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Peripheral Immune and Metabolic Dysregulation in Migraine, Ménière's Disease, and Vestibular Migraine: A Single-Cell Atlas Study.
BACKGROUND: Migraine (MI), Ménière's disease (MD), and vestibular migraine (VM) share significant clinical and pathological similarities, particularly their link to neurological dysfunction and immune cell activity, though mechanisms remain poorly understood. METHODS: We utilized a single-cell RNA sequencing dataset of peripheral blood mononuclear cells from eight patients with MD, five patients with MI, five patients with VM, and six healthy controls. A cross-disease cell atlas was constructed via cellular heterogeneity and dynamic cell abundance analysis. Further studies analyzed metabolic heterogeneity and performed differential expression analysis across all groups. The core regulatory pathways were identified using gene set enrichment and pathway analyses. Additionally, herbal and compound screenings related to targets in MI were performed. Pseudotime analysis was then employed to infer the evolutionary trajectories, identifying key genes associated with differentiation. RESULTS: We identified 42,198 cells grouped into 16 clusters and classified into five cell types: T cells, B cells, dendritic cells, natural killer cells, and monocytes. Among these, T cell abundance significantly increased, whereas monocytes were essential for metabolic reprogramming. Notably, the upregulated MAPK signaling pathway was identified as the core regulatory pathway. A total of 1571 interaction pairs were screened between matched targets for herbs and compounds. T cell trajectory analysis revealed two differentiation pathways originating from CD8+ T cells that diverged into CD4+ T cells and naïve T cells. PRKCA was significantly upregulated during differentiation, being highly expressed in the disease groups. CONCLUSIONS: This study identified distinct immune cell patterns in MI, MD, and VM, with notable T cell imbalances. PRKCA was highlighted as a core regulator of disease mechanisms via the MAPK pathway, laying the groundwork for future research into therapies and disease understanding.
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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.
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Single-nucleus RNA sequencing reveals transcriptional heterogeneity in the blastema of favorable-histology Wilms tumor.
While Wilms tumors commonly arise from renal precursor cells and maintain features of the developing kidney, recent studies have demonstrated substantial genetic, histologic, and molecular heterogeneity. To further investigate tumor variability as well as unifying features in tumor biology, we performed single-nucleus RNA sequencing (snRNA-seq) on treatment-naive, favorable-histology Wilms tumors utilizing a reference atlas established from tumor-adjacent kidney samples and fetal kidney. Transcriptional profiles of blastemal, stromal, and epithelial components were correlated with tumor histology and demonstrated developmental-lineage plasticity, with PAX2 and PAX8 expression normally restricted to the nephron lineage of the fetal kidney found to be expressed in tumor stroma, as well as the stromal marker POSTN identified in tumor blastema. Further analyses of the blastema show shared transcriptional features with the differentiation trajectory of "uninduced" to "early differentiating" fetal nephron progenitor cells as well as aberrant expression of stromal signatures. A number of pathways from fetal nephron progenitors were maintained in the blastema, including regulation of stem cell maintenance and axonogenesis, whereas other pathways appear enriched in specific tumor samples, demonstrating the ability of snRNA-seq to identify both unifying transcriptional signatures and uncover distinct molecular targets in signaling pathways and/or biological drivers of Wilms tumorigenesis.
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Single-Cell RNA Sequencing Reveals Cellular Heterogeneity and Developmental Dynamics of Goose Satellite Cells During Embryogenesis.
Skeletal muscle satellite cells (SMSCs) are essential for embryonic myogenesis and postnatal muscle regeneration; however, their cellular heterogeneity and transcriptional dynamics during avian development remain largely unexplored. Here, we performed single-cell RNA sequencing (scRNA-seq) on 42,886 cells isolated from goose leg muscles across four embryonic stages (E13, E15, E18, and E23), with each stage comprising pooled tissues from four female embryos. Unbiased clustering resolved 22 transcriptionally distinct clusters representing six major cell types-satellite cells, myocytes, fibro-adipogenic progenitors, endothelial cells, immune cells, and Schwann cells-with satellite cells being the most abundant. Satellite cells were further subdivided into three functional states (quiescent, activated, and proliferative/differentiating), which followed a continuous, linear pseudotime trajectory from early to late embryonic stages. This trajectory was marked by a progressive downregulation of stemness-associated regulators (e.g., PAX7) and upregulation of myogenic commitment and differentiation factors (e.g., MYF5, MYOD1, and MYOG), faithfully mirroring chronological development. Cell-cell communication analysis revealed that quiescent satellite cells exhibited the most extensive intercellular signaling networks (e.g., FGFR, Ephrin, collagen, CADM), whereas activated and proliferative/differentiating cells showed progressively diminished communication capacity. Across developmental stages, the contribution intensities of key signaling pathways-including SEMA6, CDH, FGF, LAMININ, MK, MPZ, CADM, FN1, and COLLAGEN-varied significantly among satellite cell states, indicating state-specific responsiveness to microenvironmental cues. Collectively, these findings demonstrate that satellite cells dynamically coordinate extrinsic signal integration with intrinsic differentiation programs to achieve orderly myogenic progression. This study provides a high-resolution single-cell atlas of goose SMSC development, uncovering subpopulation heterogeneity, state-specific molecular signatures, and key signaling pathways, with important implications for avian muscle biology and genetic improvement of poultry.
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Single-Cell Profiling of Splenic Immune Ageing and Chronic Stress Adaptations in Mice With Natural Microbiota.
Immune ageing impairs adaptive and innate responses, yet the spleen remains underexplored by cross-cohort single-cell studies. We profiled splenocytes from young, old and chronically stressed old mice with natural microbiota using single-cell RNA sequencing. Ageing was characterised by reduced lymphocyte competence and elevated stress responses. Within Gzmk+ CD8+ T cells, young mice were enriched for Gzmk-high cells, whereas in old mice, both Gzmk-high and Gzmk-low cells showed greater heterogeneity and functional alterations: exhaustion in Gzmk-high and inflammation in Gzmk-low cells. Natural killer (NK) cells and macrophages exhibited reduced cytotoxic potential and sustained pro-inflammatory polarisation, respectively. Chronic stress caused modest compositional shifts that partially counteracted age-related changes. Furthermore, we integrated our dataset with six published datasets to build a comprehensive atlas with > 272,000 splenocytes. Atlas-level annotation showed reproducible compositional shifts across datasets. Conserved ageing signatures included loss of NK effector genes (Zeb2, Prf1), decline of naïve T quiescence (Lef1, Il7r) with stress induction (Rbm3, Socs3), gain of survival/pro-inflammatory/exhaustion genes (Bcl2, S100a6, Ccl5, Lag3) in effector T cells, and altered differentiation and regulation (Zbtb32, Zbtb20, Zfp318, Ighd, Cr2) in B cells. Our results define conserved features of splenic immunosenescence and provide an atlas for dissecting splenic immune alterations.
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Characterization of Ovarian Cell Types and Molecular Signatures in Mauremys reevesii Using Single-Cell Sequencing.
The ovary orchestrates female reproduction, where cellular composition and intercellular communication dictate reproductive cycles. Despite advances in chelonian reproductive biology, the cellular composition and regulatory mechanisms of the ovary remain unclear, thereby restricting insights into reproductive ecology and conservation strategies. Here, we performed single-cell RNA sequencing (scRNA-seq) to systematically characterize the molecular signatures of ovarian cell types in the Chinese pond turtle (Mauremys reevesii). By integrating differential gene expression analysis and functional enrichment, we constructed a high-resolution ovarian cell atlas and identified major cell populations, including granulosa cells and oocytes. Specifically, we identified Wnt family member 4 (WNT4) and Wnt family member 6 (WNT6) as specific markers for granulosa cells and Ubiquitin C-terminal hydrolase L1 (UCHL1) for oocytes. Furthermore, the specific expression of these granulosa cell markers was validated using dual-color in situ hybridization. Collectively, this study elucidates the ovarian biology of M. reevesii at the cellular and molecular levels, providing a vital theoretical foundation for understanding chelonian reproductive ecology and offering important insights into reproductive ecology in turtles.
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Ultrafast and reference-free sequence discovery in single-cell data.
Knowledge of RNA sequences, expression, splicing, isoforms, structure and modifications is central for understanding and targeting cellular processes. Revolutionary single-cell and spatial transcriptomics technologies-for example, as deployed by consortia such as the Human Cell Atlas-partially capture this diversity and generate cellular profiles that expand at petabyte scale each year1-5. Yet researchers cannot search sequences across these datasets: standard pipelines do not scale or rely on references, retaining only gene or isoform counts, whereas accessing raw sequences requires collecting, downloading and processing millions of large files. Here we present Malva, a computational platform that enables ultrafast, species-agnostic and reference-free interrogation of the raw sequence space, enabling searching for any sequence, mutation, splice junction or pathogen, or spatial location of arbitrary transcripts. The continuously expanding Malva Index currently comprises around 74 million cells from thousands of experiments in health and disease. Malva enables reference-free discovery-researchers can, for example, identify cell types and predict cell-cell similarity directly from sequence composition. Building on Malva's speed and accuracy, we demonstrate how Malva can be flexibly connected to state-of-the-art neural networks and how to execute complex searches and enable automated analyses. Malva transforms single-cell atlases from static gene count tables into dynamic, sequence-resolved resources that may help to bridge human-machine reasoning about biology.
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Cross-species insights into placental evolution and diseases at the single-cell resolution.
The placenta is essential for fetal development, yet its molecular evolution across mammals remains elusive. Here, we present a comprehensive single-cell transcriptomic atlas of ~300,000 cells from ten species representing the four primary placental types: discoid, cotyledonary, diffuse, and zonary. Our cross-species analysis identifies trophoblast lineages as the primary drivers of placental diversification. By reconstructing differentiation trajectories, we elucidate the regulatory networks shaping trophoblast development across diverse architectures. We propose that the unique gene expression profile of human trophoblasts underlies the susceptibility to preeclampsia and miscarriage. Functional experiments demonstrate that TGIF1 acts as a key upstream regulator of extravillous trophoblast growth and migration. TGIF1 and its targets, including ADAM12, WNT3A, and ZNF831, are associated with preeclampsia and pregnancy loss. Collectively, this high-resolution framework provides fundamental insights into the molecular evolution of the placenta and its contribution to reproductive success and diseases.