Three-dimensional mapping of human lung fibrosis identifies spatial coupling between tissue microarchitecture and maladaptive repair states

Human lung fibrosis progressively destroys three-dimensional tissue architecture, yet how the structural microenvironment shapes cellular states remains unclear. Integrating 3D X-ray histology with spatial omics, we generate a volumetric multimodal atlas of human lung fibrosis that enables direct interrogation of relationships between tissue microarchitecture and spatial molecular programmes. We identify collapse of the alveolar-capillary unit - the coupled loss of alveolar type 1 epithelial cells, capillary endothelial cells, and basement membrane integrity - as a structural transition associated with early fibrogenesis. Surrounding transitional zones exhibit aberrant epithelial differentiation and proteolytic matrix remodelling, with epithelium shifting toward bronchiolised, airway-like states. Stromal activation converges on spatially restricted fibrogenic cores, sites of maximal collagen maturation and matrix stabilisation that function as signalling hubs within surrounding perifocal and vascular microenvironments. Molecular signatures of atlas-defined tissue states were associated with lung function and mortality across independent patient cohorts. Together, these data support a model in which fibrosis emerges as a spatial tissue-state process, with alveolar-capillary collapse redirecting repair towards mechanically stabilised niches that reinforce pathological remodelling.

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Publication Details

Journal
bioRxiv (Cold Spring Harbor Laboratory)
Published
2026-11-08
DOI
https://doi.org/10.64898/2026.11.05.764175
Primary Topic
Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
Type
preprint

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preprint

Three-dimensional mapping of human lung fibrosis identifies spatial coupling between tissue microarchitecture and maladaptive repair states

Sonya James, Aiman Alzetani, Victor Barozi, T Wallis et al.
3 links
bioRxiv (Cold Spring Harbor Laboratory)
Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
preprint

Three-dimensional mapping of human lung fibrosis identifies spatial coupling between tissue microarchitecture and maladaptive repair states

Sonya James, Aiman Alzetani, Victor Barozi, T Wallis, Nina Vyas, James Parkin, Dipanjan Bhattacharya, Sumeet Mahajan, Donna E. Davies, Sanjay Jogai, Michael Eyres, Aurélie Fabre, Adam Szmul, Philip James Basford, Kerstin E. Geillinger‐Kästle, Robert Pedley, Serena Chee, Emily Offer, Christian H. H. Ottensmeier, Jon Ward, Orestis L. Katsamenis, Ian G. Reddin, Gayle B. Marshall, Peter Seither, Mark G. Jones, Stephanie Robinson, Matthew C. Thomas, Lucy N Sayer, Andrés F. Vallejo, Jeanette Norman, Kedar Natarajan, David Johnston, Joseph Jacob, Grace Haydon, Rebekah Allen, Yihua Wang, Jaya Thomas, Gautam Ahuja, Ben G. Marshall, Gareth Thomas, Joseph A. Bell
preprint en

Abstract

Human lung fibrosis progressively destroys three-dimensional tissue architecture, yet how the structural microenvironment shapes cellular states remains unclear. Integrating 3D X-ray histology with spatial omics, we generate a volumetric multimodal atlas of human lung fibrosis that enables direct interrogation of relationships between tissue microarchitecture and spatial molecular programmes. We identify collapse of the alveolar-capillary unit - the coupled loss of alveolar type 1 epithelial cells, capillary endothelial cells, and basement membrane integrity - as a structural transition associated with early fibrogenesis. Surrounding transitional zones exhibit aberrant epithelial differentiation and proteolytic matrix remodelling, with epithelium shifting toward bronchiolised, airway-like states. Stromal activation converges on spatially restricted fibrogenic cores, sites of maximal collagen maturation and matrix stabilisation that function as signalling hubs within surrounding perifocal and vascular microenvironments. Molecular signatures of atlas-defined tissue states were associated with lung function and mortality across independent patient cohorts. Together, these data support a model in which fibrosis emerges as a spatial tissue-state process, with alveolar-capillary collapse redirecting repair towards mechanically stabilised niches that reinforce pathological remodelling.

bioRxiv (Cold Spring Harbor Laboratory)
University College Dublin (IE), Boehringer Ingelheim (Germany) (DE), University of Liverpool (GB), University Hospital Southampton NHS Foundation Trust (GB), Ashoka University (IN), Liverpool Heart and Chest Hospital (GB), Medicines Discovery Catapult (GB), St. Vincent's University Hospital (IE), NIHR Southampton Biomedical Research Centre (GB), University of Southampton (GB), University College London (GB)
Chan Zuckerberg Initiative, Rosetrees Trust, Engineering and Physical Sciences Research Council
Good health and well-being
Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
DOISourceOpenAlex
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