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Cross-species single-cell spatial transcriptomic atlases of the cerebellar cortex.
The molecular and cellular organization of the primate cerebellum remains poorly characterized. We obtained single-cell spatial transcriptomic atlases of macaque, marmoset, and mouse cerebella and identified primate-specific cell subtypes, including Purkinje cells and molecular-layer interneurons, that show different expression of the glutamate ionotropic receptor Delta type subunit 2 (GRID2) gene. Distinct gene expression profiles were found in anterior, posterior, and vestibular regions in all species, whereas region-selective gene expression was predominantly observed in the granular layer of primates and in the Purkinje layer of mice. Gene expression gradients in the cerebellar cortex matched well with functional connectivity gradients revealed with awake functional magnetic resonance imaging, with more lobule-specific differences between primates and mice than between two primate species. These comprehensive atlases and comparative analyses provide the basis for understanding cerebellar evolution and function.
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Finding new cancer epigenetic and genetic biomarkers from cell-free DNA by combining SALP-seq and machine learning.
The effective non-invasive diagnosis and prognosis are critical for cancer treatment. The plasma cell-free DNA (cfDNA) provides a good material for cancer liquid biopsy and its worth in this field is increasingly explored. Here we describe a new pipeline for effectively finding new cfDNA-based biomarkers for cancers by combining SALP-seq and machine learning. Using the pipeline, 30 cfDNA samples from 26 esophageal cancer (ESCA) patients and 4 healthy people were analyzed as an example. As a result, 103 epigenetic markers (including 54 genome-wide and 49 promoter markers) and 37 genetic markers were identified for this cancer. These markers provide new biomarkers for ESCA diagnosis, prognosis and therapy. Importantly, these markers, especially epigenetic markers, not only shed important new insights on the regulatory mechanisms of this cancer, but also could be used to classify the cfDNA samples. We therefore developed a new pipeline for effectively finding new cfDNA-based biomarkers for cancers by combining SALP-seq and machine learning. In this study, we also discovered new clinical worth of cfDNA distinct from other reported characters.
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A single-nucleus transcriptomic atlas characterizes cell types and their molecular features in the ovary of adult Nile tilapia.
In fish species, there is limited analysis of signature transcriptome profiles at the single-cell level in gonadal cells. Here, the molecular signatures of distinct ovarian cell categories in adult Nile tilapia (Oreochromis niloticus) were analysed using single-nucleus RNA sequencing (snRNA-seq). We identified four cell types (oogonia, oocytes, granulosa cell, and thecal cell) based on their specifically expressed genes and biological functions. Similarly, we found some key pathways involved in ovarian development that may affect germline-somatic interactions. A cell-to-cell communication network between the distinct cell types was constructed. We found that the bidirectional communication is mandatory for the development of germ cells and somatic cells in fish ovaries, and the granulosa cells and thecal cells play a central regulating role in the cell network in fish ovary. Additionally, we identified some novel candidate marker genes for various types of ovarian cells and also validated them using in situ hybridization. Our work reveals an ovarian atlas at the cellular and molecular levels and contributes to providing insights into oogenesis and gonad development in fish.
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Single-nucleus RNA sequencing reveals regulatory mechanisms of bile acids on lipid metabolism in Litopenaeus vannamei.
During lipid metabolism, bile acids are involved in the emulsification and absorption of lipids, and the liver serves as the primary organ responsible for mediating their regulatory functions. Crustaceans lack de novo bile acid synthesis and may differ substantially from vertebrates in bile acid metabolism. To investigate the role of bile acids in the lipid metabolism of crustaceans, this study divided 480 Litopenaeus vannamei (initial weight: 0.640 ± 0.003 g) into three groups. Each group included four replicate tanks, with 40 shrimp per tank. Fed the following diets for an 8-week feeding trial, respectively: high fishmeal diet (HF; 25% fish meal), low fishmeal diet (LF; 12.5% fish meal), or low fishmeal diet supplemented with 400 mg/kg bile acid (LFB). The final body weight, weight gain rate and average daily gain of the LFB group were significantly higher than those of the LF and HF groups (P < 0.05). Hepatopancreatic histomorphological and biochemical analyses revealed that the bile acid supplementation alleviated the accumulation of collagen fibers in the hepatopancreas and reduced the activity of glutamic-pyruvic transaminase (GPT) (P < 0.001). Single-nucleus RNA sequencing (snRNA-Seq) enabled the construction of the first comprehensive hepatopancreatic cell atlas in invertebrates, with 11 major cell types identified via transcriptomic profiling. Bile acid administration significantly increased F cell abundance while reducing the number of R cell and B cell populations (P < 0.05). Intercellular communication analysis demonstrated that bile acid supplementation decreased signal enrichment in neural cell adhesion molecule (NCAM) and collagen pathways, with differential functional pathways between the LFB group and LF group predominantly enriched in non-alcoholic fatty liver disease (NAFLD) pathways. Notably, Maribacter and Tamlana emerged as significantly differentiated genera in the bile acid treatment group, exhibiting functional associations with the mitigation of NAFLD and the catalysis of short-chain fatty acid degradation. Pseudotime trajectory analysis further uncovered potential hepatopancreatic cell differentiation pathways: E cells, as progenitor cells, differentiate into R cells, which subsequently bifurcate into B cell and F cell lineages. Collectively, bile acids alleviate hepatopancreatic fibrosis and inflammation by inhibiting cell junction-related signaling pathways, while concurrently regulating lipid metabolism through the enhancement of F cell proportions.
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AnnoGCD: a generalized category discovery framework for automatic cell type annotation.
The identification of cell types in single-cell RNA sequencing (scRNA-seq) data is a critical task in understanding complex biological systems. Traditional supervised machine learning methods rely on large, well-labeled datasets, which are often impractical to obtain in open-world scenarios due to budget constraints and incomplete information. To address these challenges, we propose a novel computational framework, named AnnoGCD, building on Generalized Category Discovery (GCD) and Anomaly Detection (AD) for automatic cell type annotation. Our semi-supervised method combines labeled and unlabeled data to accurately classify known cell types and to discover novel ones, even in imbalanced datasets. AnnoGCD includes a semi-supervised block to first classify known cell types, followed by an unsupervised block aimed at identifying and clustering novel cell types. We evaluated our approach on five human scRNA-seq datasets and a mouse model atlas, demonstrating superior performance in both known and novel cell type identification compared to existing methods. Our model also exhibited robustness in datasets with significant class imbalance. The results suggest that AnnoGCD is a powerful tool for the automatic annotation of cell types in scRNA-seq data, providing a scalable solution for biological research and clinical applications. Our code and the datasets used for evaluations are publicly available on GitHub: https://github.com/cecca46/AnnoGCD/.
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DPSCs regulate epithelial-T cell interactions in oral submucous fibrosis.
BACKGROUND: Oral submucous fibrosis (OSF) is a precancerous lesion characterized by fibrous tissue deposition, the incidence of which correlates positively with the frequency of betel nut chewing. Prolonged betel nut chewing can damage the integrity of the oral mucosal epithelium, leading to chronic inflammation and local immunological derangement. However, currently, the underlying cellular events driving fibrogenesis and dysfunction are incompletely understood, such that OSF has few treatment options with limited therapeutic effectiveness. Dental pulp stem cells (DPSCs) have been recognized for their anti-inflammatory and anti-fibrosis capabilities, making them promising candidates to treat a range of immune, inflammatory, and fibrotic diseases. However, the application of DPSCs in OSF is inconclusive. Therefore, this study aimed to explore the pathogenic mechanism of OSF and, based on this, to explore new treatment options. METHODS: A human cell atlas of oral mucosal tissues was compiled using single-cell RNA sequencing to delve into the underlying mechanisms. Epithelial cells were reclustered to observe the heterogeneity of OSF epithelial cells and their communication with immune cells. The results were validated in vitro, in clinicopathological sections, and in animal models. In vivo, the therapeutic effect and mechanism of DPSCs were characterized by histological staining, immunohistochemical staining, scanning electron microscopy, and atomic force microscopy. RESULTS: A unique epithelial cell population, Epi1.2, with proinflammatory and profibrotic functions, was predominantly found in OSF. Epi1.2 cells also induced the fibrotic process in fibroblasts by interacting with T cells through receptor-ligand crosstalk between macrophage migration inhibitory factor (MIF)-CD74 and C-X-C motif chemokine receptor 4 (CXCR4). Furthermore, we developed OSF animal models and simulated the clinical local injection process in the rat buccal mucosa using DPSCs to assess their therapeutic impact and mechanism. In the OSF rat model, DPSCs demonstrated superior therapeutic effects compared with the positive control (glucocorticoids), including reducing collagen deposition and promoting blood vessel regeneration. DPSCs mediated immune homeostasis primarily by regulating the numbers of KRT19 + MIF + epithelial cells and via epithelial-stromal crosstalk. CONCLUSIONS: Given the current ambiguity surrounding the cause of OSF and the limited treatment options available, our study reveals that epithelial cells and their crosstalk with T cells play an important role in the mechanism of OSF and suggests the therapeutic promise of DPSCs.
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Single-cell RNA sequencing reveals the ameliorative effects of Kai-Xin-San on depression via regulating neuroplasticity and inflammation in the hypothalamus of rats.
Kai-Xin-San (KXS) is widely used as a traditional Chinese herbal formula for treating depression, while its regulatory mechanisms on the hypothalamic microenvironment remain unclear. This study systematically elucidated the molecular mechanisms by which KXS alleviates chronic unpredictable mild stress (CUMS)-induced depression in rats through single-cell RNA sequencing (scRNA-seq) combined with behavioral and molecular biology experiments. Behavioral tests revealed that KXS significantly ameliorated depressive-like behaviors in CUMS-induced rats. The scRNA-seq analysis of 45,482 hypothalamic cells isolated from control rats, CUMS-induced rats, KXS-treated rats and fluoxetine-treated rats revealed nine major cell types. The transcriptional atlas of these cells revealed that CUMS reduced the numbers of astrocytes and adipocytes, while increasing the number of proinflammatory microglia and endothelial cells. KXS intervention restored astrocyte subpopulations (Astro_1), upregulated the protein expression of mitochondrial metabolism-related enzyme CPT1A, reduced the M1/M2 microglial polarization ratio, suppressed the protein expression of proinflammatory cytokines TNF-α and CXCL10, and elevated the protein expression of anti-inflammatory TGF-β. KXS remodeled hypothalamic intercellular communication networks, enhancing astrocyte-neuron interactions. The protein expression of neuronal nuclear antigen, microtubule-associated protein 2, synapsin, and postsynaptic density-95 in hypothalamus was significantly increased in KXS group, which reflected changes in the number of neurons and altered synaptic plasticity. Our study is the first to demonstrate that KXS can alleviate depression through the inhibition of proactivity, restoration of astrocytic mitochondrial metabolism, and reshaping of neuro-astrocyte interaction networks to enhance synaptic plasticity through scRNA-seq in hypothalamus. These results provide a theoretical foundation for the development of hypothalamic microenvironment-targeted antidepressant strategies.
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Microdissection of the gene expression codes driving nephrogenesis.
The kidney represents an excellent model system for learning the principles of organogenesis. It is intermediate in complexity, and employs many commonly used developmental processes. As such, kidney development has been the subject of intensive study, using a variety of techniques, including in situ hybridization, organ culture and gene targeting, revealing many critical genes and pathways. Nevertheless, proper organogenesis requires precise patterns of cell type specific differential gene expression, involving very large numbers of genes. This review is focused on the use of global profiling technologies to create an atlas of gene expression codes driving development of different mammalian kidney compartments. Such an atlas allows one to select a gene of interest, and to determine its expression level in each element of the developing kidney, or to select a structure of interest, such as the renal vesicle, and to examine its complete gene expression state. Novel component specific molecular markers are identified, and the changing waves of gene expression that drive nephrogenesis are defined. As the tools continue to improve for the purification of specific cell types and expression profiling of even individual cells it is possible to predict an atlas of gene expression during kidney development that extends to single cell resolution.
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Single-Cell RNA Sequencing of Childhood Ependymoma Reveals Neoplastic Cell Subpopulations That Impact Molecular Classification and Etiology.
Ependymoma (EPN) is a brain tumor commonly presenting in childhood that remains fatal in most children. Intra-tumoral cellular heterogeneity in bulk-tumor samples significantly confounds our understanding of EPN biology, impeding development of effective therapy. We, therefore, use single-cell RNA sequencing, histology, and deconvolution to catalog cellular heterogeneity of the major childhood EPN subgroups. Analysis of PFA subgroup EPN reveals evidence of an undifferentiated progenitor subpopulation that either differentiates into subpopulations with ependymal cell characteristics or transitions into a mesenchymal subpopulation. Histological analysis reveals that progenitor and mesenchymal subpopulations co-localize in peri-necrotic zones. In conflict with current classification paradigms, relative PFA subpopulation proportions are shown to determine bulk-tumor-assigned subgroups. We provide an interactive online resource that facilitates exploration of the EPN single-cell dataset. This atlas of EPN cellular heterogeneity increases understanding of EPN biology.
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Single-cell RNA sequencing reveals extensive fibrotic remodeling and pathogenic chondrocyte subpopulations in developmental dysplasia of the hip.
BACKGROUND: Developmental dysplasia of the hip (DDH) is a common pediatric orthopedic disorder that predisposes affected children to early-onset osteoarthritis (OA), yet the cellular heterogeneity and fibrotic remodeling of acetabular cartilage are poorly understood. METHODS: We performed single-cell RNA sequencing (scRNA-seq) on acetabular cartilage obtained from three children with DDH and two age-matched controls, thereby generating a transcriptomic atlas of 10,550 chondrocytes. RESULTS: Nine chondrocyte subpopulations were identified, including four previously unrecognized subsets (C1-C4). Compared with controls, DDH cartilage exhibited a marked shift toward fibrocartilage-like phenotypes, characterized by upregulation of fibrotic and matrix-remodeling genes, such as COL1A1, COL1A2, COL3A1, POSTN, MMP13, and MMP14, together with downregulation of key cartilage matrix genes, including COL2A1, ACAN, CHAD, and CNMD. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses revealed enrichment of extracellular matrix (ECM) organization and related pathways. Pseudotime analysis demonstrated a trajectory toward fibrotic and proliferative states, and CellChat analysis identified enhanced collagen and TGF-β signaling among fibrotic subsets. These transcriptional findings were validated by polymerase chain reaction (PCR), immunohistochemistry (IHC), and histological staining. CONCLUSIONS: These findings reveal molecular remodeling of cartilage obtained from dislocated hips in DDH and identify fibrosis-associated chondrocyte subpopulations that may contribute to early degenerative changes.