Junb, Stat6, Mxd1, Maff, Fos, and Irf7, involved in gestational maintenance. Additionally, we revealed that maternal high-fat diet exposure preferentially affects this interface, exacerbating inflammatory responses and disrupting angiogenic homeostasis. Collectively, our findings furnish a comprehensive, spatially resolved atlas that offers valuable insights and benchmarks for future explorations into placental morphogenesis and pathology.