Macrophage and neutrophil heterogeneity at single-cell spatial resolution in human inflammatory bowel disease

TLDR

Ulcerative colitis and Crohn’s disease are chronic inflammatory intestinal disorders characterized by perplexing heterogeneity in clinical presentation and treatment response. The study aims to use single‑cell technologies to map transcriptional states within intestinal tissues and thereby elucidate the molecular basis of this heterogeneity. Researchers performed single‑cell RNA‑sequencing of inflamed human intestine and applied CosMx Spatial Molecular Imaging to spatially resolve macrophage and neutrophil subsets, revealing distinct myeloid populations and a communication network with inflammatory fibroblasts. The analyses uncovered that inter‑patient differences are most pronounced in the myeloid compartment, with macrophages and neutrophils forming a strong interaction network with fibroblasts, underscoring the myeloid and stromal cells as key drivers of disease heterogeneity.

Abstract

Abstract Ulcerative colitis and Crohn’s disease are chronic inflammatory intestinal diseases with perplexing heterogeneity in disease manifestation 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 localize 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.