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Bulk RNAseq expression data of colon biopsies from intestinal mucosa of non-IBD controls and patients with Crohn's disease or ulcerative colitis

ABSTRACT: Ulcerative colitis and Crohn’s disease are chronic inflammatory intestinal diseases with perplexing heterogeneity in manifestations and response to treatment. While the molecular basis for this heterogeneity remains uncharacterized, single-cell technologies allow us to explore the transcriptional states within tissues at an unprecedented resolution which could further understanding of these complex diseases. Here, we apply single-cell RNA-sequencing to human inflamed intestine and show that the largest differences among patients are present within the myeloid compartment including macrophages and neutrophils. Using spatial transcriptomics in human tissue at single-cell resolution (CosMx Spatial Molecular Imaging) we spatially localized each of the macrophage and neutrophil subsets identified by single-cell RNA-sequencing and unravel further macrophage diversity based on their tissue localization. Finally, single-cell RNA-sequencing combined with single-cell spatial analysis reveals a strong communication network involving macrophages and inflammatory fibroblasts. Our data sheds light on the cellular complexity of these diseases and points towards the myeloid and stromal compartments as important cellular subsets for understanding patient-to-patient heterogeneity.

ORGANISM(S): Homo sapiens

PROVIDER: GSE235236 | GEO | 2023/06/20

REPOSITORIES: GEO

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IBD CosMx NanoString data from colonic mucosa

Project description:Inflammatory bowel diseases (IBDs) including ulcerative colitis (UC) and Crohn’s disease (CD) are chronic inflammatory diseases with increasing worldwide prevalence that show a perplexing heterogeneity in manifestations and response to treatment. We applied spatial transcriptomics at single-cell resolution (CosMx Spatial Molecular Imaging) to human inflamed and uninflamed intestine.

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Trackable Intratumor Microdosing and Spatial Profiling Provide Early Insights into Activity of Investigational Agents in the Intact Tumor Microenvironment

Project description:Purpose: Cancer drug development is currently limited by a paradigm of preclinical evaluation that does not adequately recapitulate the complexity of the intact human tumor microenvironment (TME). To overcome this, we combined trackable intratumor microdosing (CIVOTM) with spatial biology readouts to directly assess drug effects in patient tumors in situ. Patients and Methods: In a first-of-its-kind Phase 0 clinical trial, we explored the effects of an investigational stage SUMOylation Activating Enzyme (SAE) inhibitor, subasumstat (TAK-981) in 12 patients with head and neck carcinoma (HNC). Patients scheduled for tumor resection received percutaneous intratumor injections of subasumstat and vehicle control 1 to 4 days prior to surgery, resulting in spatially localized and graded regions of drug exposure (~1000-2000 microns in diameter). Drug-exposed (n=214) and unexposed regions (n=140) were compared 2 by GeoMx Digital Spatial Profiler, with evaluation at single cell resolution in a subset of these by CosMx Spatial Molecular Imager. Results: Localized regions of subasumstat exposure revealed SUMO pathway inhibition, elevation of Type I interferon (IFN-I) response, and inhibition of cell cycle across all tumor samples. Single cell analysis by CosMx demonstrated cell cycle inhibition specific to the tumor epithelium, and IFN pathway induction commensurate with a TME shift from immune- suppressive to immune-permissive. Conclusions: Pairing CIVO with spatial profiling enabled detailed investigation of response to subasumstat across a diverse sampling of native and intact TMEs. We demonstrate that drug mechanism of action can be directly evaluated in a spatially precise manner in the most translationally relevant setting: an in situ human tumor.

2023-06-28 | GSE235475 | GEO

Spatial and temporal heterogeneity of mouse and human microglia at single-cell resolution

Project description:Spatial and temporal heterogeneity of mouse and human microglia at single-cell resolution

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Mapping the origin and fate of myeloid cells in distinct compartments of the eye by single-cell profiling

Project description:Similar to the brain, the eye is considered an immune-privileged organ where tissue-resident macrophages provide the major immune cell constituents. However, little is known about spatially restricted macrophage subsets within different eye compartments with regard to their origin, function and fate during health and disease. Here, we combined single-cell analysis, fate mapping, parabiosis and computational modelling to comprehensively examine myeloid subsets in distinct parts of the eye during homeostasis. This approach allowed us to identify myeloid subsets displaying diverse transcriptional states. During choroidal neovascularization, a typical hallmark of neovascular age-related macular degeneration (AMD), we recognized disease-specific macrophage subpopulations with distinct molecular signatures. Our results highlight the heterogeneity of myeloid subsets and their dynamics in the eye. This provides new insights into the innate immune system in this organ and may offer new therapeutic targets for ophthalmological diseases.

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Single-Cell RNA Sequencing Uncovers Heterogenous Transcriptional Signatures in Macrophages during Efferocytosis

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2020-08-22 | GSE156234 | GEO

Skin single cell universe identifies IL-1B/IL23A co-producing CD14+ type 3 dendritic cells in psoriasis

Project description:Inflammatory skin diseases including atopic dermatitis (AD) and psoriasis (PSO) are underpinned by dendritic cell- (DC) mediated T cell responses. Currently, the heterogeneous human cutaneous DC population is incompletely characterized, and its contribution to these diseases remains unclear. Here, we performed index-sorted single-cell flow cytometry and RNA-sequencing of lesional and non-lesional AD and PSO skin to identify macrophages and all DC subsets, including the newly-described mature LAMP3+BIRC3+ DC enriched in immunoregulatory molecules (mregDC) and DC3. By integrating our indexed data with published skin datasets, we generated a myeloid cell universe of DC and macrophage subsets in healthy and diseased skin. Importantly, we found that CD14+ DC3 were increased in PSO lesional skin and co-produced IL1B and IL23A, which are pathologic in PSO. Our study comprehensively describes the molecular characteristics of macrophages and DC subsets in AD and PSO at single-cell resolution, and identifies CD14+ DC3 as potential promotors of inflammation in PSO.

2021-06-10 | GSE176509 | GEO

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