Spatial single-cell profiling reveals macrophage niches in severe COVID-19 lungs
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Spatial single-cell profiling reveals macrophage niches in severe COVID-19 lungs

Joan Abinet
1,2,*,#
,
Cecilia Ruscitti
1,2,*,#
,
Mutien Garigliany
2,3
,
Maude Liégeois
1,2
,
Coraline Radermecker
1,2,†
,
Thomas Marichal
1,2,4,†
*Correspondence to: Joan Abinet, Laboratory of Immunophysiology, GIGA Institute, University of Liège, Liège 4000, Belgium; Faculty of Veterinary Medicine, University of Liège, Liège 4000, Belgium. E-mail: Joan.Abinet@uliege.be
Cecilia Ruscitti, Laboratory of Immunophysiology, GIGA Institute, University of Liège, Liège 4000, Belgium; Faculty of Veterinary Medicine, University of Liège, Liège 4000, Belgium. E-mail: Cecilia.Ruscitti@uliege.be
Myeloid Cells. 2026;1:202612. 10.70401/mc.2026.0014
Received: May 26, 2026Accepted: September 14, 2026Published: September 15, 2026
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This manuscript is made available in its unedited form to allow early access to the reported findings. Further editing will be completed before final publication. As such, the content may include errors, and standard legal disclaimers are applicable.

Abstract

Aims: Severe COVID-19 is characterized by marked heterogeneity in lung pathology, including diffuse alveolar damage, inflammation, and fibrosis. However, how spatially organized cellular interactions contribute to these divergent pathological outcomes remains incompletely understood. We aimed to define the spatial organization of cellular microenvironments in severe COVID-19 lungs and identify niche-specific cellular interactions associated with distinct histopathological states.

Methods: We applied imaging-based single-cell spatial transcriptomics to post-mortem lung tissues from patients with severe COVID-19 and control subjects, enabling high-resolution mapping of cellular composition, spatial neighborhoods, and predicted ligand-receptor interactions within intact tissue architecture.

Results: Analysis of 76,973 cells identified 20 distinct cell populations and revealed marked heterogeneity between COVID-19 samples, corresponding to different histopathological states. Spatial niche analysis identified discrete macrophage-associated microenvironments. Fibrotic niches were enriched in CHI3L1/MMP9hi macrophages spatially associated with COL1A1+ fibroblasts and basal cells. Ligand-receptor inference predicted macrophage-derived TGF-β and galectin-3 signaling as drivers of pathogenic fibroblast activation and extracellular matrix remodeling. In contrast, alveolar niches contained SPP1hi macrophages exposed to epithelial-derived cues, including WNT ligands and GM-CSF, consistent with differentiation toward an alveolar macrophage-like state.

Conclusion: Severe COVID-19 lungs are organized into distinct spatial niches associated with divergent immunopathological trajectories. Imaging-based spatial transcriptomics provides a framework to link histopathological states with localized cellular interactions and macrophage-driven tissue remodeling programs.

Keywords

Macrophage, single-cell spatial transcriptomics, COVID-19

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© The Author(s) 2026. This is an Open Access article licensed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, sharing, adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

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Abinet J, Ruscitti C, Garigliany M, Liégeois M, Radermecker C, Marichal T. Spatial single-cell profiling reveals macrophage niches in severe COVID-19 lungs. Myeloid Cells. 2026;1:202612. https://doi.org/10.70401/mc.2026.0014

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