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Accelerated cognitive decline in obese mouse model of Alzheimer's disease is linked to sialic acid-driven immune deregulation
[article]
2022
bioRxiv
pre-print
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Systemic immunity supports healthy brain homeostasis. Accordingly, conditions causing systemic immune deregulation may accelerate onset of neurodegeneration in predisposed individuals. Here we show that, in the 5xFAD mouse model of Alzheimer's disease (AD), high-fat diet-induced obesity accelerated cognitive decline, which was associated with immune deviations comprising increased splenic frequencies of exhausted CD4+ T effector memory cells and CD4+FOXP3+ regulatory T cells (Tregs).
doi:10.1101/2022.02.05.479219
fatcat:3uxfmnsfvjh6zicxlthu7sasf4
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... d plasma metabolomics identified N-acetylneuraminic acid (NANA), the predominant sialic acid, as the major obesity-induced metabolite in 5xFAD mice, the levels of which directly correlated with Tregs abundance and inversely correlated with cognitive performance. Visceral adipose tissue macrophages were identified by sNuc-Seq as one potential source of NANA. Exposure to NANA led to immune deregulation in middle-aged wild-type mice, and ex vivo in human T cells. Our study identified diet-induced immune deregulation, potentially via sialic acid, as a previously unrecognized link between obesity and AD.
Single-nucleus RNA-Seq reveals a new type of brown adipocyte regulating thermogenesis
[article]
2020
bioRxiv
pre-print
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Adipose tissue usually is classified as either white, brown or beige/brite, based on whether it functions as an energy storage or thermogenic organ. It serves as an important regulator of systemic metabolism, exemplified by the fact that dysfunctional adipose tissue in obesity leads to a host of secondary metabolic complications such as diabetes, cardiovascular diseases and cancer. In addition, adipose tissue is an important endocrine organ, which regulates the function of other metabolic
doi:10.1101/2020.01.20.890327
fatcat:vdtmihxem5hndmyfufjvdslwlu
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... s through paracrine and endocrine signals. Work in recent years has demonstrated that tissue heterogeneity is an important factor regulating the functionality of various organs. Here we used single nucleus analysis in mice and men to deconvolute adipocyte heterogeneity. We are able to identify a novel subpopulation of adipocytes whose abundance is low in mice (2~8%) and which is increased under higher ambient temperatures. Interestingly, this population is abundant in humans who live close to thermoneutrality. We demonstrate that this novel adipocyte subtype functions as a paracrine cell regulating the activity of brown adipocytes through acetate-mediated regulation of thermogenesis. These findings could explain, why human brown adipose tissue is substantially less active than mouse tissue and targeting this pathway in humans might be utilized to restore thermogenic activity of this tissue.
Cumulus: a cloud-based data analysis framework for large-scale single-cell and single-nucleus RNA-seq
[article]
2019
bioRxiv
pre-print
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Massively parallel single-cell and single-nucleus RNA-seq (sc/snRNA-seq) have opened the way to systematic tissue atlases in health and disease, but as the scale of data generation is growing, so does the need for computational pipelines for scaled analysis. Here, we developed Cumulus, a cloud-based framework for analyzing large scale sc/snRNA-seq datasets. Cumulus combines the power of cloud computing with improvements in algorithm implementations to achieve high scalability, low cost,
doi:10.1101/823682
fatcat:xw5om6lt4vhg7mc7thkh24xjk4
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... endliness, and integrated support for a comprehensive set of features. We benchmark Cumulus on the Human Cell Atlas Census of Immune Cells dataset of bone marrow cells and show that it substantially improves efficiency over conventional frameworks, while maintaining or improving the quality of results, enabling large-scale studies.
Epithelial microRNAs regulate gut mucosal immunity via epithelium–T cell crosstalk
2011
Nature Immunology
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Colonic homeostasis entails epithelium-lymphocyte cooperation, yet many participants in this process are unknown. We show here that epithelial microRNAs mediate the mucosa-immune system crosstalk necessary for mounting protective T helper type 2 (T H 2) responses. Abolishing the induction of microRNA by gut-specific deletion of Dicer1 (Dicer1 Dgut ), which encodes an enzyme involved in microRNA biogenesis, deprived goblet cells of RELMb, a key T H 2 antiparasitic cytokine; this predisposed the
doi:10.1038/ni.1994
pmid:21278735
fatcat:ezfaoakeg5dyxbwty2lz67qzfa
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... ost to parasite infection. Infection of Dicer1 Dgut mice with helminths favored a futile T H 1 response with hallmarks of inflammatory bowel disease. Interleukin 13 (IL-13) induced the microRNA miR-375, which regulates the expression of TSLP, a T H 2-facilitating epithelial cytokine; this indicated a T H 2-amplification loop. We found that miR-375 was required for RELMb expression in vivo; miR-375-deficient mice had significantly less intestinal RELMb, which possibly explains the greater susceptibility of Dicer1 Dgut mice to parasites. Our findings indicate that epithelial microRNAs are key regulators of gut homeostasis and mucosal immunity.
Single cell census of human kidney organoids shows reproducibility and diminished off-target cells after transplantation
2019
Nature Communications
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Human iPSC-derived kidney organoids have the potential to revolutionize discovery, but assessing their consistency and reproducibility across iPSC lines, and reducing the generation of off-target cells remain an open challenge. Here, we profile four human iPSC lines for a total of 450,118 single cells to show how organoid composition and development are comparable to human fetal and adult kidneys. Although cell classes are largely reproducible across time points, protocols, and replicates, we
doi:10.1038/s41467-019-13382-0
pmid:31784515
pmcid:PMC6884507
fatcat:efgsqz5fjfb3dlsasjbstneuqa
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... tect variability in cell proportions between different iPSC lines, largely due to off-target cells. To address this, we analyze organoids transplanted under the mouse kidney capsule and find diminished off-target cells. Our work shows how single cell RNA-seq (scRNA-seq) can score organoids for reproducibility, faithfulness and quality, that kidney organoids derived from different iPSC lines are comparable surrogates for human kidney, and that transplantation enhances their formation by diminishing off-target cells.
Kidney organoid reproducibility across multiple human iPSC lines and diminished off target cells after transplantation revealed by single cell transcriptomics: Supplemental Tables
[article]
2019
bioRxiv
pre-print
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Human iPSC-derived kidney organoids have the potential to revolutionize discovery, but assessing their consistency and reproducibility across iPSC lines, and reducing the generation of off-target cells remain an open challenge. Here, we used single cell RNA-Seq (scRNA-Seq) to profile 415,775 cells to show that organoid composition and development are comparable to human fetal and adult kidneys. Although cell classes were largely reproducible across iPSC lines, time points, protocols, and
doi:10.1101/516807
fatcat:ncn3wqt4v5h7thhhjgk42wnr2y
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... tes, cell proportions were variable between different iPSC lines. Off-target cell proportions were the most variable. Prolonged in vitro culture did not alter cell types, but organoid transplantation under the mouse kidney capsule diminished off-target cells. Our work shows how scRNA-seq can help score organoids for reproducibility, faithfulness and quality, that kidney organoids derived from different iPSC lines are comparable surrogates for human kidney, and that transplantation enhances their formation by diminishing off-target cells.
RAAS blockade, kidney disease, and expression of ACE2, the entry receptor for SARS-CoV-2, in kidney epithelial and endothelial cells
[article]
2020
bioRxiv
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SARS-CoV-2, the coronavirus that causes COVID-19, binds to angiotensin-converting enzyme 2 (ACE2) on human cells. Beyond the lung, COVID-19 impacts diverse tissues including the kidney. ACE2 is a key member of the Renin-Angiotensin-Aldosterone System (RAAS) which regulates blood pressure, largely through its effects on the kidney. RAAS blockers such as ACE inhibitors (ACEi) and Angiotensin Receptor Blockers (ARBs) are widely used therapies for hypertension, cardiovascular and chronic kidney
doi:10.1101/2020.06.23.167098
fatcat:tcz2z7mafrhhdoshtqyr44aaxi
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... ases, and therefore, there is intense interest in their effect on ACE2 expression and its implications for SARS-CoV-2 pathogenicity. Here, we analyzed single-cell and single-nucleus RNA-seq of human kidney to interrogate the association of ACEi/ARB use with ACE2 expression in specific cell types. An integrated analysis aggregating 176,421 cells across 49 donors, 8 studies and 8 centers, and adjusting for sex, age, donor and center effects, showed a statistically significant increase in ACE2 expression in tubular epithelial cells of the thin loop of Henle (tLoH) in males relative to females at younger ages, the trend reversing, and losing significance with older ages. ACE2 expression in tLoH increases with age in females, with an opposite, weak effect in males. In an independent cohort, we detected a statistically significant increase in ACE2 expression with ACEi/ARB use in epithelial cells of the proximal tubule and thick ascending limb, and endothelial cells, but the association was confounded in this small cohort by the underlying disease. Our study illuminates the dynamics of ACE2 expression in specific kidney cells, with implications for SARS-CoV-2 entry and pathogenicity.
Single cell profiling of immature human postnatal thymocytes resolves the complexity of intra-thymic lineage differentiation and thymus seeding precursors
[article]
2020
bioRxiv
pre-print
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During postnatal life, thymopoiesis depends on the continuous colonization of the thymus by bone marrow derived hematopoietic progenitors that migrate through the bloodstream. In human, the nature of these thymus immigrants has remained unclear. Here, we employ single-cell RNA sequencing on approximately 70.000 CD34+ thymocytes to unravel the heterogeneity of the human immature postnatal thymocytes. Integration of bone marrow and peripheral blood precursors datasets identifies several putative
doi:10.1101/2020.04.07.007237
fatcat:2zncj3dgpbggvfehb2xyqau3nm
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... hymus seeding precursors that display heterogeneity for currently used surface markers as revealed by CITEseq. Besides T cell precursors, we discover branches of intrathymic developing dendritic cells with predominantly plasmacytoid DCs. Trough trajectory inference, we delineate the transcriptional dynamics underlying early human T-lineage development from which we predict transcription factor modules that drive stage-specific steps of human T cell development. Thus, our work resolves the heterogeneity of thymus seeding precursors in human and reveals the molecular mechanisms that drive their in vivo cell fate.
Single Cell, Single Nucleus and Spatial RNA Sequencing of the Human Liver Identifies Hepatic Stellate Cell and Cholangiocyte Heterogeneity
[article]
2021
bioRxiv
pre-print
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Recently, Slyper et al. ...
doi:10.1101/2021.03.27.436882
fatcat:bwfipihdk5bd5mj3iswkrcanzu
Single‐Cell, Single‐Nucleus, and Spatial RNA Sequencing of the Human Liver Identifies Cholangiocyte and Mesenchymal Heterogeneity
2021
Hepatology Communications
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Recently, Slyper et al. ...
doi:10.1002/hep4.1854
pmid:34792289
pmcid:PMC8948611
fatcat:t7txnec7pfbbnj5p34iowa3kou
Obesity-instructed TREM2high macrophages identified by comparative analysis of diabetic mouse and human kidney at single cell resolution
[article]
2021
bioRxiv
pre-print
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Mouse models are a tool for studying the mechanisms underlying complex diseases; however, differences between species pose a significant challenge for translating findings to patients. Here, we used single-cell transcriptomics and orthogonal validation approaches to provide cross-species taxonomies, identifying shared broad cell classes and unique granular cellular states, between mouse and human kidney. We generated cell atlases of the diabetic and obese kidney using two different mouse
doi:10.1101/2021.05.30.446342
fatcat:hg5fjkq6prcubbz334iy474oli
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... a high-fat diet (HFD) model and a genetic model (BTBR ob/ob), at multiple time points along disease progression. Importantly, we identified a previously unrecognized, expanding Trem2high macrophage population in kidneys of HFD mice that matched human TREM2high macrophages in obese patients. Taken together, our cross-species comparison highlights shared immune and metabolic cell-state changes.
Rewiring of the cellular and inter-cellular landscape of the human colon during ulcerative colitis
[article]
2018
bioRxiv
pre-print
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Genome-wide association studies (GWAS) have revealed risk alleles for ulcerative colitis (UC), but their cell type and pathway specificities are often unknown. Here, we generate an atlas of 115,517 cells from the colon mucosa of seven UC patients and ten healthy individuals, revealing 51 epithelial, stromal, and immune cell subsets, including a subset of BEST4+ enterocytes, which may sense and respond to pH, and IL13RA2+IL-11+ inflammatory fibroblasts, which we associate with resistance to
doi:10.1101/455451
fatcat:seaj5eukdjbgvcs4tewvyy2jzu
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... TNF therapy. Inflammatory fibroblasts, inflammatory monocytes, microfold-like cells, and CD8+IL-17+ T cells expand during disease, and form intercellular interaction hubs that mediate cross-talk between diverse cellular lineages. We identify hundreds of putative autocrine and paracrine cell-cell interactions that may explain the migration, expansion, or inhibition of cell types with disease. Surprisingly, UC risk genes are often cell type specific and co-regulated in relatively few gene modules, suggesting convergence onto limited sets of cell types and pathways. Using this observation, we nominate and infer putative functions for UC risk genes across all GWAS loci. Our atlas thus provides a framework for interrogating complex human diseases and mapping risk variants onto their cell types and pathways of activity.
Intra- and Inter-cellular Rewiring of the Human Colon during Ulcerative Colitis
2019
Cell
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B 57, 289-300.Biton, M., Levin, A., Slyper, M., Alkalay, I., Horwitz, E., Mor, H., Kredo-Russo, S., Avnit-Sagi, T.,Cojocaru, G., Zreik, F., et al. (2011). ...
Slyper, J.W., M. Sud, S.V., J.Y., E.A.C., and A.N.D. C.S.S. designed and performed computational analyses with A.R., R.J.X., D.B.G., R.H.H., A.L.H., K.J., A.-C.V., M.H., H.H., M.B., J.O. ...
doi:10.1016/j.cell.2019.06.029
pmid:31348891
pmcid:PMC6662628
fatcat:t2pihb74ofglvcn7pq2rnwp2dq
Expansion Sequencing: Spatially Precise In Situ Transcriptomics in Intact Biological Systems
[article]
2020
bioRxiv
pre-print
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Methods for highly multiplexed RNA imaging are limited in spatial resolution, and thus in their ability to localize transcripts to nanoscale and subcellular compartments. We adapt expansion microscopy, which physically expands biological specimens, for long-read untargeted and targeted in situ RNA sequencing. We applied untargeted expansion sequencing (ExSeq) to mouse brain, yielding readout of thousands of genes, including splice variants and novel transcripts. Targeted ExSeq yielded
doi:10.1101/2020.05.13.094268
fatcat:bqg76veirvaz7ky7mqnnr6nfg4
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... resolution maps of RNAs throughout dendrites and spines in neurons of the mouse hippocampus, revealing patterns across multiple cell types; layer-specific cell types across mouse visual cortex; and the organization and position-dependent states of tumor and immune cells in a human metastatic breast cancer biopsy. Thus ExSeq enables highly multiplexed mapping of RNAs, from nanoscale to system scale.
Decoding human fetal liver haematopoiesis
2019
Nature
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Definitive haematopoiesis in the fetal liver supports self-renewal and differentiation of haematopoietic stem cells and multipotent progenitors (HSC/MPPs) but remains poorly defined in humans. Here, using single-cell transcriptome profiling of approximately 140,000 liver and 74,000 skin, kidney and yolk sac cells, we identify the repertoire of human blood and immune cells during development. We infer differentiation trajectories from HSC/MPPs and evaluate the influence of the tissue
doi:10.1038/s41586-019-1652-y
pmid:31597962
pmcid:PMC6861135
fatcat:z4ftvzz4ljfq3jjxkq7o2ud3ai
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... ment on blood and immune cell development. We reveal physiological erythropoiesis in fetal skin and the presence of mast cells, natural killer and innate lymphoid cell precursors in the yolk sac. We demonstrate a shift in the haemopoietic composition of fetal liver during gestation away from being predominantly erythroid, accompanied by a parallel change in differentiation potential of HSC/MPPs, which we functionally validate. Our integrated map of fetal liver haematopoiesis provides a blueprint for the study of paediatric blood and immune disorders, and a reference for harnessing the therapeutic potential of HSC/MPPs.
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