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Single-cell atlas reveals meningeal leukocyte heterogeneity in the developing mouse brain.

ABSTRACT: The meninges are important for brain development and pathology. Using single-cell RNA sequencing, we have generated the first comprehensive transcriptional atlas of neonatal mouse meningeal leukocytes under normal conditions and after perinatal brain injury. We identified almost all known leukocyte subtypes and found differences between neonatal and adult border-associated macrophages, thus highlighting that neonatal border-associated macrophages are functionally immature with regards to immune responses compared with their adult counterparts. We also identified novel meningeal microglia-like cell populations that may participate in white matter development. Early after the hypoxic-ischemic insult, neutrophil numbers increased and they exhibited increased granulopoiesis, suggesting that the meninges are an important site of immune cell expansion with implications for the initiation of inflammatory cascades after neonatal brain injury. Our study provides a single-cell resolution view of the importance of meningeal leukocytes at the early stage of development in health and disease.

SUBMITTER: Zelco A

PROVIDER: S-EPMC8336895 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Single-cell atlas reveals meningeal leukocyte heterogeneity in the developing mouse brain

Project description:The meninges are important for brain development and pathology. Using single-cell RNA-sequencing, we have generated the first comprehensive transcriptional atlas of neonatal mouse meningeal leukocytes under normal conditions and after perinatal brain injury. We identified almost all known leukocyte subtypes and found differences between neonatal and adult border-associated macrophages, thus highlighting that neonatal border-associated macrophages are functionally immature with regards to immune responses compared to their adult counterparts. We also identified novel meningeal microglia-like populations that appear to participate in white matter development. Early after hypoxic-ischemic insult, neutrophil numbers increased and they exhibited increased granulopoiesis, suggesting that the meninges are an important site of immune cell expansion with implications for the initiation of inflammatory cascades after neonatal brain injury. Our study provides a single-cell-resolution view of the importance of meningeal leukocytes at different stages of development in health and disease. DOI:10.1101/gad.348190.120

2021-07-23 | GSE173769 | GEO

Single-cell atlas reveals meningeal leukocyte heterogeneity in the developing mouse brain

Project description:Single-cell atlas reveals meningeal leukocyte heterogeneity in the developing mouse brain

| PRJNA726986 | ENA

A single-cell atlas of the mouse and human prostate reveals heterogeneity and conservation of epithelial progenitors.

Project description:Understanding the cellular constituents of the prostate is essential for identifying the cell of origin for prostate adenocarcinoma. Here, we describe a comprehensive single-cell atlas of the adult mouse prostate epithelium, which displays extensive heterogeneity. We observe distal lobe-specific luminal epithelial populations (LumA, LumD, LumL, and LumV), a proximally enriched luminal population (LumP) that is not lobe-specific, and a periurethral population (PrU) that shares both basal and luminal features. Functional analyses suggest that LumP and PrU cells have multipotent progenitor activity in organoid formation and tissue reconstitution assays. Furthermore, we show that mouse distal and proximal luminal cells are most similar to human acinar and ductal populations, that a PrU-like population is conserved between species, and that the mouse lateral prostate is most similar to the human peripheral zone. Our findings elucidate new prostate epithelial progenitors, and help resolve long-standing questions about anatomical relationships between the mouse and human prostate.

| S-EPMC7529463 | biostudies-literature

DNA methylation atlas of the mouse brain at single-cell resolution.

Project description:Mammalian brain cells show remarkable diversity in gene expression, anatomy and function, yet the regulatory DNA landscape underlying this extensive heterogeneity is poorly understood. Here we carry out a comprehensive assessment of the epigenomes of mouse brain cell types by applying single-nucleus DNA methylation sequencing1,2 to profile 103,982 nuclei (including 95,815 neurons and 8,167 non-neuronal cells) from 45 regions of the mouse cortex, hippocampus, striatum, pallidum and olfactory areas. We identified 161 cell clusters with distinct spatial locations and projection targets. We constructed taxonomies of these epigenetic types, annotated with signature genes, regulatory elements and transcription factors. These features indicate the potential regulatory landscape supporting the assignment of putative cell types and reveal repetitive usage of regulators in excitatory and inhibitory cells for determining subtypes. The DNA methylation landscape of excitatory neurons in the cortex and hippocampus varied continuously along spatial gradients. Using this deep dataset, we constructed an artificial neural network model that precisely predicts single neuron cell-type identity and brain area spatial location. Integration of high-resolution DNA methylomes with single-nucleus chromatin accessibility data3 enabled prediction of high-confidence enhancer-gene interactions for all identified cell types, which were subsequently validated by cell-type-specific chromatin conformation capture experiments4. By combining multi-omic datasets (DNA methylation, chromatin contacts, and open chromatin) from single nuclei and annotating the regulatory genome of hundreds of cell types in the mouse brain, our DNA methylation atlas establishes the epigenetic basis for neuronal diversity and spatial organization throughout the mouse cerebrum.

| S-EPMC8494641 | biostudies-literature

Single-Cell Atlas of Neonatal Mouse Hearts Reveals an Unexpected Cardiomyocyte.

Project description:BackgroundSingle-cell RNA sequencing is widely used in cancer research and organ development because of its powerful ability to analyze cellular heterogeneity. However, its application in cardiomyocytes is dissatisfactory mainly because the cardiomyocytes are too large and fragile to withstand traditional single-cell approaches.Methods and resultsThrough designing the isolation procedure of neonatal mouse cardiac cells, we provide detailed cellular atlases of the heart at single-cell resolution across 4 different stages after birth. We have obtained 10 000 cardiomyocytes; to our knowledge, this is the most extensive reference framework to date. Moreover, we have discovered unexpected erythrocyte-like cardiomyocyte-terminal cardiomyocytes, comprising more than a third of all cardiomyocytes. Only a few genes are highly expressed in these cardiomyocytes. They are highly differentiated cardiomyocytes that function as contraction pumps. In addition, we have identified 2 cardiomyocyte-like conducting cells, lending support to the theory that the sinoatrial node pacemaker cells are specialized cardiomyocytes. Notably, we provide an initial blueprint for comprehensive interactions between cardiomyocytes and other cardiac cells.ConclusionsThis mouse cardiac cell atlas improves our understanding of cardiomyocyte heterogeneity and provides a valuable reference in response to varying physiological conditions and diseases.

| S-EPMC10727353 | biostudies-literature

Kidney Single-Cell Atlas Reveals Myeloid Heterogeneity in Progression and Regression of Kidney Disease.

Project description:BackgroundLittle is known about the roles of myeloid cell subsets in kidney injury and in the limited ability of the organ to repair itself. Characterizing these cells based only on surface markers using flow cytometry might not provide a full phenotypic picture. Defining these cells at the single-cell, transcriptomic level could reveal myeloid heterogeneity in the progression and regression of kidney disease.MethodsIntegrated droplet- and plate-based single-cell RNA sequencing were used in the murine, reversible, unilateral ureteric obstruction model to dissect the transcriptomic landscape at the single-cell level during renal injury and the resolution of fibrosis. Paired blood exchange tracked the fate of monocytes recruited to the injured kidney.ResultsA single-cell atlas of the kidney generated using transcriptomics revealed marked changes in the proportion and gene expression of renal cell types during injury and repair. Conventional flow cytometry markers would not have identified the 12 myeloid cell subsets. Monocytes recruited to the kidney early after injury rapidly adopt a proinflammatory, profibrotic phenotype that expresses Arg1, before transitioning to become Ccr2 + macrophages that accumulate in late injury. Conversely, a novel Mmp12 + macrophage subset acts during repair.ConclusionsComplementary technologies identified novel myeloid subtypes, based on transcriptomics in single cells, that represent therapeutic targets to inhibit progression or promote regression of kidney disease.

| S-EPMC7790206 | biostudies-literature

Acoel single-cell atlas reveals expression dynamics and heterogeneity of adult pluripotent stem cells.

Project description:Adult pluripotent stem cell (aPSC) populations underlie whole-body regeneration in many distantly-related animal lineages, but how the underlying cellular and molecular mechanisms compare across species is unknown. Here, we apply single-cell RNA sequencing to profile transcriptional cell states of the acoel worm Hofstenia miamia during postembryonic development and regeneration. We identify cell types shared across stages and their associated gene expression dynamics during regeneration. Functional studies confirm that the aPSCs, also known as neoblasts, are the source of differentiated cells and reveal transcription factors needed for differentiation. Subclustering of neoblasts recovers transcriptionally distinct subpopulations, the majority of which are likely specialized to differentiated lineages. One neoblast subset, showing enriched expression of the histone variant H3.3, appears to lack specialization. Altogether, the cell states identified in this study facilitate comparisons to other species and enable future studies of stem cell fate potentials.

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A single-cell atlas reveals heterogeneity of meningeal immunity in a mouse model of Methyl CpG binding protein 2 deficiency

Project description:Methyl CpG binding protein 2 (MeCP2) is a DNA methylation reader protein, and mutations in MeCP2 are the major cause of Rett syndrome (RTT). Increasing evidence has shown that dysregulated immunity and chronic subclinical inflammation are linked to MeCP2 deficiency and contribute to RTT development and deterioration. The meninges surrounding the central nervous system (CNS) contain a wide repertoire of immune cells that participate in immune surveillance of the CNS and influence brain functions. However, the characterization and role of meningeal immunity in CNSs with MeCP2 deficiency remain poorly understood. We applied a single-cell sequence to profile Mecp2 deficient meningeal immune cells from the dura mater, which has been reported to have the most numerous meningeal immune cells in homeostasis. The data showed that the meninges of Mecp2-null mice contained the same diverse immune cell populations as control mice and showed an up-regulation of immune-related processes. B cell populations were great larger in Mecp2-null mice than in control mice, and the expression of genes coding for immune globulins was remarkably higher. For T cells, Mecp2 deficient meninges were more enriched in cytotoxic CD8+ T cells than in the control. With increased interferon-γ transcription in T and natural killer cells, meningeal macrophages showed less suppression and were more active in Mecp2 deficiency mice. Our study provides novel insights into meningeal immunity, which is a less studied aspect of neuroimmune interactions in Mecp2 mutated diseases and offers an essential resource for comparative analyses and data exploration for a better understanding of the functional role of meningeal immunity in RTT.

2022-12-29 | GSE221361 | GEO

Single-Cell Atlas Reveals Fatty Acid Metabolites Regulate the Functional Heterogeneity of Mesenchymal Stem Cells.

Project description:Bone marrow mesenchymal stem cells (MSCs) are widely used clinically due to their versatile roles in multipotency, immunomodulation, and hematopoietic stem cell (HSC) niche function. However, cellular heterogeneity limits MSCs in the consistency and efficacy of their clinical applications. Metabolism regulates stem cell function and fate decision; however, how metabolites regulate the functional heterogeneity of MSCs remains elusive. Here, using single-cell RNA sequencing, we discovered that fatty acid pathways are involved in the regulation of lineage commitment and functional heterogeneity of MSCs. Functional assays showed that a fatty acid metabolite, butyrate, suppressed the self-renewal, adipogenesis, and osteogenesis differentiation potential of MSCs with increased apoptosis. Conversely, butyrate supplement significantly promoted HSC niche factor expression in MSCs, which suggests that butyrate supplement may provide a therapeutic approach to enhance their HSC niche function. Overall, our work demonstrates that metabolites are essential to regulate the functional heterogeneity of MSCs.

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A rat liver cell atlas reveals intrahepatic myeloid heterogeneity.

Project description:The large size and vascular accessibility of the laboratory rat (Rattus norvegicus) make it an ideal hepatic animal model for diseases that require surgical manipulation. Often, the disease susceptibility and outcomes of inflammatory pathologies vary significantly between strains. This study uses single-cell transcriptomics to better understand the complex cellular network of the rat liver, as well as to unravel the cellular and molecular sources of inter-strain hepatic variation. We generated single-cell and single-nucleus transcriptomic maps of the livers of healthy Dark Agouti and Lewis rat strains and developed a factor analysis-based bioinformatics analysis pipeline to study data covariates, such as strain and batch. Using this approach, we discovered transcriptomic variation within the hepatocyte and myeloid populations that underlie distinct cell states between rat strains. This finding will help provide a reference for future investigations on strain-dependent outcomes of surgical experiment models.

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